Coverage of large burns may be difficult when skin graft donor sites are limited. This study expl... more Coverage of large burns may be difficult when skin graft donor sites are limited. This study explored the use of the split-thickness dermal graft (STDG), as an alternative to the standard split-thickness skin graft (STSG). STSGs and STDGs were compared experimentally by their ability to resurface full thickness skin defects in a pig model. Both types of grafts were harvested from the backs of six pigs and placed on full thickness wounds. From the same donor site a 0.012 in. thick STSG and another two 0.012 in. thick STDGs were harvested. Thus the deep surface of grafts measured 0.012, 0.024 and 0.036 in. from the skin surface, respectively. All grafts were placed on 6 cm × 6 cm full thickness wounds. The donor areas healed at 1 week. Epithelialization of the STDGs, was assessed by computerized planimetry, and was 100% at 4 weeks. Graft biopsies revealed that STSGs were significant thinner than STDGs at 1 week (P = 0.0422, 0.0135), 2 weeks (P = 0.0240) and 4 weeks (P = 0.0516, 0.0425). We conclude that STDGs my provide definitive coverage of full thickness skin deficits in a pig wound model.
Journal of Biomedical Materials Research Part A, Jun 7, 2013
Titanium-10 wt % 45S5 Bioglass nanocomposites and their scaffolds were prepared by mechanical all... more Titanium-10 wt % 45S5 Bioglass nanocomposites and their scaffolds were prepared by mechanical alloying (MA) followed by pressing, sintering, or combination of MA and a "space-holder" sintering process, respectively. An amorphous structure was obtained at 15 h of milling. The crystallization of the amorphous phase upon annealing led to the formation of a nanostructured Ti-10 wt % 45S5 Bioglass composite with a grain size of approximately 7 nm. The in vitro cytocompatibility of these materials was evaluated and compared with a conventional microcrystalline titanium. During the studies, established cell line of human fibroblasts CCD-39Lu was cultured in the presence of tested materials and its survival rate, and proliferation activity were examined. Furthermore, the influence of the Ti-45S5 Bioglass nanocomposites and microcrystalline titanium was tested on the growth of Candida albicans yeast. Biocompatibility tests carried out indicate that the nanocomposite Ti-10 wt % 45S5 Bioglass scaffolds could be a possible candidate for dental implants and other medicinal applications.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Background: The role of CYP1A1, CYP1B1 and CYP3A4 polymorphism in pathogenesis of breast cancer h... more Background: The role of CYP1A1, CYP1B1 and CYP3A4 polymorphism in pathogenesis of breast cancer has not been fully elucidated. From three CYP1A1 polymorphisms *2A (3801T>C), *2C (2455A>G), and *2B variant, which harbors both polymorphisms, the *2A variant is potentially carcinogenic in African Americans and the Taiwanese, but not in Caucasians, and the CYP1B1*2 (355G>T) and CYP1B1*3 (4326C>G) variants might increase breast cancer risk. Although no association of any CYP3A4 polymorphisms and breast cancer has been documented, the CYP3A4*1B (392A>G) variant, correlates with earlier menarche and endometrial cancer secondary to tamoxifen therapy. Objective: The present study was designed to investigate the frequency of CYP1A1, CYP1B1 and CYP3A4 polymorphisms in a sample of breast cancer patients from the Polish population and to correlate the results with the clinical and laboratory findings. Material and methods: The frequencies of CYP1A1*2A; CYP1A1*2C; CYP1B1*3; CYP3A4*1B CYP3A4*2 polymorphisms were determined in 71 patients aged 36-87, with primary breast cancer and 100 healthy individuals. Genomic DNA was extracted from the tumor and individual gene fragments were PCR-amplified. The polymorphisms were determined by RFLP and were correlated with the patients' TNM stage, grade, estrogen and progesterone receptor status as well as the level of c-erbB-2 protein. Results: CYP1A1 polymorphisms were more frequent in younger patients and in the patients with high level of c-erbB-2 protein. No correlation between these polymorphisms and the cancer stage or grade, as well as the receptor status was demonstrated. Conclusions: CYP1A1 polymorphisms probably predispose to an earlier onset of breast cancer and might be associated with higher c-erbB-2 protein level, but further studies on a much larger group are required to substantiate our findings.
Contribution of the protein kinase A (PKA) and protein kinase C (PKC) signalling pathways to the ... more Contribution of the protein kinase A (PKA) and protein kinase C (PKC) signalling pathways to the regulation of 11beta-hydroxysteroid dehydrogenase type II (HSD11B2) gene expression was investigated in human breast cancer cell line MCF-7. Treatment of the cells with an adenylyl cyclase activator, forskolin, known to stimulate the PKA pathway, resulted in an increase in HSD11B2 mRNA content. Semi-quantitative RT-PCR revealed attenuation of the effect of forskolin by phorbol ester, tetradecanoyl phorbol acetate (TPA), an activator of the PKC pathway. It was also demonstrated that specific inhibitors significantly reduced the effect of activators of the two pathways. Stimulation of the PKA pathway did not affect, whereas stimulation of the PKC pathway significantly reduced MCF-7 cell proliferation in a time-dependent manner. A cell growth inhibitor, dexamethasone, at high concentrations, caused a 40% decrease in proliferation of MCF-7 cells and this effect was abolished under conditions of increased HSD11B2 expression. It was concluded that in MCF-7 cells, stimulation of the PKA signal transduction pathway results in the induction of HSD11B2 expression and that this effect is markedly reduced by activation of the PKC pathway. Activation of the PKC pathway also resulted in inhibition of cell proliferation, while activation of the PKA pathway abolished the antiproliferative effect of dexamethasone. These effects might be due to oxidation of dexamethasone by the PKA-inducible HSD11B2.
The present study was designed to identify the biological activity of three ecdysones, i.e., 20-h... more The present study was designed to identify the biological activity of three ecdysones, i.e., 20-hydroxyecdysone (20-HE), ajugasterone C, and polypodine B isolated from Serratula coronata. The main objective was to investigate the molecular mechanism of the biological activity of those compounds and to assess their impact on breast cancer cell survival and cell cycle. Cell lines were selected according to their hormone receptor status since this factor is perceived as a crucial one in the cancer prognosis as well as cancer cell response to therapy. Consequently, MCF7 (ER/PR+, HER2-), T-47D (ER/PR+, HER2-/+), and MDA-MB-231 (ER/PR-, HER2-) were enrolled in the study. Additionally, a non-tumorigenic, MCF10A cells were selected to verify any potential specificity to cancer cells. Interestingly, none of the studied compounds affected the viability of MCF10A cells while cancer cells were altered, albeit in different ways. Polypodine B did not affect the viability or cell cycle distribution of studied breast cancer cells. By contrast, 20-HE and ajugasterone C significantly inhibited the viability of triple-negative cell line, MDA-MB-231. Interestingly, 20-HE revealed proapoptotic activity in MDA-MB-231 and T-47D cells that was manifested by alterations in PARP, Bax, and Bcl-2 levels as well as caspase-3 activation. Moreover, 20-HE induced autophagy that was mediated by modification of autophagy-associated proteins, i.e., LC3, p62, and mTOR, but only in MDA-MB-231 cells. This study is the first to report diverse biological activity of phytoecdysones in different breast cancer cells, that suggests association with molecular characteristics including receptor status but also other biological properties and genetic markers.
Cellular and Molecular Life Sciences, Jun 16, 2017
It is well known that a decreased expression or inhibited activity of telomerase in cancer cells ... more It is well known that a decreased expression or inhibited activity of telomerase in cancer cells is accompanied by an increased sensitivity to some drugs (e.g., doxorubicin, cisplatin, or 5-fluorouracil). However, the mechanism of the resistance resulting from telomerase alteration remains elusive. There are theories claiming that it might be associated with telomere shortening, genome instability, hTERT translocation, mitochondria functioning modulation, or even alterations in ABC family gene expression. However, association of those mechanisms, i.e., drug resistance and telomerase alterations, is not fully understood yet. We review the current theories on the aspect of the role of telomerase in cancer cells resistance to therapy. We believe that revealing/unravelling this correlation might significantly contribute to an increased efficiency of cancer cells elimination, especially the most difficult ones, i.e., drug resistant.
International Journal of Molecular Sciences, Aug 12, 2021
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Telomerase has been recognized as a relevant factor distinguishing cancer cells from normal cells... more Telomerase has been recognized as a relevant factor distinguishing cancer cells from normal cells. Thus, it has become a very promising target for anticancer therapy. The cell proliferative potential can be limited by replication end problem, due to telomeres shortening, which is overcome in cancer cells by telomerase activity or by alternative telomeres lengthening (ALT) mechanism. However, this multisubunit enzymatic complex can be regulated at various levels, including expression control but also other factors contributing to the enzyme phosphorylation status, assembling or complex subunits transport. Thus, we show that the telomerase expression targeting cannot be the only possibility to shorten telomeres and induce cell apoptosis. It is important especially since the transcription expression is not always correlated with the enzyme activity which might result in transcription modulation failure or a possibility for the gene therapy to be overcome. This review summarizes the current state of knowledge of numerous telomerase regulation mechanisms that take place after telomerase subunits coding genes transcription. Thus we show the possible mechanisms of telomerase activity regulation which might become attractive anticancer therapy targets.
Każdego roku odnotowuje się 11 000 nowych przypadków zachorowań na raka piersi, a prawie połowa c... more Każdego roku odnotowuje się 11 000 nowych przypadków zachorowań na raka piersi, a prawie połowa chorych umiera. Tak wysoka umieralność może być spowodowana zbyt późnym rozpoznaniem choroby, brakiem specyficznych i skutecznych leków, a także wystąpieniem zjawiska oporności wielolekowej (multiple drug resistance-MDR) w komórkach nowotworowych. Podstawowym mechanizmem wywołującym to zjawisko jest nadekspresja i zwiększona aktywność transporterów błonowych, z których większość należy do nadrodziny transporterów ABC (ATP binding casette). Spośród tych białek najlepiej poznanym jest glikoproteina P, produkt ekspresji genu ABCB1, odpowiedzialna m.in. za usuwanie ksenobiotyków i leków poza obszar komórki. Szerokie spektrum substratowe glikoproteiny P obejmuje: ksenobiotyki oraz leki cytotoksyczne, inhibitory białek, immunosupresanty, steroidy, statyny, blokery kanału wapniowego, beta-blokery, leki antyhistaminowe, przeciwdepresyjne oraz przeciwwymiotne. W sekwencji genu ABCB1 opisano szereg polimorfizmów, spośród których największe znaczenie kliniczne mają trzy-zamiana cytozyny na tyminę w pozycji 1236 egzonu 12 (C1236T, rs1128503), zamiana w egzonie 21 G2677A/T (rs2032582) oraz w egzonie 26 C3435T (rs1045642). Występowanie tych polimorfizmów może wpływać na zmianę ekspresji genu ABCB1 (C3435T), strukturę glikoproteiny P (G2677T/A) czy zdolność wiązania się białka z substratem (C1236T). Jak się podejrzewa, obecność tych polimorfizmów może w efekcie modyfikować odpowiedź komórek nowotworowych na chemioterapię. Niniejsza praca opisuje modulujący wpływ polimorfizmów genu ABCB1 na odpowiedź komórek raka piersi na chemioterapię.
Bleomycin is a redox-active drug with anticancer and other clinical applications. It is also freq... more Bleomycin is a redox-active drug with anticancer and other clinical applications. It is also frequently used as a tool in fundamental research on cellular responses to DNA double-strand breaks (DSBs). A conversion of bleomycin into its DNA-breaking form requires Fe, one-electron donors and O 2. Here, we examined how a major biological antioxidant ascorbate (reduced vitamin C), which is practically absent in standard cell culture, impacts cellular responses to bleomycin. We found that restoration of physiological levels of vitamin C in human cancer cells increased their killing by bleomycin in 2D cultures and 3D tumor spheroids. Higher cytotoxicity of bleomycin occurred in cells with normal and shRNA-depleted p53. Cellular vitamin C enhanced the ability of bleomycin by produce DSBs, which was established by direct measurements of these lesions in three cell lines. Vitamin C-restored cancer cells also showed a higher sensitivity to killing by low-dose bleomycin in combination with inhibitors of DSB repair-activating ATM or DNA-PK kinases. The presence of ascorbate in bleomycin-treated cells suppressed a DSBindependent activation of the ATM-CHK2 axis by blocking superoxide radical. In vitro studies detected a greatly superior ability of ascorbate over other cellular reducers to catalyze DSB formation by bleomycin. Ascorbate was faster than other antioxidants in promoting two steps in activation of bleomycin. Our results demonstrate strong activation effects of vitamin C on bleomycin, shifting its toxicity further toward DNA damage and making it more sensitive to manipulations of DNA repair.
Journal Of Environmental Science And Health, Part A, Jan 29, 2010
Although the estrogenic properties of numerous chloroorganic pesticides have been widely recogniz... more Although the estrogenic properties of numerous chloroorganic pesticides have been widely recognized, population studies do not give clear results indicating the link between the exposure to these compounds and breast cancer development. Because of the weak affinity of these pesticides to estrogen receptors, they probably act by affecting the expression of CYP genes encoding cytochromes P450 engaged in the metabolism of environmental as well as natural estrogens. To examine the possible correlation between environmental estrogen levels in adipose tissue and breast cancer stage, grade, receptor status and onset of the disease, adipose tissue was isolated from 54 breast cancer patients and 23 healthy individuals. Clinical characteristics were obtained from the medical records, while the information concerning exposure to environmental estrogens where obtained from questionnaires. The environmental estrogens were identified and quantified by GC-chromatography. The data was analyzed with the use of Student t-test and Spearman correlation. The levels of most environmental estrogens did not differ between the patients and the controls, except the beta-HCH (beta-hexachlorocyclohexane) level, which was higher in the patients than in the healthy individuals. Significantly higher levels of DDE (1,1-bis(4-chlorophenyl)-2,2-dichloroethene) and DDT (1,1,1-trichloro-2,2-bis(4-chlorophenol)ethane) (P < 0.05) were observed in the patients with late onset of the disease which was probably due to the time of exposure. Moreover, in the patients exposed to environmental estrogens, significantly higher concentrations of DDD (1,1-bis(4-chlorophenyl)-2,2-dichloroethane) were found (P < 0.05). We also evidenced that estrogen-independent cancer was more frequent in the patients exposed to numerous risk factors in which higher levels of HCB (hexachlorobenzene), gamma-HCH (gamma-hexachlorocyclohexane), DDD and DDT in adipose tissue were detected. Breast cancer development is probably related to the accumulation of DDT and its derivatives, but the effect appears only in older patients. We postulate that environmental estrogens acting together with other risk factors might influence the progress and exacerbate the prognosis of breast cancer.
Despite the growing interest by researchers into cellular senescence, a hallmark of cellular agin... more Despite the growing interest by researchers into cellular senescence, a hallmark of cellular aging, its role in human skin remains equivocal. The skin is the largest and most accessible human organ, reacting to the external and internal environment. Hence, it is an organ of choice to investigate cellular senescence and to target root‐cause aging processes using senolytic and senomorphic agents, including naturally occurring plant‐based derivatives. This review presents different aspects of skin cellular senescence, from physiology to pathology and signaling pathways. Cellular senescence can have both beneficial and detrimental effects on the skin, indicating that both prosenescent and antisenescent therapies may be desirable, based on the context. Knowledge of molecular mechanisms involved in skin cellular senescence may provide meaningful insights for developing effective therapeutics for senescence‐related skin disorders, such as wound healing and cosmetic skin aging changes.
Breast cancer is one of the most frequently observed malignancies worldwide and represents a hete... more Breast cancer is one of the most frequently observed malignancies worldwide and represents a heterogeneous group of cancers. For this reason, it is crucial to properly diagnose every single case so a specific and efficient therapy can be adjusted. One of the most critical diagnostic parameters evaluated in cancer tissue is the status of the estrogen receptor (ER) and epidermal growth factor receptor (EGFR). Interestingly, the expression of the indicated receptors may be used in a personalized therapy approach. Importantly, the promising role of phytochemicals in the modulation of pathways controlled by ER and EGFR was also demonstrated in several types of cancer. One such biologically active compound is oleanolic acid, but due to poor water solubility and cell membrane permeability that limits its use, alternative derivative compounds were developed. These are HIMOXOL and Br-HIMOLID, which were demonstrated to be capable of inducing apoptosis and autophagy or diminishing the migrato...
Coverage of large burns may be difficult when skin graft donor sites are limited. This study expl... more Coverage of large burns may be difficult when skin graft donor sites are limited. This study explored the use of the split-thickness dermal graft (STDG), as an alternative to the standard split-thickness skin graft (STSG). STSGs and STDGs were compared experimentally by their ability to resurface full thickness skin defects in a pig model. Both types of grafts were harvested from the backs of six pigs and placed on full thickness wounds. From the same donor site a 0.012 in. thick STSG and another two 0.012 in. thick STDGs were harvested. Thus the deep surface of grafts measured 0.012, 0.024 and 0.036 in. from the skin surface, respectively. All grafts were placed on 6 cm × 6 cm full thickness wounds. The donor areas healed at 1 week. Epithelialization of the STDGs, was assessed by computerized planimetry, and was 100% at 4 weeks. Graft biopsies revealed that STSGs were significant thinner than STDGs at 1 week (P = 0.0422, 0.0135), 2 weeks (P = 0.0240) and 4 weeks (P = 0.0516, 0.0425). We conclude that STDGs my provide definitive coverage of full thickness skin deficits in a pig wound model.
Journal of Biomedical Materials Research Part A, Jun 7, 2013
Titanium-10 wt % 45S5 Bioglass nanocomposites and their scaffolds were prepared by mechanical all... more Titanium-10 wt % 45S5 Bioglass nanocomposites and their scaffolds were prepared by mechanical alloying (MA) followed by pressing, sintering, or combination of MA and a "space-holder" sintering process, respectively. An amorphous structure was obtained at 15 h of milling. The crystallization of the amorphous phase upon annealing led to the formation of a nanostructured Ti-10 wt % 45S5 Bioglass composite with a grain size of approximately 7 nm. The in vitro cytocompatibility of these materials was evaluated and compared with a conventional microcrystalline titanium. During the studies, established cell line of human fibroblasts CCD-39Lu was cultured in the presence of tested materials and its survival rate, and proliferation activity were examined. Furthermore, the influence of the Ti-45S5 Bioglass nanocomposites and microcrystalline titanium was tested on the growth of Candida albicans yeast. Biocompatibility tests carried out indicate that the nanocomposite Ti-10 wt % 45S5 Bioglass scaffolds could be a possible candidate for dental implants and other medicinal applications.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Background: The role of CYP1A1, CYP1B1 and CYP3A4 polymorphism in pathogenesis of breast cancer h... more Background: The role of CYP1A1, CYP1B1 and CYP3A4 polymorphism in pathogenesis of breast cancer has not been fully elucidated. From three CYP1A1 polymorphisms *2A (3801T>C), *2C (2455A>G), and *2B variant, which harbors both polymorphisms, the *2A variant is potentially carcinogenic in African Americans and the Taiwanese, but not in Caucasians, and the CYP1B1*2 (355G>T) and CYP1B1*3 (4326C>G) variants might increase breast cancer risk. Although no association of any CYP3A4 polymorphisms and breast cancer has been documented, the CYP3A4*1B (392A>G) variant, correlates with earlier menarche and endometrial cancer secondary to tamoxifen therapy. Objective: The present study was designed to investigate the frequency of CYP1A1, CYP1B1 and CYP3A4 polymorphisms in a sample of breast cancer patients from the Polish population and to correlate the results with the clinical and laboratory findings. Material and methods: The frequencies of CYP1A1*2A; CYP1A1*2C; CYP1B1*3; CYP3A4*1B CYP3A4*2 polymorphisms were determined in 71 patients aged 36-87, with primary breast cancer and 100 healthy individuals. Genomic DNA was extracted from the tumor and individual gene fragments were PCR-amplified. The polymorphisms were determined by RFLP and were correlated with the patients' TNM stage, grade, estrogen and progesterone receptor status as well as the level of c-erbB-2 protein. Results: CYP1A1 polymorphisms were more frequent in younger patients and in the patients with high level of c-erbB-2 protein. No correlation between these polymorphisms and the cancer stage or grade, as well as the receptor status was demonstrated. Conclusions: CYP1A1 polymorphisms probably predispose to an earlier onset of breast cancer and might be associated with higher c-erbB-2 protein level, but further studies on a much larger group are required to substantiate our findings.
Contribution of the protein kinase A (PKA) and protein kinase C (PKC) signalling pathways to the ... more Contribution of the protein kinase A (PKA) and protein kinase C (PKC) signalling pathways to the regulation of 11beta-hydroxysteroid dehydrogenase type II (HSD11B2) gene expression was investigated in human breast cancer cell line MCF-7. Treatment of the cells with an adenylyl cyclase activator, forskolin, known to stimulate the PKA pathway, resulted in an increase in HSD11B2 mRNA content. Semi-quantitative RT-PCR revealed attenuation of the effect of forskolin by phorbol ester, tetradecanoyl phorbol acetate (TPA), an activator of the PKC pathway. It was also demonstrated that specific inhibitors significantly reduced the effect of activators of the two pathways. Stimulation of the PKA pathway did not affect, whereas stimulation of the PKC pathway significantly reduced MCF-7 cell proliferation in a time-dependent manner. A cell growth inhibitor, dexamethasone, at high concentrations, caused a 40% decrease in proliferation of MCF-7 cells and this effect was abolished under conditions of increased HSD11B2 expression. It was concluded that in MCF-7 cells, stimulation of the PKA signal transduction pathway results in the induction of HSD11B2 expression and that this effect is markedly reduced by activation of the PKC pathway. Activation of the PKC pathway also resulted in inhibition of cell proliferation, while activation of the PKA pathway abolished the antiproliferative effect of dexamethasone. These effects might be due to oxidation of dexamethasone by the PKA-inducible HSD11B2.
The present study was designed to identify the biological activity of three ecdysones, i.e., 20-h... more The present study was designed to identify the biological activity of three ecdysones, i.e., 20-hydroxyecdysone (20-HE), ajugasterone C, and polypodine B isolated from Serratula coronata. The main objective was to investigate the molecular mechanism of the biological activity of those compounds and to assess their impact on breast cancer cell survival and cell cycle. Cell lines were selected according to their hormone receptor status since this factor is perceived as a crucial one in the cancer prognosis as well as cancer cell response to therapy. Consequently, MCF7 (ER/PR+, HER2-), T-47D (ER/PR+, HER2-/+), and MDA-MB-231 (ER/PR-, HER2-) were enrolled in the study. Additionally, a non-tumorigenic, MCF10A cells were selected to verify any potential specificity to cancer cells. Interestingly, none of the studied compounds affected the viability of MCF10A cells while cancer cells were altered, albeit in different ways. Polypodine B did not affect the viability or cell cycle distribution of studied breast cancer cells. By contrast, 20-HE and ajugasterone C significantly inhibited the viability of triple-negative cell line, MDA-MB-231. Interestingly, 20-HE revealed proapoptotic activity in MDA-MB-231 and T-47D cells that was manifested by alterations in PARP, Bax, and Bcl-2 levels as well as caspase-3 activation. Moreover, 20-HE induced autophagy that was mediated by modification of autophagy-associated proteins, i.e., LC3, p62, and mTOR, but only in MDA-MB-231 cells. This study is the first to report diverse biological activity of phytoecdysones in different breast cancer cells, that suggests association with molecular characteristics including receptor status but also other biological properties and genetic markers.
Cellular and Molecular Life Sciences, Jun 16, 2017
It is well known that a decreased expression or inhibited activity of telomerase in cancer cells ... more It is well known that a decreased expression or inhibited activity of telomerase in cancer cells is accompanied by an increased sensitivity to some drugs (e.g., doxorubicin, cisplatin, or 5-fluorouracil). However, the mechanism of the resistance resulting from telomerase alteration remains elusive. There are theories claiming that it might be associated with telomere shortening, genome instability, hTERT translocation, mitochondria functioning modulation, or even alterations in ABC family gene expression. However, association of those mechanisms, i.e., drug resistance and telomerase alterations, is not fully understood yet. We review the current theories on the aspect of the role of telomerase in cancer cells resistance to therapy. We believe that revealing/unravelling this correlation might significantly contribute to an increased efficiency of cancer cells elimination, especially the most difficult ones, i.e., drug resistant.
International Journal of Molecular Sciences, Aug 12, 2021
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Telomerase has been recognized as a relevant factor distinguishing cancer cells from normal cells... more Telomerase has been recognized as a relevant factor distinguishing cancer cells from normal cells. Thus, it has become a very promising target for anticancer therapy. The cell proliferative potential can be limited by replication end problem, due to telomeres shortening, which is overcome in cancer cells by telomerase activity or by alternative telomeres lengthening (ALT) mechanism. However, this multisubunit enzymatic complex can be regulated at various levels, including expression control but also other factors contributing to the enzyme phosphorylation status, assembling or complex subunits transport. Thus, we show that the telomerase expression targeting cannot be the only possibility to shorten telomeres and induce cell apoptosis. It is important especially since the transcription expression is not always correlated with the enzyme activity which might result in transcription modulation failure or a possibility for the gene therapy to be overcome. This review summarizes the current state of knowledge of numerous telomerase regulation mechanisms that take place after telomerase subunits coding genes transcription. Thus we show the possible mechanisms of telomerase activity regulation which might become attractive anticancer therapy targets.
Każdego roku odnotowuje się 11 000 nowych przypadków zachorowań na raka piersi, a prawie połowa c... more Każdego roku odnotowuje się 11 000 nowych przypadków zachorowań na raka piersi, a prawie połowa chorych umiera. Tak wysoka umieralność może być spowodowana zbyt późnym rozpoznaniem choroby, brakiem specyficznych i skutecznych leków, a także wystąpieniem zjawiska oporności wielolekowej (multiple drug resistance-MDR) w komórkach nowotworowych. Podstawowym mechanizmem wywołującym to zjawisko jest nadekspresja i zwiększona aktywność transporterów błonowych, z których większość należy do nadrodziny transporterów ABC (ATP binding casette). Spośród tych białek najlepiej poznanym jest glikoproteina P, produkt ekspresji genu ABCB1, odpowiedzialna m.in. za usuwanie ksenobiotyków i leków poza obszar komórki. Szerokie spektrum substratowe glikoproteiny P obejmuje: ksenobiotyki oraz leki cytotoksyczne, inhibitory białek, immunosupresanty, steroidy, statyny, blokery kanału wapniowego, beta-blokery, leki antyhistaminowe, przeciwdepresyjne oraz przeciwwymiotne. W sekwencji genu ABCB1 opisano szereg polimorfizmów, spośród których największe znaczenie kliniczne mają trzy-zamiana cytozyny na tyminę w pozycji 1236 egzonu 12 (C1236T, rs1128503), zamiana w egzonie 21 G2677A/T (rs2032582) oraz w egzonie 26 C3435T (rs1045642). Występowanie tych polimorfizmów może wpływać na zmianę ekspresji genu ABCB1 (C3435T), strukturę glikoproteiny P (G2677T/A) czy zdolność wiązania się białka z substratem (C1236T). Jak się podejrzewa, obecność tych polimorfizmów może w efekcie modyfikować odpowiedź komórek nowotworowych na chemioterapię. Niniejsza praca opisuje modulujący wpływ polimorfizmów genu ABCB1 na odpowiedź komórek raka piersi na chemioterapię.
Bleomycin is a redox-active drug with anticancer and other clinical applications. It is also freq... more Bleomycin is a redox-active drug with anticancer and other clinical applications. It is also frequently used as a tool in fundamental research on cellular responses to DNA double-strand breaks (DSBs). A conversion of bleomycin into its DNA-breaking form requires Fe, one-electron donors and O 2. Here, we examined how a major biological antioxidant ascorbate (reduced vitamin C), which is practically absent in standard cell culture, impacts cellular responses to bleomycin. We found that restoration of physiological levels of vitamin C in human cancer cells increased their killing by bleomycin in 2D cultures and 3D tumor spheroids. Higher cytotoxicity of bleomycin occurred in cells with normal and shRNA-depleted p53. Cellular vitamin C enhanced the ability of bleomycin by produce DSBs, which was established by direct measurements of these lesions in three cell lines. Vitamin C-restored cancer cells also showed a higher sensitivity to killing by low-dose bleomycin in combination with inhibitors of DSB repair-activating ATM or DNA-PK kinases. The presence of ascorbate in bleomycin-treated cells suppressed a DSBindependent activation of the ATM-CHK2 axis by blocking superoxide radical. In vitro studies detected a greatly superior ability of ascorbate over other cellular reducers to catalyze DSB formation by bleomycin. Ascorbate was faster than other antioxidants in promoting two steps in activation of bleomycin. Our results demonstrate strong activation effects of vitamin C on bleomycin, shifting its toxicity further toward DNA damage and making it more sensitive to manipulations of DNA repair.
Journal Of Environmental Science And Health, Part A, Jan 29, 2010
Although the estrogenic properties of numerous chloroorganic pesticides have been widely recogniz... more Although the estrogenic properties of numerous chloroorganic pesticides have been widely recognized, population studies do not give clear results indicating the link between the exposure to these compounds and breast cancer development. Because of the weak affinity of these pesticides to estrogen receptors, they probably act by affecting the expression of CYP genes encoding cytochromes P450 engaged in the metabolism of environmental as well as natural estrogens. To examine the possible correlation between environmental estrogen levels in adipose tissue and breast cancer stage, grade, receptor status and onset of the disease, adipose tissue was isolated from 54 breast cancer patients and 23 healthy individuals. Clinical characteristics were obtained from the medical records, while the information concerning exposure to environmental estrogens where obtained from questionnaires. The environmental estrogens were identified and quantified by GC-chromatography. The data was analyzed with the use of Student t-test and Spearman correlation. The levels of most environmental estrogens did not differ between the patients and the controls, except the beta-HCH (beta-hexachlorocyclohexane) level, which was higher in the patients than in the healthy individuals. Significantly higher levels of DDE (1,1-bis(4-chlorophenyl)-2,2-dichloroethene) and DDT (1,1,1-trichloro-2,2-bis(4-chlorophenol)ethane) (P < 0.05) were observed in the patients with late onset of the disease which was probably due to the time of exposure. Moreover, in the patients exposed to environmental estrogens, significantly higher concentrations of DDD (1,1-bis(4-chlorophenyl)-2,2-dichloroethane) were found (P < 0.05). We also evidenced that estrogen-independent cancer was more frequent in the patients exposed to numerous risk factors in which higher levels of HCB (hexachlorobenzene), gamma-HCH (gamma-hexachlorocyclohexane), DDD and DDT in adipose tissue were detected. Breast cancer development is probably related to the accumulation of DDT and its derivatives, but the effect appears only in older patients. We postulate that environmental estrogens acting together with other risk factors might influence the progress and exacerbate the prognosis of breast cancer.
Despite the growing interest by researchers into cellular senescence, a hallmark of cellular agin... more Despite the growing interest by researchers into cellular senescence, a hallmark of cellular aging, its role in human skin remains equivocal. The skin is the largest and most accessible human organ, reacting to the external and internal environment. Hence, it is an organ of choice to investigate cellular senescence and to target root‐cause aging processes using senolytic and senomorphic agents, including naturally occurring plant‐based derivatives. This review presents different aspects of skin cellular senescence, from physiology to pathology and signaling pathways. Cellular senescence can have both beneficial and detrimental effects on the skin, indicating that both prosenescent and antisenescent therapies may be desirable, based on the context. Knowledge of molecular mechanisms involved in skin cellular senescence may provide meaningful insights for developing effective therapeutics for senescence‐related skin disorders, such as wound healing and cosmetic skin aging changes.
Breast cancer is one of the most frequently observed malignancies worldwide and represents a hete... more Breast cancer is one of the most frequently observed malignancies worldwide and represents a heterogeneous group of cancers. For this reason, it is crucial to properly diagnose every single case so a specific and efficient therapy can be adjusted. One of the most critical diagnostic parameters evaluated in cancer tissue is the status of the estrogen receptor (ER) and epidermal growth factor receptor (EGFR). Interestingly, the expression of the indicated receptors may be used in a personalized therapy approach. Importantly, the promising role of phytochemicals in the modulation of pathways controlled by ER and EGFR was also demonstrated in several types of cancer. One such biologically active compound is oleanolic acid, but due to poor water solubility and cell membrane permeability that limits its use, alternative derivative compounds were developed. These are HIMOXOL and Br-HIMOLID, which were demonstrated to be capable of inducing apoptosis and autophagy or diminishing the migrato...
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Papers by Błażej Rubiś