Cells: Thymoquinone: A Tie-Breaker in Sars-Cov2-Infected Cancer Patients?

cells
Review
Thymoquinone: A Tie-Breaker in SARS-CoV2-Infected
Cancer Patients?
Sawsan Elgohary 1,† , Aya A. Elkhodiry 1,† , Nada S. Amin 1,† , Ulrike Stein 2,3,4 and Hend M. El Tayebi 1, *
1 Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology,

Faculty of Pharmacy and Biotechnology, German University in Cairo, 11835 Cairo, Egypt;
[email protected] (S.E.); [email protected] (A.A.E.); [email protected] (N.S.A.)
2 Experimental and Clinical Research Center, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany;
[email protected]
3 Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
4 German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
* Correspondence: [email protected]; Tel.: +20-100-5566415; Fax: +20-2-27581041
† These authors have contributed equally to the manuscript.
Abstract: Since the beginning of the SARS-CoV-2(severe acute respiratory syndrome-coronavirus-

2) pandemic, a race to develop a vaccine has been initiated, considering the massive and rather
significant economic and healthcare hits that this virus has caused. The pathophysiology occurring
following COVID-19(coronavirus disease-2019) infection has given hints regarding the supportive
and symptomatic treatments to establish for patients, as no specific anti-SARS-CoV-2 is available
yet. Patient symptoms vary greatly and range from mild symptoms to severe fatal complications.
Supportive treatments include antipyretics, antiviral therapies, different combinations of broad-
spectrum antibiotics, hydroxychloroquine and plasma transfusion. Unfortunately, cancer patients
are at higher risk of viral infection and more likely to develop serious complications due to their

immunocompromised state, the fact that they are already administering multiple medications, as
Citation: Elgohary, S.; Elkhodiry, well as combined comorbidity compared to the general population. It may seem impossible to find
A.A.; Amin, N.S.; Stein, U.; El Tayebi,
a drug that possesses both potent antiviral and anticancer effects specifically against COVID-19
H.M. Thymoquinone: A Tie-Breaker
infection and its complications and the existing malignancy, respectively. Thymoquinone (TQ) is
in SARS-CoV2-Infected Cancer
the most pharmacologically active ingredient in Nigella sativa seeds (black seeds); it is reported to
Patients? Cells 2021, 10, 302.
have anticancer, anti-inflammatory and antioxidant effects in various settings. In this review, we
https://doi.org/10.3390/
cells10020302
will discuss the multiple effects of TQ specifically against COVID-19, its beneficial effects against
COVID-19 pathophysiology and multiple-organ complications, its use as an adjuvant for supportive
Academic Editor: Chae-OK Yun COVID-19 therapy and cancer therapy, and finally, its anticancer effects.
Received: 20 December 2020
Accepted: 28 January 2021 Keywords: SARS-CoV-2; COVID-19; cancer; thymoquinone; apoptosis; COVID-19 treatments; anti-
Published: 2 February 2021 cancer drugs; COVID-19 complications; Nrf2; GRP78; RAS
Publisher’s Note: MDPI stays neutral

with regard to jurisdictional claims in
published maps and institutional affil- 1. Introduction
iations.
In March 2020, the WHO declared coronavirus disease -2019 (COVID-19) as a pan-
demic; this served as the spark that ignited the global race for the development of a vaccine
against the novel coronavirus, severe acute respiratory syndrome-coronavirus-2(SARS-
CoV-2). This was evidently important amidst the sudden and substantial increase in
Copyright: © 2021 by the authors. hospitalizations for pneumonia associated with multi-organ disease. The pathophysiol-
Licensee MDPI, Basel, Switzerland. ogy of COVID-19 patients gave clues to suitable supportive and symptomatic treatment
This article is an open access article of this pandemic; however, no specific treatment against COVID-19 has been found to
distributed under the terms and
date. COVID-19 patients have many symptoms that vary in severity, including dry cough,
conditions of the Creative Commons
fever [1], sore throat, fatigue, diarrhea, shortness of breath, myalgia, in addition to ra-
Attribution (CC BY) license (https://
diographic and laboratory or biochemical abnormalities [2]. Moreover, cardiovascular
creativecommons.org/licenses/by/
manifestations include. Acute cardiac injury, myocarditis, arrhythmia and cardiovascular
4.0/).
Cells 2021, 10, 302. https://doi.org/10.3390/cells10020302 https://www.mdpi.com/journal/cells

Cells 2021, 10, 302 2 of 29
thromboembolism havebeen frequently reported in COVID-19 patients [3]. Furthermore,

dizziness, headache, taste and smell dysfunctions, or impaired consciousness has been
frequently shown among neurological manifestations in COVID-19 patients [4,5]. Cases in-
volving either viral co-infection or co-infection with both viral and bacterial pathogens that
cause pneumonia have been described, particularly in the period following the initial phase
of viral respiratory infection [6]. In severe cases, acute lung injury (ALI), acute respiratory
distress syndrome (ARDS), respiratory failure, heart failure, sepsis, multiple organ dys-
function, and sudden cardiac arrest occur within a few days [7]. The supportive treatments
include antipyretics, antiviral therapies, different combinations of broad-spectrum antibi-
otics, hydroxychloroquine and plasma transfusion [8]. Cancer patients are at higher risk
(two-folds) for COVID-19 and are more likely to develop severe outcomes compared to the
general population [9–11]. This is greatly attributed to immunosuppressive conditions, con-
sumption of multiple medications, combined comorbidity, and are more likely to require
ventilatory support or ICU admission [12–15]. They also have significantly higher fatality
rates (28.6% compared to 2.3% for all COVID-19 patients in China) [12]. Patients who have
received cancer treatment within 14 days of getting a COVID-19 diagnosis are considered
to have a risk factor for developing adverse events, such as ARDS, septic shock, and
acute myocardial infarction [12]. Despite this observation, delaying cancer treatment for
patients also has well-documented complications [12]. It may seem rather challenging
to discover a drug that shows not only antiviral effects specifically against SARS-CoV-2
infection and entry but also antimicrobial (antiviral, -bacterial, -fungal) that protects against
SARS-CoV-2 co-infection induced pneumonia, ameliorate respiratory symptoms, as well
as acts as an antioxidant thereby protecting against COVID-19 associated multiple organ
dysfunction (i.e., cardio-protective, hepato-protective, gastro-protective and protects the
kidney from injury). Moreover, this drug should also ideally have anti-inflammatory effects
that are sufficient enough to ameliorate COVID-19 induced cytokine storm and whose
overall pharmacological effects are consistent with the pathophysiology of COVID-19 in
cancer patients.
TQ shows all the above-mentioned effects [16–26]. TQ is the most pharmacologically
active ingredient in Nigella sativa seeds (black seeds) extract [27,28]. In this review, we
will be discussing the potential effects of TQ as a SARS-CoV-2 antiviral drug, its beneficial
effects against COVID-19 pathophysiology with a focus on cancer patients, as well as
some of its anticancer effects and its use as an adjuvant besides supportive COVID-19
therapy and cancer therapy. To achieve the purpose ofthe review, research was conducted
at the States National Library of Medicine (PubMed). For the search in databases, the
descriptors used were: “thymoquinone” and “COVID-19”/“SARS-CoV-2” or “cancer”,
“COVID-19”/“SARS-CoV-2” and “cancer” or “apoptosis”, “thymoquinone” and various
COVID-19 complications and key molecular pathways. Research papers, books, and
published data were reviewed for their relevance to the aim of the review and summarized.
Criteria for inclusion were complete, relevant publication, available online, in English,
published between 2010 and 2020, with detailed information about participants, methods,
and analyses. Data collection was done during August 2020, and data abstracted was in
the form of descriptive information, covering the type of samples used, techniques, and
findings or effects reported. Bias was limited through the evaluation of the studies through
their internal validity rather than the conclusion.
2. Sars-Cov-2 Structural Features Involved in Entry

Understanding the structural features of SARS-CoV-2 and its replication is pivotal to
focus on molecular targets lessening the viral entry, replication and to fully understand the
possible treatment options. SARS-CoV-2 belongs to the family of beta-corona viruses (β-
CoVs) [29] that have the crown-shaped spike (S) trans-membrane glycoprotein. The human
serine proteases participate in viral attachment and RNA entry into the cell. The transmem-
brane serine protease 9 (TMPRSS2) and endogenous serine proteases, such as furin, prime
and cleave the S spike into S1 and S2; this separation is essential for the attachment of
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Abbreviations:
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DLBC
the viral spike proteins, were found
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Table
HNSC
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head essential
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LGG
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cell
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fects in
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adenocarcinoma;
against the neck
SKCM,
disease squamous
skin cell carcinoma;
cutaneous
manifestations melanoma;
are KICH, STAD,
undertaken kidney chromophobe;
stomach
as adenocarcinom
reviewed in LGG,
[35,36
UCEC
KICH
THYM diffuse large B-cell lymphoma;
neoplasm that
lower
TQ
Asgrade
improved
ESCA,
mentioned
glioma;
oxygenation
esophageal carcinoma;
previously,
PAAD, pancreatic
when
there GBM,iscombined
no glioblastoma
adenocarcinoma; targeted with steroids
multi-
therapy
PRAD, forand
prostate
showed protect
SARS-CoV-2;
READ
UCS THYM,
portive
3. Benefits thymoma;
therapyof UCEC,
includes
steroids corpus
as to
an endometrial
alleviate
Adjuvant the
in carcinoma
inflammatory
COVID-19 [34]. status; literature sh
Abbreviations:
PRADHNSC, head
CESC
forme; TMPRSS,
UCEC transmembrane
and neck fects
squamous
rectum in
treatments the
serine
cell lungs
carcinoma;
adenocarcinoma;
against [37].
protease;the Non-steroidal
CTSL;
KICH,
SKCM,
disease cathepsin
kidney
skin anti-inflammatory
L;
chromophobe;
cutaneous
manifestations DLBC, lymphoid
are LGG,
melanoma; drugs
brain
STAD,
undertaken like
stomach
as diclofenac
adenocarcinom
reviewed in are
[35,36als
UCEC
KICH
neoplasm
lower diffuse large B-cellpancreaticthat TQ
lymphoma; As improved
ESCA,
mentioned oxygenation
previously, when
there GBM,iscombined
no glioblastoma
targeted with steroids
multi-
therapy forand showed protect
SARS-CoV-2; supp
UCS grade
READ glioma; PAAD,
Abbreviations: THYM,
portive
3.
TMPRSS,
adenocarcinoma;
Benefits thymoma;
therapy
transmembrane UCEC,
includes
of protease;
Thymoquinone
PRAD,
serineCTSL;uterine
protease;
prostate
steroids corpus
as an
CTSL;
adenocarcinoma;
endometrial
to anti-inflammatory
alleviate
Adjuvant
cathepsin L;the
in
DLBC,
READ,
carcinoma
inflammatory
COVID-19
lymphoid [34]. status;
neoplasm literature
diffuse sh
Abbreviations:
PRAD
forme; HNSC,
rectum adenocarcinoma;TMPRSS,
head and transmembrane
neck
SKCM, fects
squamous in
skin cutaneous
treatments the
serine
cell lungs
carcinoma; [37].
melanoma;
against the Non-steroidal
KICH,
disease cathepsin
kidney
STAD,GBM, L;
chromophobe;
stomach
manifestations DLBC,
adenocarcinoma;lymphoid
are LGG, drugs
brain
undertaken like
as diclofenac
reviewed in are
[35,36als
UCEC
KICH large B-cell lymphoma; that ESCA,
TQ esophageal
improved carcinoma;
oxygenation when glioblastoma
combined multiforme;
with HNSC,
steroids head
and and
showedneck protect
neoplasm
lower
READgrade
THYM, diffuse
thymoma;glioma;large
PAAD,
UCEC,
squamous B-cell lymphoma;
pancreatic
uterine
cell corpus
carcinoma; As ESCA,
mentioned
adenocarcinoma;
endometrial
KICH, esophageal PRAD,
carcinoma carcinoma;
previously, there
prostate
[34]. GBM,is no glioblastoma
adenocarcinoma;targeted multi- PAAD,
therapy
READ, for SARS-CoV-2; supp
portive
3. Benefits
fects therapy
inprostate
the ofkidney
lungs
chromophobe;
includes
Thymoquinone
[37]. steroids
Non-steroidal asLGG,
an brain
Adjuvant lower
to anti-inflammatory
alleviate the
ingrade glioma;
inflammatory
COVID-19 drugs
pancreatic
status; literature sh
Abbreviations:
PRADHNSC,
forme;
rectum TMPRSS,
head
adenocarcinoma; transmembrane
and neckSKCM,
adenocarcinoma; squamous
skin cutaneous
treatments
PRAD, serine
cell protease;
carcinoma;
melanoma;
against the
adenocarcinoma; CTSL;
KICH, STAD,
disease cathepsin
kidney
READ, stomach
manifestations
rectum L;adenocarcinoma;
chromophobe; DLBC, lymphoid
are LGG,
adenocarcinoma; brain
undertaken SKCM, likeas
skin diclofenac
cutaneousin are
reviewed [35,36als
UCEC
neoplasm
lower grade diffuse
glioma;large
PAAD,
melanoma; B-cell that
lymphoma;
pancreatic
STAD, stomach
TQ
As improved
ESCA,
mentioned
adenocarcinoma;
adenocarcinoma;
oxygenation
previously,
PRAD,
THYM,
when
there
prostate
thymoma; GBM, combined
is no glioblastoma
adenocarcinoma;targeted with
corpustherapy
steroids
READ,
and
multi- forcarcinoma showed
SARS-CoV-2; protect
supp
READ
THYM,
3. Benefitsthymoma;
Abbreviations: ofhead UCEC,
Thymoquinone
TMPRSS,
uterine
transmembrane
corpus
portive
as an
fects in
endometrial
therapy
Adjuvant
the
serinelungs incarcinoma
includes
[37].
protease; COVID-19
Non-steroidal
CTSL;
[34].
steroids
cathepsin toUCEC,
alleviate uterine
anti-inflammatory
L; DLBC, the
lymphoid
endometrial
inflammatory
drugs like status;
diclofenac
[34].
literature
are sh
als
forme;
rectumHNSC,
adenocarcinoma; and neckSKCM, squamous
skin cell
cutaneous
treatments carcinoma;
melanoma; KICH,
against oxygenation STAD, kidney chromophobe;
stomach
the disease manifestations adenocarcinoma; LGG,
arewith brain
undertaken asandreviewed inprotect
[35,36
UCEC
neoplasm
lower As
grade diffuse
mentioned
glioma;large B-cell
previously,
PAAD,
that
lymphoma;
pancreatic
TQ
there improved
ESCA,
is esophageal
no targeted
adenocarcinoma; carcinoma;
therapy
PRAD,
when
for
prostate GBM, combined
SARS-CoV-2; glioblastoma
adenocarcinoma; supportive steroids
multi-
READ,
showed
THYM, thymoma; 3. UCEC,
Benefits of Thymoquinone
uterine corpus
portive endometrial
therapy as inan Adjuvant
carcinoma
includes [34].
steroids into COVID-19
alleviate the inflammatory
3. Benefits
Abbreviations:
forme;
rectum
treatmentsHNSC,
ofhead
Thymoquinone
TMPRSS,
adenocarcinoma;
against and
the transmembrane
neck
SKCM,
disease
as an
fects
squamous
skin inAdjuvant
the
serine
cell
cutaneous
manifestations lungs
carcinoma; [37].
protease;
melanoma;
are
COVID-19
Non-steroidal
CTSL;
KICH,
undertakenSTAD, cathepsin
kidney anti-inflammatory
L;adenocarcinoma;
chromophobe;
stomach
as reviewed DLBC, in lymphoid
LGG, brain
[35,36]. drugs likestatus;
Sup- diclofenacliterature
are als sh
neoplasm
lower As
grade diffuse
mentioned
glioma;large As mentioned
B-cell
previously,
PAAD,
that
lymphoma;
pancreatic therepreviously,
TQ improved
ESCA,
is
adenocarcinoma;
there
esophageal
no targeted is
oxygenation no targeted
carcinoma;
therapy
PRAD,
when therapy
GBM,
for SARS-CoV-2;
prostate
combined for
glioblastoma
adenocarcinoma;
SARS-CoV-2;
with steroids
multi-
supportive
READ,
supportive
and showed protect
THYM,
portive
3. Benefitsthymoma;
therapy
ofhead UCEC,
includes
steroids corpus
as an to endometrial
alleviate incarcinoma
the inflammatory [34]. status; literature showed
forme;
rectum
treatmentsHNSC, treatments
adenocarcinoma;
against and
the neck
SKCM,
diseaseagainstfects
squamous
skin inAdjuvant
the disease
the
cell
cutaneous
manifestations lungs
carcinoma; [37].
melanoma;
are
COVID-19
manifestations
Non-steroidal
KICH,
undertakenSTAD, kidney are undertaken
anti-inflammatory
chromophobe;
stomach
as reviewed adenocarcinoma;
in as
LGG, reviewed
[35,36]. drugs
brain
Sup- inlike
[35,36]. Sup- are als
diclofenac
that
lower
TQ
As
grade
improved
mentioned
glioma;
oxygenation
previously,
PAAD, pancreatic
when
there combined
is no targeted with steroids
therapy for and showed
SARS-CoV-2; protective
supportive ef-
THYM,
portive
3. Benefits
fects
thymoma;
therapy UCEC,
includes
of Thymoquinone
inadenocarcinoma;
the lungs [37].
uterine
steroids
Non-steroidal
corpus
endometrial
alleviate
Adjuvant
anti-inflammatory
PRAD, prostate
incarcinoma
the inflammatory
COVID-19 [34]. status;
drugsstomachlike
adenocarcinoma;
diclofenac literatureare
READ,
showed
also used
rectum
treatments against the SKCM, skin
disease cutaneous
manifestations melanoma;
are undertakenSTAD, as reviewed adenocarcinoma;
in [35,36]. Sup-
that TQAs improved oxygenation
mentioned previously, wheniscombined
there no targeted with steroids
therapy for and showed protective
SARS-CoV-2; supportive ef-
THYM,
portive
3. Benefitsthymoma;
therapy
of UCEC,
includes
steroids corpus
as to
an endometrial
alleviate
Adjuvant the
in carcinoma
inflammatory
COVID-19 [34]. status; literature showed
fects in
treatments the lungs [37]. Non-steroidal
against oxygenation
the disease manifestations anti-inflammatory arewithundertaken drugs like diclofenac
as reviewed are also used
that TQ improved
As mentioned previously, there wheniscombined no targeted steroids
therapy forand showedinprotective
SARS-CoV-2;
[35,36]. Sup-
supportive ef-
Cells 2021, 10, 302 4 of 29
portive therapy includes steroids to alleviate the inflammatory status; literature showed
that TQ improved oxygenation when combined with steroids and showed protective ef-
fects in the lungs [37]. Non-steroidal anti-inflammatory drugs like diclofenac are also
used to counteract COVID-19-induced fever and myalgia [38]. Furthermore, COVID-19
and cancer patients are at high-risk of acetaminophen-induced hepatotoxicity as reviewed
in [39], diclofenac-induced gastrointestinal side effects as reviewed in [40], along with renal
toxicity [41]; luckily, TQ administration protects against acetaminophen-induced hepatotox-
icity [42]. In a recent study, TQ protected against diclofenac-induced kidney injury [42,43]
and ameliorated GIT toxicity with proton pump inhibition activity [44,45]. Moreover,
TQ counteracted the toxic effects of other supportive therapies like gentamicin [46,47],
chloroquine [48] and vancomycin [25] and showed a synergistic effect when administered
with ranitidine [44,45]. Furthermore, tocilizumab, an IL-6 receptor antagonist, has been
used in various cancers, such as multiple myeloma and solid tumors, including renal,
prostate, lung, colorectal and ovarian cancers, to decrease cancer-associated inflammation.
It is used alone or in combination with conventional chemotherapy, as reviewed in [49].
In COVID-19 patients, tocilizumab is given to decrease the viral-induced IL-6 elevation,
cytokine storm, and inflammation [50]. TQ is reported as a potent anti-inflammatory drug
that decreases IL-6 expression and inhibits NFkB [51]. Hence, giving TQ with tocilizumab
could give double beneficial effects in COVID-19 patients. It has been reported that even a
single dose of tocilizumab caused gut ulceration in COVID-19 patients [52], and since TQ
showed gastroprotective effects, it would be beneficial to investigate the GIT protective
effects of TQ in combination with tocilizumab against gut ulceration. Table 2 shows details
about the use of TQ as a potential adjuvant therapy to minimize COVID-19 supportive
treatments’ side effects.
Table 2. Thymoquinone (TQ) as a potential adjuvant therapy to minimize SARS-CoV-2(severe acute respiratory syndrome-
coronavirus-2) treatments’ side effects.
Drug Beneficial Effect of Thymoquinone as Adjuvant Reference

-Reversal of acetaminophen-induced lipid peroxide increase in ALT, total nitrate/nitrite,
and a decrease in GSH and ATP.
Acetaminophen -TQ is effective in protecting mice against acetaminophen-induced hepatotoxicity, liver [23,53]
cirrhosis and fibrosis via increased resistance to oxidative and nitrosative stress and
decreased serum biomarker enzymes (SGOT, SGPT and ALP)
-TQ could ameliorate gastrointestinal and renal toxicity induced by high dose diclofenac
treatment.
Diclofenac [42,43]
-TQ administration, with Diclofenac treatment, alleviated the buildup of poly-unsaturated
fatty acids (PUFAs) and diclofenac-induced cell death in kidney cells.
Gentamicin (severe -TQ showed a protective role against Gentamicin ototoxicity
secondary bacterial -TQ significantly prevented the Gentamicin-induced elevations of serum AST, ALT and [46,47]
infections) LDH activities and also tumor necrosis factor-alpha (TNF-α) and total bilirubin levels
-TQ provides cardio-protective effects by reducing myocardial enzymes following
Chloroquine [48]
chloroquine induced cardiotoxicity.
-TQ reversed the vancomycin induced elevated serum blood urea nitrogen, creatinine and
Vancomycin [25]
MDA and showed protective effects against injury
Steroids -TQ improved oxygenation and protected lung tissue from hazardous effects of human
[37]
(methylprednisolone) gastric juice (pH 1.2)
-TQ and montelukast have dose-dependent effects on cilia beat frequency (CBF),
Montelukast [54]
extending their mechanism of action in respiratory diseases.
Ranitidine, H2 -TQ+ ranitidine showed synergistic effects and a more significant decrease in ulcer index.
blockers, Proton pump -TQ has novel gastroprotective mechanisms via inhibiting proton pump, acid secretion [44,45]
inhibitors and neutrophil infiltration while enhancing mucin secretion, and nitric oxide production
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GSH, glutathione; ALP, alkaline phosphatase; SGOT,
serum glutamic oxaloacetic transaminase, SGPT, serum glutamic pyruvic transaminase.
Cells 2021, 10, 302 5 of 29
Thus, far, this literature review has attempted to highlight how TQ could represent
a potential adjuvant molecule to COVID-19 standard supportive treatments. To create a
full picture, and in order to visualize the true value of TQ in COVID-19 cancer patients,
the potential anticancer effects of TQ will be reviewed in the next section, as well as its
potential benefit as an adjuvant to chemotherapy.
4. Anticancer Effects of Thymoquinone

For more than 50 years, TQ has been known for its anti-neoplastic and chemo-
preventive effects that have been proven in various types of cancer [55]. Even though
TQ is not an FDA-approved drug for cancer therapy, several in vitro and in vivo studies
showed that the anticancer activity of TQ is mediated through different pathways involved
in proliferation, cell cycle regulation of apoptosis, angiogenesis and cancer metastasis.
Apoptosis or programmed cell death is considered to be the most powerful shield against
cancer, as it maintains body homeostasis by eliminating aged or diseased cells from the
body [56]. This is why mutations or dysregulations in genes regulating apoptosis, such
as members of the Bcl-2 family, caspases, p53 and PTEN, are usually present in human
cancers [57–60]. The antiproliferative and apoptotic effects of TQ are modulated through
several mediators and transcription factors, along with its anti-angiogenic, antimetastatic
and chemo, radio-sensitizing effects.
TQ and apoptosis: the downregulation of the antiapoptotic proteins Bcl-2, Bcl-xl, XIAP,
survivin, and the upregulation of proapoptotic proteins Bax, p21 and p53 have been
associated with TQ-induced apoptosis in various cancers [61–63]. TQ upregulating effect on
the proapoptotic transcription factor, p53, was clearly emphasized in numerous in vitro and
in vivo studies on cancer models, where TQ induced apoptosis through the upregulation of
p53 in breast cancer [64–66], renal cell carcinoma [67], leukemia [68], glioblastoma [69,70],
squamous cell carcinoma [71], cervical cancer [72], lung cancer [73], and osteosarcoma [74].
The downstream protein of p53, p21 [75–77], was shown to be upregulated in pancreatic
ductal adenocarcinoma as well [78]. The diminished expression of Bcl-2, Bcl-xl, survivin, c-
FLIP and XIAP following TQ treatment has been established in several cell lines and animal
models [79–84]. This diminished expression of Bcl-2 is usually coupled to increased Bax
expression as reported in liver cancer [85], leukemia [83], bladder cancer [84], squamous
cell carcinoma [86], ovarian cancer [82], and renal cancer [87]. Consequently, the disruption
in the Bcl-2/Baxratio, accompanied by reactive oxygen species (ROS) generation induced
by TQ inside cancer cells, damages mitochondrial membrane potential, leading to the
release of cytochrome c. This triggers the intrinsic pathway and activates procaspases 9, 7, 3
and PARP enzyme cleavage. This cascade of events is seen in leukemia/lymphoma [88,89],
glioblastoma [79,90], renal cell carcinoma [91], colon [92], brain [93], bladder [84] and
ovarian cancers [82]. TQ has been reported to exert a dual effect in which it acts as both
pro-oxidant and antioxidant in a dose-dependent manner; the antioxidant effect occurs at
low concentration (<5 µM) whereas, at higher concentrations (>20 µM), it possesses pro-
oxidant property [94]. TQ-induced cell death was mediated through caspase-3 activation
in glioblastoma [79], liver [95,96] and cervical cancer [72], while caspases 9 and 3 mediated
apoptosis wasseen in lymphoma [88], lung [73], and liver cancer [97]. Moreover, the
induction of apoptosis in leukemia was mediated by caspases 8 and 3 involving more than
one apoptotic pathway [83].
TQ and cell cycle arrest: since microtubule assembly is important in cell cycle progres-
sion, microtubule targeting is a potential mechanism for chemotherapy. TQ was reported
to induce cell cycle arrest through depolymerizing microtubule network and disrupting
the mitotic spindle organization in A549 lung cancer cells [98]. Several studies reported
TQ’s cell cycle arrest action through inhibition of cyclin D, cyclin E and cyclin-dependent
kinase 2 (Cdk-2) in various cancers [77,92,99,100]. Additionally, a death receptor-mediated-
apoptosis was seen with TQ treatment, as TQ caused re-localization of CD95/Fas from
cytoplasm to the membrane, enhancing apoptosis in multiple myeloma [101] and enhancing
TRAIL/TRAILR expression in medulloblastoma [93], liver [96,97] and lung cancers [76].
Cells 2021, 10, 302 6 of 29
TQ vs. carcinogen activation: One of TQ’s anticancer mechanisms is the suppression

of carcinogen activation through inhibiting metabolizing enzymes that are responsible
for the biotransformation process of various pro-carcinogens into highly active carcino-
gens. These reactive carcinogens lead to oxidative damage, or covalent modification of
DNA, as well as changes in signaling networks [102–104]. Of particular interest in the
cytochrome p450 family are CYP1 members, specifically CYP1A1 phase I enzyme, that
was found to be subject to inhibition by TQ, accompanied byan elevation in glutathione
and phase II GST enzyme in HepG2 cells [85]. Another anticancer mechanism lies in the
anti-inflammatory effects of TQ through inhibiting or modulating cyclooxygenase-2 (COX-
2) enzyme, which is known to catalyze the formation of the proinflammatory mediators,
prostaglandins (PGs). TQ was reported to inhibit COX-2 and PGE in colorectal cancer [105]
and cholangiocarcinoma cell lines [80].
TQ vs. angiogenesis and metastasis: TQ is thought to inhibit tumor angiogenesis by
inhibiting the expression of vascular endothelial growth factor (VEGF) and its down-
stream signaling on cholangiocarcinoma [80], stomach [106] and triple-negative breast
cancer (TNBC) cells [107]. Moreover, TQ is known to inhibit tumor migration, invasion
and consequently tumor metastasis through modulating genes, transcription factors, and
proteins responsible for facilitating the migration process [108]. A study on TNBC con-
cluded that TQ exhibited its effect through inhibiting eEF-2K-signaling pathway with its
downstream targets, Src kinase, focal adhesion kinase (FAK) and AKT following NF-kB
inhibition [109]. Other studies reported that the antimetastatic effect of TQ is exhibited
through the inhibition of PI3K/AKT/mTOR pathways, leading to the reversal of endothe-
lial mesenchymal transformation (EndMT). This results in the upregulation of endothelial
markers E-cadherin and cytokeratin-19, and downregulation of mesenchymal markers
N-cadherin, vimentin, Twist, Slug, Snail, ZEB1 in renal cell carcinoma [110], gastric [111],
prostate [112], cervical [113,114], bladder [115] and breast cancer [107,116]. A study on
renal cancer cells concluded that the antimetastatic effect of TQ, facilitated by autophagy, is
regulated by the AMPK/mTOR pathway [117]. Furthermore, the anti-migratory action of
TQ is also exerted by the inhibition of MMP-2, MMP-9 along with integrin B1, urokinase-
type plasminogen activator (u-PA), fibronectin, RhoA, and suppression of the activation
of JNK, p38, EGFR/IKKa/b/NF-kB-signaling, paxillin and Gαi2. This was observed in
cancers like TNBC [107], lymphoma [118], glioblastoma [119], renal cell carcinoma [120],
colon [121,122] and ovarian cancers [123]. It was also reported that TQ causes down-
regulation in the TGF-β/Smad2/3-signaling pathway and reduction in CXCR4/CXCL12
pathway mediated by NF-kB expression [112,124,125]. Finally, TQ caused inhibition in
Wnt/B-catenin signaling with a consequent reduction in β-catenin target genes, Myc,
Axin-2, MMP-7, cyclin D1 and Met in bladder cancer cells [126], and inhibiting ERK1/2
phosphorylation in glioblastoma [127] and lung cancer [128].
TQ vs. gene transcription: the effects of TQ are related and can possibly be linked
together by the transcription factors involved. TQ treatment inhibits signal transducer and
activator of transcription-3 (STAT3) phosphorylation, causing downregulation of STAT3
and its related genes, Janus activated kinase-2 (JAK2), c-Src, Bcl-2, cyclin D, survivin, VEGF
and caspases 3, 7 and 9 in gastric cancer [129]. The downregulation of the PI3K/Akt path-
way and NF-kB leads to changes in various related genes, NF-kB p65, GSK3B, XIAP, Bcl-2,
VEGF, COX-2, PGE2, inducing apoptosis and inhibiting metastasis in cancer cells [130–132].
Another TQ-affected signaling pathway is the tumor necrosis factor (TNF) pathway, which
usually induces NF-kB-signaling, hence modulating apoptosis and inflammation. This path-
way was found to be modulated following the treatment of HeLa cells with TQ [133].
Following NF-kB inhibition, NLRP3 inflammasome is inhibited, causing inactivation of
caspase-1 and inhibition of IL-1 and IL-18 in melanoma cells [134]. Moreover, TQ binds
to PAK1, causing conformational changes, affecting RAF/MEK/ERK1/2-signaling path-
way [105]. Figure 1 summarizes the signaling pathways contributing to carcinogenesis and
how TQ inhibits them through its anticancer mechanisms.
Cells 2021, 10, 302 7 of 29
Cells 2021, 10, x FOR PEER REVIEW 7 of 30
Figure 1. Molecular mechanisms of TQ in cancer development (A) pathways involved in cancer development; (B) path-
Figureways
1. Molecular mechanisms of TQ in cancer development (A) pathways involved in cancer development; (B) path-
inhibited by TQ that appear transparent in the figure while opaque molecules are activated.
ways inhibited by TQ that appear transparent in the figure while opaque molecules are activated.
TQ as a chemo-adjuvant: adding to the previously mentioned anticancer effects of TQ,
TQ asstudies
several a chemo-adjuvant: adding to effect
reported the potentiating the previously
of combining mentioned anticancer effects of
TQ with chemotherapeutic
TQ,agents
several
andstudies reported
radiation. the potentiating
It was shown effect
to enhance their of combining
anticancer activity,TQ with chemo-
causing chemothera-
peutic agents and radiation.
or radio-sensitization, It was[135–137].
respectively shown to It enhance
also reducedtheir
oranticancer
attenuated activity,
some treat-causing
chemo- or radio-sensitization,
ment-induced toxicities, such asrespectively
nephropathy[135–137]. It also reduced
or hepatotoxicity, seen with or attenuated
cisplatin treat- some
ment [138–141]. Table
treatment-induced 3 discusses
toxicities, suchsome of the chemo-modulating
as nephropathy effects ofseen
or hepatotoxicity, TQ in combi-
with cisplatin
nation with known anticancer drugs. However, as with any other drug,
treatment [138–141]. Table 3 discusses some of the chemo-modulating effects of TQ in further studies
should be done
combination withtoknown
investigate the standardization
anticancer of TQ administration
drugs. However, as with anywhen otherused with
drug, further
cancer drugs, as literature showed that CYP1A2, CYP2C9, CYP2D6 and CYP3A4
studies should be done to investigate the standardization of TQ administration when used were
subject to inhibition by TQ, hinting at various potential drug–drug interactions [142].
with cancer drugs, as literature showed that CYP1A2, CYP2C9, CYP2D6 and CYP3A4 were
subject to inhibition by TQ, hinting at various potential drug–drug interactions [142].
Table 3. The chemomodulatory/chemosensitizing and protective effects of thymoquinone in combination with chemothera-
peutic agents.
Drugs Effects Mechanism Experimental Model Reference

Downregulating Twist1
Breast cancer T47D and
Paclitaxel Chemomodulatory Increase apoptotic cell death and [143]
MCF-7 cells
autophagy
Blocking PI3K/AKT pathways
Prostate cancer DU145
Docetaxel Chemomodulatory Enhance Bax, Bid, caspase 3 and [144,145]
and C4-2B cells
inhibiting Bcl-XL
Upregulate PTEN Inhibiting AKT
Breast cancer MCF-7
Chemomodulatory Increasing Bax/Bcl2 ratio [146,147]
cells
Increase ROS formation
Doxorubicin
ROS generation T cell leukemia cells
Chemomodulatory and
Higher mitochondrial disruption Lymphoblastic [148–150]
protective
Maintain cardiac myocyte survival leukemia
Cells 2021, 10, 302 8 of 29
Table 3. Cont.
Drugs Effects Mechanism Experimental Model Reference

Inactivating AKT, XIAP, bcl-xl and
Bcl-2
Chemomodulatory and Activating caspase-3, Bax, cytochrome
Tamoxifen Breast cancer cells [151–153]
protective c and p27
Hepatoprotective via antioxidant and
anti-inflammatory actions
Downregulate Bcl-2, Wnt/β-catenin,
NF-kB, Cox2, iNOS, VEGF and Colorectal cancer stem
5-fluorouracil Chemomodulatory PI3k/AKT cells [154–156]
Upregulate Bax, Bcl-2, TGF-β1 and Gastric cancer cells
Samd4
Block JAK2/STAT3 pathway
Inhibition of PI3K/AKT pathway Esophageal cancer cells
Chemomodulatory and Activating Bax, cytochrome c and Gastric cancer cells
Cisplatin [138,139,157–160]
protective caspases Oral squamous cell
Reduced hepatorenal toxicity through carcinoma
antioxidant effect
5. Thymoquinone’s Double Hits in COVID-19 Infected Cancer Patients

First of all, a recent study showed that TQ could work as an antiviral against SARS-
CoV-2 since it revealed that TQ mighthave inhibitory activities against its viral protease in
silico [161], and several other studies are also working on proving the same effect through
insilico computational analysis. This rather interesting observation prompted the analysis
of TQ’s reported roles in regulating proteins that are involved in COVID-19 as well as in
cancer pathogenesis. This review, therefore, aims to summarize in the following sections
the common protein targets that are subject to regulation by TQ and whose roles are
furthermore crucial in COVID-19 cancer patients.
Heat shock protein A5 (HSPA5)/GRP78 is also known as immunoglobulin heavy
chain-binding protein (BiP) or glucose-regulated protein (GRP78). GRP78 overexpression
can occur under a variety of stressful conditions. This overexpression can cause the protein
to be, in turn, highly abundant on the cell surface, where it can further potentiate the
stressful conditions under which its expression was increased. For instance, overexpression
of GRP78 on the cell membranes can increase viral entry via recognition and binding to
the substrate-binding domain (SBD) of GRP78. This is true for several viruses [162], and
molecular docking also showed that SARS-CoV-2 spike protein could bind to the host
cell surface GRP78 [163]. Furthermore, the literature confirmed the in vitro presence of
GRP78 protein in airway epithelial cells and in situ protein expression of GRP78 in the
respiratory mucosa [164]. Higher serum GRP78 concentrations were found in COVID-19
patients compared to patients with pneumonia and the control group [165]. In another
example, GRP78 can be overexpressed in the setting of a malignancy, where its abundance
on cancer cell membranes endows antiapoptotic properties to the tumor cell by increasing
the levels of antiapoptotic proteins such as Bcl-2 and reducing the levels of proapoptotic
proteins, such as Bax. Ultimately, this results in promoting tumor survival, progression,
angiogenesis, invasion, metastasis, as well as resistance to therapy [166]. This has been
observed in various types of cancers [167–171].
HSPA5/GRP78 and TQ: TQ decreases the expression of HSPA5/GRP78 and improved
mitochondrial function [172]. Furthermore, molecular docking showed that TQ might in-
terfere with SARS-CoV-2 attachment to HSPA5 by tightly binding to this protein on the cell
surface [173]. Collectively, TQ produces a dual hit, where it tightly binds to HSPA5/GRP78,
reducing its expression. Thus both reduces the risk of SARS-CoV-2 infection and decrease
chemotherapy resistance, cancer invasion, metastasis, and survival, as illustrated briefly in
Figure 2 [173].
CoV-2 infection, inhibiting NF-ĸB[205], thus ameliorating the COVID-19-associated cyto-
kine storm and inflammation. This would indeed also be beneficial in cancer patients who
suffer from elevated cytokines and inflammation. On the other hand, Nrf2 appears to have
contrasting roles in cancer patients, where it protects against chemical and radiation-in-
duced carcinogenesis [180–182] but also leads to tumor-promoting effects. It would be
Cells 2021, 10, 302 beneficial to investigate the effects of TQ on Nrf2/HO-1/NF-ĸB in cancer patients with 9 of 29
COVID-19.
Figure 2. Effect of TQ on Nrf2, GRP78 and SARS-CoV-2 infection. A diagram showing the effect of TQ on Nrf2; it activates
Nrf2 by phosphorylation, causing its translocation inside the nucleus, binding to ARE (antioxidant response element) and
Maf. This binding results in the reduction of NF-kB, cytokine production, inflammation, oxidative damage and an increase
Figure 2. Effect of TQ on Nrf2, GRP78 and SARS-CoV-2 infection. A diagram showing the effect of TQ on Nrf2; it acti-
in detoxifying cytoprotective genes and enzymes such as the HO-1 enzyme. Moreover, TQ decreases GRP78 expression,
vates Nrf2 by phosphorylation, causing its translocation inside the nucleus, binding to ARE(antioxidant response element)
angiotensin-converting enzyme
and Maf. This binding 2 (ACE)-receptor
results expression
in the reduction of and hence
NF-kB, cytokine decreases
production, viral entry.oxidative damage and an
inflammation,
increase in detoxifying cytoprotective genes and enzymes such as the HO-1 enzyme. Moreover, TQ decreases GRP78 ex-
Nrf2
pression, angiotensin-converting (nuclear
enzyme factor erythroid-derived
2 (ACE)-receptor 2 related
expression and hence factor
decreases viral2) is an important transcription
entry.
factor that counteracts oxidative stress, where it acts as a sensor of oxidative stress, pre-
venting genomic instability. It regulates about 250 genes involved in cellular homeostasis,
including detoxifying enzymes, antioxidant proteins, and cytoprotective proteins [174].
Under normal physiological conditions, Nrf2 is sequestered by the cytoplasmic keap1
(Kelch-like ECH-associated protein 1), which maintains the Nrf2 at low levels through
targeting it for proteasomal degradation (ubiquitination) [175]. Disruption of Nrf2 home-
ostasis can be seen in various settings, including viral infection and cancer. During a viral
infection, intracellular expression of viral proteins leads to an increase in the oxidative stress
of a cell. This leads to the dissociation of Nrf2 from keap1, which consequently prevents
its ubiquitination [176,177]. Nrf2 is now able to translocate to the nucleus and activate the
transcription of detoxifying, cytoprotective genes such as heme oxygenase (HO-1) [178,179].
This mechanism is also involved in the setting of cancer, where Nrf2 is additionally able
to protect a cell from chemical and radiation-induced carcinogenesis [180–183]. Moreover,
literature revealed that Nrf2 is able to enhance innate immune system activity, as well as
participate in the inhibition of inflammatory cytokine expression, including IL-1β, IL-6,
and NF-kB, ultimately decreasing inflammation [184–186]. Although some studies show
that the continuous activation of Nrf2, as a result of excessive levels of ROS, could have
deleterious effects on the host cell [187,188], it usually does not happen in viral infections
since the virus needs to keep optimal oxidative stress levels allowing it to maintain viral
metabolism without causing death in the host cell [189]. A recent study in 2020 involving 40
patients showed that the severity of COVID-19 is inversely associated with Nrf2 expression
and directly linked to age and intensity of inflammatory response [190]. Interestingly,
recent studies showed that Nrf2 deficiency upregulates ACE2 receptors, while activation
of Nrf2 downregulates ACE2 receptors, with Nrf2 knock-out mice showing enhanced
ACE2 expression. In cultured immortalized renal proximal tubule cells, treatment with
Nrf2 inhibitor (Trigonelline) or transfection with Nrf2 small interfering RNA led to an
increase in ACE2 transcription [191]. The exact mechanism of how Nrf2 downregulates the
Cells 2021, 10, 302 10 of 29
ACE2 receptor remains unclear. Additionally, Nrf2 activators downregulate the mRNA
expression of TMPRSS2 [192,193] via upregulating TMPRSS2 inhibitors PAI-1 plasminogen
activator inhibitor-1 encoded by the SERPINE gene (SERPINE/PAI-1) [192] and secretory
leukocyte protease inhibitor (SLPI) [193]. This may highlight the important role of Nrf2
in downregulating TMPRSS2, ACE2 receptor expression and subsequently decreasing
SARS-CoV-2 infection load. Despite the numerous cytoprotective mechanisms of Nrf2, it
still appears to be a double-edged molecule since there is cumulative evidence establishing
the fact that Nrf2 is one of the pathways that drive cancer progression, spread or metastasis,
and chemo-resistance [194–203], and hence further dedicated studies may still be required.
Nrf2 and TQ: in keratinocytes, TQ works as a pro-oxidant that activates Nrf2 and
increases its nuclear accumulation, leading to increased mRNA and protein expression of
HO-1 [204], enhancing its binding to ARE, thus decreasing ACE2 expression, as demon-
strated in Figure 2 [205]. During the course of COVID-19, white blood cells become acti-
vated, releasing excessive, prolonged inflammatory cytokines, leading to what is called the
cytokine storm, acute respiratory distress syndrome, multiple organ dysfunction, and even
death [206,207]. In addition, SARS-CoV-2 might invade the central nervous system induc-
ing neurological diseases [208] manifested as headache, nausea, and vomiting. TQ showed
inhibitory effects on NF-kB mediated neuroinflammation, as mentioned in Table 4, report-
ing other TQ effects in COVID-19-induced neurological disease. Altogether, TQ activates
Nrf2 [204] that decreases ACE2 expression [205], potentially decreasing SARS-CoV-2 infec-
tion, inhibiting NF-kB [205], thus ameliorating the COVID-19-associated cytokine storm
and inflammation. This would indeed also be beneficial in cancer patients who suffer
from elevated cytokines and inflammation. On the other hand, Nrf2 appears to have con-
trasting roles in cancer patients, where it protects against chemical and radiation-induced
carcinogenesis [180–182] but also leads to tumor-promoting effects. It would be beneficial
to investigate the effects of TQ on Nrf2/HO-1/NF-kB in cancer patients with COVID-19.
Table 4. The beneficial effects of TQ against COVID-19 pathophysiological effects.
COVID-19
Thymoquinone References
Complications
-Protects against hyperlipidemia, cyclophosphamide, doxorubicin and diesel
exhaust particle-induced cardiac damage or changes
Cardiac damage -Counteracts sepsis-induced elevation in p62 and increases beclin-1 expression [21,48,209–212]
-Reduced infarct size, improved cardiac function, reduced myocardial enzyme LDH
and CK-MB activities and inhibited oxidative stress
-Inhibited nuclear factor kappa-B (NF-kB) in lung tissue
-Ameliorates the pathological changes of chronic asthma, inhibits inflammatory
changes by antagonizing IL-4/5, and a single dose prevented asthma in the guinea
pig model
-Showed anti-neoangiogenic effects through inhibition of expression of
VEGFR2/PI3K/Akt-signaling pathway
-Decreased the inflammatory and apoptotic index levels in rats exposed to cigarette
smoke and showed anti-inflammatory and cytoprotective effects against cigarette
smoke-induced COPD and LPS induced acute lung injury by COX inhibition
-Downregulated pro-fibrosis genes and decreased oxidative stress in lung fibrosis
Lung injury, ARDS,
-Counteracted emphysema in air alveoli, lymphoid hyperplastic cells activation
COPD, pulmonary [22,213–223]
surrounding the bronchioles, inflammatory cell infiltration
fibrosis
-Ameliorated pulmonary arterial hypertension, Induced relaxation of the
precontracted pulmonary artery and caused a decrease in the tension of pulmonary
arterial rings precontracted with phenylephrine
-Reduced alterations in lungs and inflammatory markers induced by
cyclophosphamide and toluene, decreased lipid peroxidation and restored
antioxidants
-Showed inhibitory effects on the aggregation of inflammatory cells in
bronchoalveolar lavage (BAL) fluid and in lung tissues
-Significantly decreased serum IgE and showed superior inhibitory effects on iNOS
and TGF-β1
Cells 2021, 10, 302 11 of 29
Table 4. Cont.
COVID-19
Thymoquinone References
Complications
-Effectively improved the plasma and liver antioxidant capacity and enhanced the
expression of liver antioxidant genes of hypercholesterolemic rats
-Protects against oxidative liver damage and ductular proliferation
-Reduced liver injury and tumor markers expressions;thus its beneficial in the treatment
of hepatocellular carcinoma
-Protected against cyclophosphamide, tamoxifen, cypermethrin, cadmium, anti-TB
Liver injury, drugs, aflatoxinB1, acetaminophen and paracetamol-induced
[20,23,24,53,153,
elevated liver hepatotoxicity/necrosis/cirrhosis and fibrosis by decreasing the elevated ALT, AST and
224–232]
enzymes ALP, enhanced regeneration after tissue damage, decreased oxidative protein damage
and increased SOD expression and GSH
-Ameliorated liver fibrosis via blocking TLR4 expression and PI3K phosphorylation on
the activated hepatic stellate cells
-Reduced thioacetamide-induced liver fibrosis and inflammation by decreasing
proinflammatory cytokines, inhibiting PI3K phosphorylation and enhanced p-AMPK
and liver kinase B (LKB-1)
-Attenuated oxidative stress and inflammation-reducing renal ischemia-induced
damage and several drugs-induced nephrotoxicities
-Reversed the vancomycin and doxorubicin-induced nephrotoxicity, reversed elevated
serum blood urea nitrogen, creatinine, MDA and urinary albumin excretion [24,25,226,233,
Kidney damage
-Protected kidney against urinary tract infections (Escherichia coli) induced 234]
pyelonephritis
-Showed protective action against cypermethrin induced shrinkage of glomeruli and
necrosis of renal tubules in kidneys (in mice)
-Induced a significant increase in expression of neuroprotective proteins such as
biliverdin reductase-A, 3-mercaptopyruvate sulfurtransferase, glutaredoxin-3, and
mitochondrial Lon protease, a significant decrease in expression of inflammatory
cytokines, and NF-κB pathway
-Decreased malondialdehyde and nitric oxide metabolites in the brain
Neurological -Enhanced the thiol content and superoxide dismutase and catalase activities and serum
disease, cognitive T4 level [51,235–237]
decline -Protected against PTU-induced memory impairments in rats
-Reversed learning and memory impairments, brain tissue-oxidative damage in
hypothyroid juvenile rats and alleviated changes in the hippocampal lipid peroxide
level and SOD and AChE activities
-Have a protective effect on learning and memory function. It significantly increased the
expression of Nrf2, HO-1 proteins and SOD in the hippocampus
-Showed significant antimicrobial activity against anaerobic bacteria, thus can be used
against diarrhea
-Prevented and significantly reduced the appearance of diarrhea and body weight loss
in mice and ameliorates dextran sulfate sodium-induced colitis
-Inhibited proton pump, acid secretion and neutrophil infiltration, while enhancing
GIT [18,26,44,45,238]
mucin secretion, reduces ulcer index, markers of oxidative stress and nitric oxide
production
-TQ+ ranitidine showed synergistic effects and a more significant decrease in ulcer index
-Suppressed spontaneously contracting rabbit jejunum and also relaxed high K induced
contractions in the jejunum and guinea-pig ileum, thus can be used in colic and diarrhea
-Inhibited histamine production
Allergy, allergic -Decreases the symptoms of allergic conjunctivitis almost the same as dexamethasone
[239,240]
conjunctivitis -Suppressed the Total IgE, OVA-specific IgE and Recruitment of Inflammatory cells
-Alleviated allergic inflammation and may be valuable for treating allergic rhinitis
-Decreased lipase\amylase ratio
Acute pancreatitis -Decreased oxidative stress markers, pancreatic 4-hydroxynonenal (4-HNE), protein
[16,241]
and elevated lipase carbonyl content and protected pancreatic acinar cells from oxidative stress
-Attenuated GSH depletion and increased the activity of GST
Abbreviations: LDH: lactate dehydrogenase; CK-MB: creatininekinase-MB; ARDS: acute respiratory distress syndrome; COPD: chronic
obstructive pulmonary disease.
Cells 2021, 10, 302 12 of 29
The Renin-Angiotensin System (RAS) is a homeostatic loop that begins when the
hepatic angiotensinogen is converted into angiotensin I (ATI) by the renal renin enzyme.
This loop then involves two arms; the ACE enzyme (from the lungs) converts ATI to
angiotensin II (ATII), increasing its circulating levels. This mediator is implicated in
vasoconstriction, fibrosis, hypertension, and inflammation. The second arm involves
the conversion of ATII to AT1-7 by ACE2, which carries out the opposite effects of its
precursor, ATII [242,243]. Many of the cardiovascular symptoms, as well as multiple
organ damage seen with COVID-19, can be linked to RAS-induced dysregulation [244].
In fact, patients with COVID-19 tend to have significantly higher levels of circulating ATII
compared to healthy individuals, and the findings of various studies that were conducted
on autopsies [245] suggest that SARS-CoV-2 may cause downregulation of ACE2 receptors.
This finding, along with receptor internalization upon viral binding, further contribute to
the increase in ATII levels and the imbalance between the pro- and anti-inflammatory roles
of the RAS, ultimately causing the proinflammatory role of the RAS to predominate [13],
endowing procoagulant properties to endothelial cells [245].
The increased ATII enhances the activity of NADPH oxidase, increasing ROS, leading
to induction of vascular smooth muscle cell (VSMC) proliferation, migration, atheroscle-
rosis [246], and hypertension via increased oxidative stress, inflammatory reactions and
production of vasoconstrictors while decreasing the vasodilator nitric oxide (NO). Thus, in-
hibition of VSMC proliferation and migration would be beneficial in preventing atheroscle-
rosis and avoiding cardiovascular complications [247]. Peroxisome proliferator-activated
receptor γ-coactivator 1α (PGC-1 α) was shown to attenuate ROS generation, thereby lim-
iting ATII-induced rat VSMC proliferation [248]. Moreover, AMPK activation attenuates
ATII induced VSMC proliferation, and PPARγ has been reported to have antiproliferative
effects in multiple cancers [249,250]. The ramifications of the prolonged basal inflamma-
tory state observed in the setting of malignancy can be closely mirrored in other statesof
inflammation, including hypertension, obesity, diabetes, and even in COVID-19 patients
with the aforementioned comorbidities. This surge in inflammatory cytokines increases
the production of local and systemic ATII [251]. Increased levels of ATII in cancer patients
has been associated with shortened survival [252]. It is therefore hypothesized that two
hits contribute to the hyper-inflammatory response that is observed in COVID-19 patients
with comorbidities; the first hit was resulting from the chronic state of inflammation, which
increases the activity of the ATII proinflammatory axis, and the second hit resulting from
SARS-CoV-2 itself, via the internalization of ACE2 receptors, and the decrease in the activity
of the anti-inflammatory ACE2 axis [253]. Together, these two hits increase tissue damage
as well as the risk for multiple organ failure.
TQ and RAS/ATII: the effect of TQ on ATII can be seen when TQ (40 mg/kg) is
injected intraperitoneally 30 min before ATII (300 mg/kg) intravenous injection. This
significantly blunted the rise in systolic blood pressure, mean arterial pressure and heart
rate that wasinduced by ATII. Thus, the antagonistic effect of TQ on ATII appears to be
beneficial in both COVID-19 patients and cancer patients [254]. TQ markedly inhibited ATII-
induced VSMC proliferation, migration, and oxidative stress. It also reversed the elevated
NADPH oxidase activity and ROS induced by ATII [255]. In addition, TQ enhanced the
expression of p-AMPK, PPARγ, and PGC-1 α that were inhibited by ATII. These particular
effects of TQ were abolished by AMPK inhibitor or PGC-1 α siRNA transfection [255].
Furthermore, TQ reduced oxidative stress, lipid peroxidation (specifically renal MDA),
renal TNF-α in unilateral ureteral obstruction (UUO), and increased antioxidant enzymes
(SOD, catalase). Meanwhile, it significantly decreased obstruction-induced apoptotic
cell death and decreased ATII renal expression [256]. Thus, collectively, TQ improves
renal oxidative damage, apoptotic cell death, TNF-α expression and also prevents the
upregulation of ATII in UUO injured rats [257]. Looking at the bigger picture, TQ can be
a promising drug in ameliorating COVID-19-induced RAS dysregulation, counteracting
multiple organ failure in COVID-19 cancer patients.
Cells 2021, 10, 302 13 of 29
6. The Significance of Thymoquinone in Other Pathological Processes in

COVID-Cancer Patients
Platelet hyper-reactivity, the novel coronavirus, promotes a state of hypercoagula-
tion [13] and additionally predisposes some patients to thromboembolic events through
altering platelet function. Literature showed that resting platelets from COVID-19 patients
had increased basal P-selectin expression, aggregated faster, and showed increased spread-
ing on both fibrinogen and collagen. The increase in platelet activation and aggregation
could partially be attributed to increased MAPK pathway activation and thromboxane gen-
eration [258,259]. Interestingly enough, TQ is able to ameliorate platelet hyper-reactivity
by suppressing COVID-19-induced MAPK activation, and another study showed that TQ
triggers apoptosis of blood platelets in a PI3K-dependent manner. Hypercoagulation in
COVID-19 is typically characterized by elevated levels of fibrinogen and D-dimer, increased
prothrombin time (PT), activated partial thromboplastin time, mild thrombocytopenia,
elevated factor 8 and Von Willebrand Factor [12]. D-dimer levels are especially increased
in critically ill patients who are administered into the ICU and is used as a prognostic
factor [13]. Evidence suggests that SARS-CoV-2-induced release of proinflammatory cy-
tokines of the innate immunity, either in close proximity to the affected organ (alveolar
cells of the lung) or in the bloodstream, represents the culprit of the inflammatory pro-
cess [12,206]. Concerning cancer patients, studies showed that multiple myeloma (MM)
patients have an increased risk for venous thromboembolism (VTE) [258,259]. In this re-
gard, TQ has been shown to reverse cancer-associated thrombosis and thus can be used as
a preventive anti-coagulant and/or as a supplement to existing chemotherapies, producing
a double protective effect in COVID-19 infected cancer patients, counteracting the viral-
and cancer-induced platelet hyperreactivity [260–262].
With regard to inflammation and multiple organ failure; treatment approaches of COVID-
19 that aim at targeting the viral replication cycle may not be enough for promoting host
survival, as it is also necessary to target the virus-induced cytokine release syndrome
(CRS) that leads to multiple organ damage and ARDS [263]. Some of the proinflammatory
cytokines that are locally and systemically elevated include IL-1β, interferon-γ (IFN-γ),
IL-1, IL-6, and monocyte chemoattractant protein 1 (MCP-1). They have been detected
in critically ill patients, and they were found to correlate to disease severity [264,265].
Furthermore, upon SARS-CoV-2 entry into the host cell, the disruption of the intracellular
environment via ion redistribution results in the activation of NLRP3 inflammasome that
increases the secretion of proinflammatory cytokines: IL-1β, IL-18, IL-6 and TNF, further
contributing to the imminent cytokine storm and tissue inflammation during respiratory
illness [266]. In this context, TQ could have a promising anti-inflammatory role, where
it significantly decreases the mRNA expression of the aforementioned proinflammatory
cytokines, IL-18, IL-1β and TNF-α, and inhibits IL-6-signaling [16,17,267–269]. In cancer
patients, inflammasomes are also overexpressed, leading to an increased inflammatory
status [270,271]. The disastrous effect of NLRP3 inflammasome in melanoma is owed
to its suppression of NK cell activation, necessary for the release of IFN-γ and killing
of tumor cells, therefore, ultimately increasing lung metastasis [272,273]. Closely exam-
ining the molecular mechanisms of inflammasome complexes in different cancer types
revealed that the overexpression of IL-1β causes mobilization of myeloid-derived sup-
pressor cells (MDSCs) and induces gastric cancer [274], while signaling of IL-1 drives
the accumulation of MDSCs, promoting primary and metastatic mammary tumors [275].
Moreover, the inflammatory mediator IL-18 is known to accumulate in cancer patients with
the ability to fine-tune the activation status of NK cells, depending on the amount of IL-
18 [12,276]. It is worth noting that inflammasomes do not always show tumor-promoting
effects; in fact, they showed protective roles in some cancer types [277]. Since TQ is an
NLRP3 inhibitor, this would consequently decrease the secreted IL-1β, IL-18 and IL-6 and
ameliorate pain and inflammation in COVID-19 cancer patients. In addition to NLRP3,
eicosanoids play a critical role in the progression of inflammation, fever, allergies, can-
cer, and pain [206,273,275]. Although the role of eicosanoids in COVID-19 is not well
Cells 2021, 10, 302 14 of 29
characterized, it is believed that cell debris is able to initiate an eicosanoid and cytokine
storm in the context of inflammatory diseases. TQ is also able to target arachidonic acid
metabolism [278]. Targeting the upstream portion of the eicosanoid storm will potently
inhibit the cytokine storm formation, protecting against inflammation-mediated multiple
organ damage in COVID-19 patients.
Oxidative stress: oxidative damage is an important aspect in which COVID-19 has a
notable impact on cancer patients. The analysis showed that interactions between viral
proteins and some of the components of the ROS pathway had been implicated in different
cancer types. These interactions may be exploited by SARS-CoV-2 to disrupt the basic pro-
cesses that modulate mitochondrial respiration, metabolism, and oxidative stress, including
certain pathways that are known to be important for the development of tumors [279].
TQ happens to demonstrate potent antioxidant properties, where it significantly attenuates
glutathione (GSH) depletion and increases the activity of the glutathione-S-transferase
(GST) enzyme. It significantly decreases oxidative stress markers, including thiobarbituric
acid reactive substance (TBARS), which is elevated in several cancer types like colon and
cervical cancer [280,281]. Furthermore, TQ induces the expression of several detoxifying
enzymes, including glutathione reductase, superoxide dismutase 1 (SOD1), catalase, and
glutathione peroxidase 2 (GPX) [16,19,20]. The reduction of oxidative stress, therefore,
gives a protective effect against multiple organ failure associated with COVID-19 and
cancer patients.
Myocardial injury: cardiac injury is significantly associated with fatal outcomes in
COVID-19. In sepsis, elevated plasma levels of troponin-T (c-Tnt) are an important indicator
of cardiac damage. Severe cases of COVID-19 showed elevated plasma levels of c-Tnt
and were in higher need of mechanical ventilation compared to those with normal Tnt
levels. They also had more frequent malignant arrhythmias and needed glucocorticoid
therapy [282]. Increased inflammatory cytokines can directly or indirectly cause cardiac
damage, but the precise mechanism of myocardial dysfunction-induced sepsis is still
unclear. This is also common in cancer patients, where cardiac injury is a risk factor
for mortality and may be indicated by elevated levels of troponin and BNP biomarkers,
which could result from either the malignancy or the treatment regimen [13]. For example,
certain anticancer medications cause patients to suffer from cardiotoxicity presenting as
ischemia or vasospasm. An example of this is CAR-T therapy, which may result in CRS,
and proteasome inhibitors, which may cause heart failure [283]. Literature showed that TQ
significantly decreased TnT levels and markedly reduced cardiac tissue-inflammatory cell
infiltration in the cecal ligation and puncture (CLP)-induced-sepsis group. Additionally,
P62 and beclin1 are two major proteins in autophagy, and previous literature showed
that P62 expression is increased, while beclin1 is decreased in cardiac damage and in
sepsis [284–286]. TQ significantly decreased P62 and increased expression of beclin1 in
CLP mice, thus decreasing sepsis-induced cardiac damage.
Lung injury: COVID-19 causes respiratory symptoms including breathlessness, pneu-
monia, severe ARDS, lung fibrosis and injury [287]. Studies show that TQ has promising
effects in lung protection; it protects against injury and fibrosis induced by LPS, toluene,
and cyclo-phosphamide. It also induces the relaxation of the precontracted pulmonary
artery [213,214,216–220]. Moreover, TQ inhibits inflammation, neoangiogenesis, and vas-
cular remodeling in various asthmatic models [215,221–223]. It also counteracts several
processes, including emphysema in air alveoli, activation of hyperplastic lymphoid cells
surrounding the bronchioles, and inflammatory cell infiltration [216]. According to Jaber
S. Alqahtani et al., 2020, chronic obstructive pulmonary disease (COPD) patients were at
a higher risk of more severe COVID-19, especially in smokers, as they were seen to have
higher expression of ACE2 in their airways [288,289]. TQ decreases the inflammatory and
apoptotic index levels in rats exposed to cigarette smoke and shows anti-inflammatory and
cytoprotective effects, as summarized in Table 4 [22].
Cells 2021, 10, 302 15 of 29
Liver injury: liver injury is a critical, life-threatening COVID-19 complication [290].

It is common in cancer patients, as some chemotherapeutic agents like cyclophosphamide
[291,292] and tamoxifen cause hepatotoxicity [293], as reviewed in De La Vega et al. [294].
This demonstrates the potentially fatal ramifications of COVID-19 in cancer patients.
TQ shows several promising hepatoprotective effects against toxicities and fibrosis
[20,23,24,53,224,226–228,230–232], where it protects against chemotherapy-induced hep-
atotoxicity through reducing liver injury and tumor markers expression, hinting atthe
use of TQ in the treatment of hepatocellular carcinoma [153,225,229]. Altogether, us-
ing TQ provides a dual benefit, where it protects against both COVID-19-induced and
chemotherapy-induced hepatotoxicity.
Kidney injury: this is another COVID-19 related serious complication as reviewed
in [295]. Certain chemotherapeutic regimens make cancer patients more susceptible to
nephrotoxicity [296]. TQ shows protective effects in the kidneys through ameliorating
oxidative stress and reversing the nephrotoxic effects of various drugs and infections
[24,25,226,233,234], as summarized in Table 4. Moreover, TQ shows reno-protective ef-
fects in sepsis-induced AKI. Since AKI is majorly mediated by dysregulated activation of
inflammasomes and proinflammatory cytokines, the aforementioned anti-inflammatory
properties of TQ also appear to be of significant benefit in this context [17], where TQ de-
creases apoptosis of kidney cells and alleviates AKI. Finally, NFκB is the main transcription
regulator of inflammatory genes and has crucial roles in inflammation and the pathophys-
iology of sepsis. TQ reverses the increased NFκB expression in the kidney from septic
mice. Collectively, TQ contributes to the alleviation of sepsis-induced AKI by regulating
pyroptosis, proinflammatory cytokines, and apoptosis-related expression [17].
Neurologic/cognitive manifestations associated with COVID-19: these manifestations in-
clude headache, memory loss, mood changes, vision changes, hearing loss, loss of smell,
loss of taste, impaired mobility, limb numbness, tremor, fatigue and myalgia [297]. This is
along with cases of encephalitis, necrotizing hemorrhagic encephalopathy, stroke, and
epileptic seizures as reviewed in [298]. TQ shows several neuroprotective effects, as sum-
marized in Table 4 [191,236].
TQ and gastrointestinal (GIT) manifestations associated with COVID-19: these include
diarrhea, loss of appetite, nausea/vomiting and abdominal pain as reviewed in [299].
TQ shows a promising effect against anaerobic bacteria, thus would alleviate diarrhea.
It also acts as a gastroprotective agent, proton pump inhibitor and enhances mucin se-
cretion, which would be additionally beneficial in cancer patients suffering from GIT
symptoms [18,26,44,45,238].
TQ and ocular manifestations and conjunctivitis associated with COVID-19 [300]: literature
showed that TQ decreases the symptoms of allergic conjunctivitis nearly as effectively as
dexamethasone [239], possibly ameliorating COVID-19 associated conjunctivitis.
Pancreatitis: pancreatic inflammation, along with increased lipases associated with
COVID-19, can be reduced with TQ since it has been shown to decrease lipases and protect
the pancreas against oxidative stress [16,241].
Collectively, TQ showed protective effects in the heart, lungs, kidney, liver, GIT, pancreas
and alleviated oxidative stress as summarized in Figure 3 and reported in detail in Table 4.
Cells 2021, 10,
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30
Figure 3. The multifunctional effects of TQ on COVID-19-associated pathophysiology. The diagram summarizes the
Figure 3. The multifunctional effects of TQ on COVID-19-associated pathophysiology. The diagram summarizes the
main organ-related and organ protective effects of TQ on the main body organs. In the heart, TQ decreases cardiac enzymes,
main organ-related and organ protective effects of TQ on the main body organs. In the heart, TQ decreases cardiac en-
cholesterol, triglycerides
zymes, cholesterol, and inflammatory
triglycerides cytokines.
and inflammatory In the In
cytokines. liver,
theTQ increases
liver, antioxidant
TQ increases enzymes
antioxidant and decreases
enzymes and de-
proinflammatory genes and
creases proinflammatory cytokines,
genes elevated liver
and cytokines, enzymes
elevated liver and liver fibrosis.
enzymes and liverIn fibrosis.
the pancreas,
In theTQ increasesTQ
pancreas, antioxidant
increases
capacity by increasing
antioxidant capacity byglutathione-S-transferase (GST) enzyme
increasing glutathione-S-transferase (GST)andenzyme
glutathione (GSH) levels
and glutathione whilelevels
(GSH) decreasing lipase and
while decreasing
oxidative
lipase andstress. In thestress.
oxidative lungs,InTQ
theinhibits
lungs, cyclooxygenase (COX) enzyme,
TQ inhibits cyclooxygenase IL-4/5
(COX) levels,IL-4/5
enzyme, NF-kB,levels,
vascular endothelial
NF-ĸB, vasculargrowth
endo-
thelial(VEGF),
factor growth transforming
factor (VEGF), transforming
growth factor-β1 growth
(TGF-β1),factor-β1
oxidative (TGF-β1), oxidativenitric
stress, inducible stress,
oxideinducible nitric oxide
synthase(iNOS) syn-
enzyme,
thase(iNOS)
lipid enzyme,
peroxidation, lipid peroxidation,
pro-fibrosis genes andpro-fibrosis
pulmonary genes
arterialand pulmonary arterial
hypertension;in hypertension;in
the kidney, TQ decreases thekidney
kidney,markers,
TQ de-
creasesurea
blood kidney markers,
nitrogen blood
(BUN), urea nitrogen
creatinine, (BUN), creatinine,
malondialdehyde (MDA) malondialdehyde
and albumin and (MDA) andantioxidant
increases albumin and increases
activity. an-
In the
tioxidant activity. In the gastrointestinal tract (GIT), TQ inhibits proton pump, acid secretion, ulcer index, neutrophil in-
gastrointestinal tract (GIT), TQ inhibits proton pump, acid secretion, ulcer index, neutrophil infiltration and oxidative stress
filtration and oxidative stress markers and increases mucin secretion and nitric oxide (NO) production.
markers and increases mucin secretion and nitric oxide (NO) production.
7. Conclusions
7. Conclusions
The clinical spectrum of COVID-19 can generally range from patients who are pauci-
symptomatic to those
The clinical experiencing
spectrum of COVID-19 severecan respiratory failurefrom
generally range and patients
ARDS, and whofinally,
are pau- to
those who suffertofrom
cisymptomatic thosesystemic manifestations
experiencing and multiple
severe respiratory organ
failure and failure.
ARDS,Cancer patients
and finally, to
are ofwho
those particular interest
suffer from in light
systemic of this pandemic;
manifestations they areorgan
and multiple morefailure.
liable Cancer
to experience
patientsa
more
are ofsevere clinical
particular course
interest inof the of
light disease, owing to multiple
this pandemic; they areconfounding
more liable to factors, such as
experience a
more severe clinical course of the disease, owing to multiple confounding
increased basal inflammatory state, increased oxidative stress, as well as the very likely factors, such as
increasedofbasal
presence inflammatory
existing comorbiditiesstate, increased
other than the oxidative stress,
malignancy as well
itself. Amidstas thethevery likely
eagerness
presence of existing
to vaccinate comorbidities
populations other than the
against COVID-19, themalignancy
aforementioneditself.points
Amidst thejustify
still eagerness to
the ra-
vaccinate populations
ther meticulous hunt foragainst
a drugCOVID-19,
or an agentthe thataforementioned
would ideally points
provide still justify the
COVID-19 rather
infected
meticulous
cancer huntwith
patients for adouble
drug orbenefits,
an agentpositively
that would ideally provide
affecting the courses COVID-19
of bothinfected can-
their malig-
cer patients with double benefits, positively affecting the courses of both
nancies and the viral infection. In this review, we have hoped to shed light on TQ from their malignancies
and thesativa
Nigella viralseeds
infection. In this
and how review,
it has been we
shownhavethroughout
hoped to shed light on
numerous TQ from
studies Nigella
to have po-
sativa seeds and how it has been shown throughout numerous studies
tential beneficial and protective effects in general and in COVID-19-infected cancer pa- to have potential
beneficial
tients and protective
in particular, effects in general
with significantly lowerand in COVID-19-infected
incidences of side effects. First,cancer patientsthe
it reduces in
particular,
probabilitywith significantly entry
of SARS-CoV-2 lowerinto
incidences of side effects.
cells. Second, it helpsFirst, it reduces
ameliorate the the probability
deleterious ef-
of SARS-CoV-2
fects of CRS in entry into cells. Second,
COVID-19-infected it helps
cancer ameliorate
patients, therebythe deleterious
protecting effectsmultiple
against of CRS
in COVID-19-infected cancer patients, thereby protecting against multiple
organ damage. Additionally, it is particularly beneficial for cancer patients because it organ damage.
Cells 2021, 10, 302 17 of 29
Cells 2021, 10, x FOR PEER REVIEW 18 of 30
Additionally, it is particularly beneficial for cancer patients because it could potentially alle-
could potentially alleviate multiple chemotherapy-induced toxicities, exhibit anticancer
viate multiple chemotherapy-induced toxicities, exhibit anticancer effects, as well as exhibit
effects, as well as exhibit chemo- and radio-sensitizing effects. Figure 4 summarizes the
chemo- and radio-sensitizing effects. Figure 4 summarizes the common molecular targets
common molecular targets and effects of TQ that are beneficial in both cancer and COVID-
and effects of TQ that are beneficial in both cancer and COVID-19 patients. Altogether, TQ
19 patients. Altogether, TQ is a promising solution that may win the battle against COVID-
is a promising solution that may win the battle against COVID-19 and cancer. While TQ is
19 and cancer. While TQ is not an FDA approved drug for the treatment of cancer or
not an FDA approved drug for the treatment of cancer or COVID-19; during the past year,
COVID-19; during the past year, onephase 3 clinical trial was done while threephase 2
onephase 3 clinical trial was done while threephase 2 clinical trials are currently studying
clinical trials are currently studying the effect of Nigella sativa extracts on immunity and
the effect of Nigella sativa extracts on immunity and clinical outcomes of COVID-19 patients
clinical outcomes of COVID-19 patients as per clinicaltrials.gov (Identifier number:
as per clinicaltrials.gov (Identifier number: NCT04347382, NCT04472585, NCT04401202
NCT04347382, NCT04472585, NCT04401202 and NCT04553705). It is clear that further
and NCT04553705). It is clear that further clinical trials investigating the use of TQ in
clinical
numerous trials investigating
cancers need to the use of TQ in numerous cancers need to be implemented.
be implemented.
Figure
Figure 4. TQ
TQ common
common effects
effects in
in SARS-CoV-2 infection and cancer.
cancer. The figure summarizes TQ’s actions on molecular
molecular
targets
targets that cause beneficial outcomes in both SARS-CoV-2 infection and cancer pathogenesis.
and cancer pathogenesis.
1.
1. Increase
IncreaseininNrf2
Nrf2that
thatdecreases
decreasesACE2
ACE2expression
expression lessening
lessening the
the viral
viral entry
entry and
and inhibits
inhibits
NF-kB
NF-kBthat
thatdownregulates
downregulatesinflammatory
inflammatory genes
genes and
and cytokine
cytokine storm
storm beneficial
beneficial in
in viral
viral
infection and cancer pathogenesis;
infection and cancer pathogenesis;
2.
2. Reduction
Reductioninininflammatory
inflammatorycytokines
cytokinesthrough
throughNLRP3
NLRP3inhibition,
inhibition,which
whichininturn
turnin-in-
hibits inflammasome formation and all inflammasome components
hibits inflammasome formation and all inflammasome components and inhibits and inhibits
COX-2
COX-2enzyme
enzymehence
hencedecreasing
decreasinginflammatory
inflammatoryPGE2 PGE2levels;
levels;
3.
3. Decrease
Decreasein inRAS
RASactivity
activityby
byattenuating
attenuatingangiotensin
angiotensinIIIIlevels
levels (ATII)
(ATII) which
which abolishes
abolishes
its
its detrimental effects such as vasoconstriction (VC), fibrosis, hypertension (HTN)
detrimental effects such as vasoconstriction (VC), fibrosis, hypertension (HTN)
and
andinflammation;
inflammation;
4. Decrease in expression of HSPA5/GRP78, which halts viral entry into the cells and
decreases cancer metastasis while enhancing apoptosis.
Cells 2021, 10, 302 18 of 29
4. Decrease in expression of HSPA5/GRP78, which halts viral entry into the cells and
decreases cancer metastasis while enhancing apoptosis.
5. Inhibition of MAPK, which decreases dysregulated platelet activity reducing risks of
clotting/coagulopathy.
6. Decrease in oxidative stress by upregulating antioxidant enzymes such as superoxide
dismutase (SOD1) and enhancing glutathione (GSH) levels.
Author Contributions: S.E., A.A.E. and N.S.A. contributed toreviewing the literature, writing the
review, and designing figures. H.M.E.T. and U.S. were responsible for designing, editing, and revising
the review. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not Applicable.
Data Availability Statement: Not Applicable.
Conflicts of Interest: The authors declare that they have no conflict of interest.
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Cells: Thymoquinone: A Tie-Breaker in Sars-Cov2-Infected Cancer Patients?

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cells

1 Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology,

Abstract: Since the beginning of the SARS-CoV-2(severe acute respiratory syndrome-coronavirus-

Publisher’s Note: MDPI stays neutral

Cells 2021, 10, 302. https://doi.org/10.3390/cells10020302 https://www.mdpi.com/journal/cells

thromboembolism havebeen frequently reported in COVID-19 patients [3]. Furthermore,

2. Sars-Cov-2 Structural Features Involved in Entry

Drug Beneficial Effect of Thymoquinone as Adjuvant Reference

4. Anticancer Effects of Thymoquinone

TQ vs. carcinogen activation: One of TQ’s anticancer mechanisms is the suppression

Drugs Effects Mechanism Experimental Model Reference

Drugs Effects Mechanism Experimental Model Reference

5. Thymoquinone’s Double Hits in COVID-19 Infected Cancer Patients

Table 4. The beneficial effects of TQ against COVID-19 pathophysiological effects.

6. The Significance of Thymoquinone in Other Pathological Processes in

Liver injury: liver injury is a critical, life-threatening COVID-19 complication [290].

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