Journal of Chromatography B Analytical Technologies in the Biomedical and Life Sciences, Sep 25, 2002
The high ingestion of soybean products in Asian countries has been suggested to be responsible fo... more The high ingestion of soybean products in Asian countries has been suggested to be responsible for a reduced incidence of prostate cancer. The mechanism of action, however, is unknown. Our data demonstrate that genistein and some isoflavone metabolites reduce the activity of 25-D3-24-hydroxylase (CYP24) in the human prostate cancer-derived cell line DU-145. CYP24 is also responsible for degradation of the active vitamin D metabolite 1,25-dihydroxyvitamin D3 which is known to be antimitotic and prodifferentiating in prostate cancer cells. High levels of CYP24 frequently found in prostate cancer cells may thus degrade the active metabolite. This could be prevented by ingestion of genistein-containing food such as soybeans.
In situ hybridization on human colon tissue demonstrates that epidermal growth factor receptor (E... more In situ hybridization on human colon tissue demonstrates that epidermal growth factor receptor (EGFR) mRNA expression is strongly increased during tumour progression. To obtain test systems to evaluate the relevance of growth factor action during carcinogenesis, primary cultures from human colorectal carcinomas were established. EGFR distribution was determined in 2 of the 27 primary cultures and was compared with that
The Journal of Steroid Biochemistry and Molecular Biology, 2003
In human prostate cancer cells, the availability of the steroid hormone 1,25-dihydroxyvitamin D 3... more In human prostate cancer cells, the availability of the steroid hormone 1,25-dihydroxyvitamin D 3 for antimitotic action is determined through the activity of the two enzymes CYP24 and CYP27B1, viz. 25-hydroxyvitamin D-24-hydroxylase and 25-hydroxyvitamin D-1␣-hydroxylase. High performance liquid chromatography (HPLC) analysis of [ 3 H]25(OH)D 3 metabolism in human prostate cancer DU-145 cells revealed that genistein and other isoflavonoids, such as dihydrogenistein and daidzein, as well as the antiestrogenic compound ICI 182,780, inhibited Vitamin D-metabolizing enzyme activities. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed that only in case of genistein this was due to transcriptional inhibition of CYP24 and CYP27B1 gene expressions. In case of CYP27B1, reduction of gene activity involves histone deacetylation because genistein was inactive in the presence of the histone deactylase inhibitor trichostatin A. In contrast, under the same condition, CYP24 gene activity was largely suppressed. In summary, our results suggest that a combined effect of genistein and trichostatin A could increase the responsiveness of human prostate cancer cells to the antiproliferative action of 1,25-dihydroxyvitamin D 3 .
The high ingestion of soybean products in Asian countries has been suggested to be responsible fo... more The high ingestion of soybean products in Asian countries has been suggested to be responsible for a reduced incidence of prostate cancer. The mechanism of action, however, is unknown. Our data demonstrate that genistein and some isoflavone metabolites reduce the activity of 25-D3-24-hydroxylase (CYP24) in the human prostate cancer-derived cell line DU-145. CYP24 is also responsible for degradation of the active vitamin D metabolite 1,25-dihydroxyvitamin D3 which is known to be antimitotic and prodifferentiating in prostate cancer cells. High levels of CYP24 frequently found in prostate cancer cells may thus degrade the active metabolite. This could be prevented by ingestion of genistein-containing food such as soybeans.
1,25 Dihydroxyvitamin D3 (1,25-D3) can be considered an antitumorigenic agent, which can be used ... more 1,25 Dihydroxyvitamin D3 (1,25-D3) can be considered an antitumorigenic agent, which can be used in the therapy of malignant diseases such as prostate cancer. In this respect, it is important to note that some prostatic cancer cells express high levels of CYP24, a cytochrome enzyme involved in degradation of 1,25-D3. Genistein, a widely occurring isoflavonoid, inhibits cytochrome enzymes and also exerts antitumorigenic effects. Here, we therefore investigated the effect of genistein on cytochrome enzymes involved in vitamin D metabolism. Treatment of DU-145 prostatic cancer cells with genistein led to a time- and dose-dependent inhibition of CYP24. Additionally CYP27B1 was also inhibited. CYP27B1 is the cytochrome enzyme that synthesizes 1,25-D3. RT-PCR showed that the effect of genistein was mainly due to inhibition of transcription. This often involves the activity of histone deacetylases (HDAC). Thus we tested if the HDAC inhibitor trichostatin A (TSA) reversed the effect of genistein on vitamin D hydroxylases. TSA per se reduced expression of CYP24 mRNA and synergized with genistein to abolish expression after an incubation of 24 h. Importantly, TSA, which itself did not affect CYP27B1 expression, rescued CYP27B1 from transcriptional inhibition by genistein. In conclusion, our data argue for the use of genistein to resensitize prostate cancer cells to 1,25-D3; the addition of TSA may preserve the ability of these cells to synthesize 1,25-D3.
We are writing to urge the IARC to reconsider its position regarding Working Group Report 5: Vita... more We are writing to urge the IARC to reconsider its position regarding Working Group Report 5: Vitamin D and Cancer. We appreciate the interest of IARC in the role of vitamin D in prevention of cancer. In our view, however, this report is not a satisfactory analysis of the evidence that vitamin D reduces the risk of cancer incidence and mortality rates. The approach and conclusions of the report are not consistent with expert opinion in the field and so the report is not an adequate or fair assessment of the scientific evidence. Major progress has been made in the field of vitamin D and chronic disease but this report fails to report this in a constructive way. We would suggest that you need urgent action to re-assess the field with a more thoroughly researched, better-anchored report which provides the views of established experts in the field. A detailed commentary on numerous errors and omissions in the Report has been published 2 along with a critical editorial commentary concerning flaws in the report. Some of the serious problems with the Report include: -It treated the Lappe et al. 4 randomized controlled trial as incidental rather than pivotal in excluding confounding, and ignored the finding that 1,100 IU/day of vitamin D between the ends of the first and fourth years was associated with a 35% reduction in allcancer incidence. One of the comments in the 2008 IARC Report, that cancer incidence was unusually high in the Lappe et al. placebo group, can easily be shown to be incorrect by calculating the cancer incidence rate from publically available data for that age group and location. 2 -It treated the Women's Health Initiative (WHI) reports, with their use of a minimal 400 IU dose and extensive noncompli-ance, as valid aspects of the evidence. However, it was shown in 2004 that such low doses have no preventive value for colorectal cancer. 5 Nonetheless, participants in the WHI study who had serum 25-hydroxyvitamin D [25(OH)D] levels <12 ng/ml at the beginning of the 8 year study had a 253% increased risk of colorectal cancer at the end of the study compared to women who had a 25(OH)D > 23 ng/ml. -The IARC report makes too little use of the results of distinguished cohort studies such as the Nurses' Health Study and the Male Health Professionals Study cohorts 7 and others. -The report did not make adequate use of the results of modern ecological studies, including studies that used multiple regression analysis to control for confounders. For example, one study of cancer mortality rates in the United States that included indices for numerous cancer risk-modifying factors (summertime solar ultraviolet-B, smoking, alcohol consumption, ethnic background, socioeconomic status, urban/rural residence) 10 was omitted from the IARC report, yet the report claimed that confounding factors were generally 'not included' in ecological studies. Solar UVB irradiance is the primary source of vitamin D for most people. Casual exposure to UVB in summer in the UK increases serum 25-hydroxyvitamin D levels by about 15 ng/mL (~38 nmol/l). 11 It has been established that +15 ng/mL would reduce the risk of colorectal cancer by about 25% 12 and that mortality rates for many types of cancer are inversely correlated with July solar UVB doses in the United States. The use of ecological studies to link solar UVB and vitamin D to cancer risk reduction is reviewed in two recent papers. 13,14 -There were no clearly stated criteria developed, a priori, upon which the committee was to evaluate the large and rapidly increasing literature on vitamin D and cancer. However, one recent report on risk factors for cancer did do so. In Box 3.8 of Food, Nutrition, Physical Activity, and the prevention of Cancer: a Global Perspective 15 the evidence was graded in five categories: 'convincing', 'probable', 'limited-suggestive', 'limited-no conclusion' and 'substantial effect on risk unlikely'.
Chick intestine maintained in organ culture at day 20 of embryonic life responds to appropriate d... more Chick intestine maintained in organ culture at day 20 of embryonic life responds to appropriate dose levels of 1,25dihydroxyvitamin D3 or vitamin D3 in the culture medium by stimulation of Na + -dependent uptake of inorganic phosphate (Pi) and D-glucose as well as by increased calcium absorption. The intensity of each single response to vitamin D varies along the small intestine: Only the jejunum shows high vitamin D increments of all three transport systems under investigation. Inhibition of vitamin D responses by actinomycin D suggests the involvement of gene activation in the sterol's action of raising intestinal transport activities. Determination of the developmental pattern of each vitamin D-dependent transport system showed that only calcium absorption could be induced in undifferentiated cells on day 15, while complete expression of vitamin D action, including elevation of Nadependent uptake of D-glucose and Pi, required a fairly advanced state of epithelial maturation and was thus not observed before the final day 20 of embryonic development. This indicates a progressive change of hormone sensitivity of absorptive cells during differentiation.
Epidemiologic studies suggest that nutritional phytoestrogens contained in soy are causally relat... more Epidemiologic studies suggest that nutritional phytoestrogens contained in soy are causally related to protection against hormone-dependent cancers. The incidence of colorectal cancer is at least 30% lower in women than in men in the United States. This suggests that estrogen and, conceivably, nutritional phytoestrogens are protective compounds against colorectal cancer for both sexes. Prevention of colorectal, mammary, and prostate cancer may also depend on optimal synthesis of the antimitotic prodifferentiating vitamin D hormonal metabolite 1,25-(OH) 2 -cholecalciferol (1,25-D3). Cytochrome-P450-hydroxylases responsible for synthesis (CYP27B1; 25-D3-1␣-hydroxylase) and catabolism (CYP24; 1,25-D3-24-hydroxylase) of 1,25-D3 are not only present in the kidney but are also expressed in human colonocytes, prostate cells, and mammary cells. In addition, levels of CYP27B1, vitamin D receptor, and estrogen receptor- (the high-affinity receptor for phytoestrogens) are enhanced early during human colorectal cancer, which suggests an interactive physiological defense against tumor progression. We demonstrate in human mammary and prostate cells concentration-dependent regulation of CYP27B1 and of CYP24 by genistein at 0.05-50 mol/L. The high concentration of 50 mol/L is very effective in eliminating CYP24 expression in prostate cancer cells. This high concentration can be achieved in vivo in the prostate by an as-yet-unknown concentrative mechanism. Soy feeding, or more effectively genistein feeding, elevates CYP27B1 and reduces CYP24 expression in the mouse colon. In mice fed low nutritional calcium, CYP24 rises in parallel to enhanced colonic proliferation, and genistein counteracts both. We suggest that nutritional soy or genistein can optimize extrarenal 1,25-D3 synthesis, which could result in growth control and, conceivably, in inhibition of tumor progression.
Sporadic colorectal cancer develops as a multistep process during decades of latency. Multiple fa... more Sporadic colorectal cancer develops as a multistep process during decades of latency. Multiple factors, in particular nutrition, influence progression. Both nutritional calcium and soy are known to reduce sporadic cancer incidence. Soy contains high levels of phytoestrogens. Among them genistein is recognized as an antioxidant and cell-cycle inhibitor.
Background: Epidemiology suggests that nutritional calcium and vitamin D together prevent colorec... more Background: Epidemiology suggests that nutritional calcium and vitamin D together prevent colorectal tumor progression. 1,25(OH) 2 D 3 is synthesized and degraded in colonocytes and, when bound to its receptor, has antiproliferative activity. Materials and Methods: 1,25(OH) 2 D 3 levels have been successfully measured in cell culture, but this is technically difficult in tissues. Double extraction coupled to an enzyme immunoassay was used to determine 1,25(OH) 2 D 3 concentration in colon mucosa. Results: In a mouse model fed low (0.04% ) nutritional calcium, expression of the vitamin D catabolizing CYP24A1, of the synthesizing CYP27B1 hydroxylase and of the vitamin D receptor was induced in the right colon only. While CYP24A1 mRNA was raised in both genders, raised CYP27B1 and VDR was found in females only. Levels of 1,25(OH) 2 D 3 were significantly higher in the right colon of females fed 0.04% calcium compared with the control group on 0.9% calcium, and with males fed either diet. Parallel to increased 1,25(OH) 2 D 3 , the intrinsic apoptotic pathway was enhanced in the right colon of females only. Conclusion: This demonstrates the significance of high nutritional calcium for colonic accumulation of 1,25(OH) 2 D 3 and suggests that female sex hormones may protect against mitotic action of low nutritional calcium by inducing 1,25(OH) 2 D 3 synthesis.
There is growing evidence that vitamin D exerts anticarcinogenic effects. Ultraviolet-B (UV-B) ra... more There is growing evidence that vitamin D exerts anticarcinogenic effects. Ultraviolet-B (UV-B) radiation, which is required for vitamin D production in the skin, was found to be inversely associated with cancer incidence and mortality. Recent studies have largely but not consistently shown that low 25-hydroxyvitamin D (25(OH)D) levels, which are considered to be the best indicator of vitamin D status, are a significant risk factor for cancer mortality. Circulating 25(OH)D levels were also associated with improved survival in colorectal and lung cancer patients and vitamin D insufficiency was observed in various other diseases such as autoimmune, infectious, musculoskeletal, neurological and cardiovascular diseases. In conclusion, we still need further studies to evaluate the association of vitamin D insufficiency and cancer incidence and mortality, but the multiple health benefits of vitamin D and the easy, safe and inexpensive way by which vitamin D can be supplemented should already guide current public health strategies to achieve 25(OH)D levels of at least 75 nmol/l (30 ng/ml) in the general population.
Although embryonic chick small intestinal segments provide a very limited amount of tissue for pr... more Although embryonic chick small intestinal segments provide a very limited amount of tissue for preparation of enterocyte brush border membrane vesicles (BBMV), we were able to develop a procedure for isolation of BBMV from cultured 20-d-old embryonic chick jejunum in high yield by modifying a divalent cation precipitation method. Total yield of the brush border marker enzyme alkaline phosphatase in the vesicle fraction as compared to the crude homogenate was approximately 40%, and the specific activity of the enzyme was increased 25-fold on the average. The brush border membrane vesicle fraction was only contaminated with other cellular organelles (basolateral membranes, mitochondria, lysosomes or endoplasmic reticulum) to a minor extent. Functional integrity of the brush border vesicles was indicated by Na+ gradient-driven electrogenic D-glucose transport leading to concentrative transfer (overshoot) of the sugar into an osmotically active intravesicular space. When jejuna were cul...
Journal of Chromatography B Analytical Technologies in the Biomedical and Life Sciences, Sep 25, 2002
The high ingestion of soybean products in Asian countries has been suggested to be responsible fo... more The high ingestion of soybean products in Asian countries has been suggested to be responsible for a reduced incidence of prostate cancer. The mechanism of action, however, is unknown. Our data demonstrate that genistein and some isoflavone metabolites reduce the activity of 25-D3-24-hydroxylase (CYP24) in the human prostate cancer-derived cell line DU-145. CYP24 is also responsible for degradation of the active vitamin D metabolite 1,25-dihydroxyvitamin D3 which is known to be antimitotic and prodifferentiating in prostate cancer cells. High levels of CYP24 frequently found in prostate cancer cells may thus degrade the active metabolite. This could be prevented by ingestion of genistein-containing food such as soybeans.
In situ hybridization on human colon tissue demonstrates that epidermal growth factor receptor (E... more In situ hybridization on human colon tissue demonstrates that epidermal growth factor receptor (EGFR) mRNA expression is strongly increased during tumour progression. To obtain test systems to evaluate the relevance of growth factor action during carcinogenesis, primary cultures from human colorectal carcinomas were established. EGFR distribution was determined in 2 of the 27 primary cultures and was compared with that
The Journal of Steroid Biochemistry and Molecular Biology, 2003
In human prostate cancer cells, the availability of the steroid hormone 1,25-dihydroxyvitamin D 3... more In human prostate cancer cells, the availability of the steroid hormone 1,25-dihydroxyvitamin D 3 for antimitotic action is determined through the activity of the two enzymes CYP24 and CYP27B1, viz. 25-hydroxyvitamin D-24-hydroxylase and 25-hydroxyvitamin D-1␣-hydroxylase. High performance liquid chromatography (HPLC) analysis of [ 3 H]25(OH)D 3 metabolism in human prostate cancer DU-145 cells revealed that genistein and other isoflavonoids, such as dihydrogenistein and daidzein, as well as the antiestrogenic compound ICI 182,780, inhibited Vitamin D-metabolizing enzyme activities. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed that only in case of genistein this was due to transcriptional inhibition of CYP24 and CYP27B1 gene expressions. In case of CYP27B1, reduction of gene activity involves histone deacetylation because genistein was inactive in the presence of the histone deactylase inhibitor trichostatin A. In contrast, under the same condition, CYP24 gene activity was largely suppressed. In summary, our results suggest that a combined effect of genistein and trichostatin A could increase the responsiveness of human prostate cancer cells to the antiproliferative action of 1,25-dihydroxyvitamin D 3 .
The high ingestion of soybean products in Asian countries has been suggested to be responsible fo... more The high ingestion of soybean products in Asian countries has been suggested to be responsible for a reduced incidence of prostate cancer. The mechanism of action, however, is unknown. Our data demonstrate that genistein and some isoflavone metabolites reduce the activity of 25-D3-24-hydroxylase (CYP24) in the human prostate cancer-derived cell line DU-145. CYP24 is also responsible for degradation of the active vitamin D metabolite 1,25-dihydroxyvitamin D3 which is known to be antimitotic and prodifferentiating in prostate cancer cells. High levels of CYP24 frequently found in prostate cancer cells may thus degrade the active metabolite. This could be prevented by ingestion of genistein-containing food such as soybeans.
1,25 Dihydroxyvitamin D3 (1,25-D3) can be considered an antitumorigenic agent, which can be used ... more 1,25 Dihydroxyvitamin D3 (1,25-D3) can be considered an antitumorigenic agent, which can be used in the therapy of malignant diseases such as prostate cancer. In this respect, it is important to note that some prostatic cancer cells express high levels of CYP24, a cytochrome enzyme involved in degradation of 1,25-D3. Genistein, a widely occurring isoflavonoid, inhibits cytochrome enzymes and also exerts antitumorigenic effects. Here, we therefore investigated the effect of genistein on cytochrome enzymes involved in vitamin D metabolism. Treatment of DU-145 prostatic cancer cells with genistein led to a time- and dose-dependent inhibition of CYP24. Additionally CYP27B1 was also inhibited. CYP27B1 is the cytochrome enzyme that synthesizes 1,25-D3. RT-PCR showed that the effect of genistein was mainly due to inhibition of transcription. This often involves the activity of histone deacetylases (HDAC). Thus we tested if the HDAC inhibitor trichostatin A (TSA) reversed the effect of genistein on vitamin D hydroxylases. TSA per se reduced expression of CYP24 mRNA and synergized with genistein to abolish expression after an incubation of 24 h. Importantly, TSA, which itself did not affect CYP27B1 expression, rescued CYP27B1 from transcriptional inhibition by genistein. In conclusion, our data argue for the use of genistein to resensitize prostate cancer cells to 1,25-D3; the addition of TSA may preserve the ability of these cells to synthesize 1,25-D3.
We are writing to urge the IARC to reconsider its position regarding Working Group Report 5: Vita... more We are writing to urge the IARC to reconsider its position regarding Working Group Report 5: Vitamin D and Cancer. We appreciate the interest of IARC in the role of vitamin D in prevention of cancer. In our view, however, this report is not a satisfactory analysis of the evidence that vitamin D reduces the risk of cancer incidence and mortality rates. The approach and conclusions of the report are not consistent with expert opinion in the field and so the report is not an adequate or fair assessment of the scientific evidence. Major progress has been made in the field of vitamin D and chronic disease but this report fails to report this in a constructive way. We would suggest that you need urgent action to re-assess the field with a more thoroughly researched, better-anchored report which provides the views of established experts in the field. A detailed commentary on numerous errors and omissions in the Report has been published 2 along with a critical editorial commentary concerning flaws in the report. Some of the serious problems with the Report include: -It treated the Lappe et al. 4 randomized controlled trial as incidental rather than pivotal in excluding confounding, and ignored the finding that 1,100 IU/day of vitamin D between the ends of the first and fourth years was associated with a 35% reduction in allcancer incidence. One of the comments in the 2008 IARC Report, that cancer incidence was unusually high in the Lappe et al. placebo group, can easily be shown to be incorrect by calculating the cancer incidence rate from publically available data for that age group and location. 2 -It treated the Women's Health Initiative (WHI) reports, with their use of a minimal 400 IU dose and extensive noncompli-ance, as valid aspects of the evidence. However, it was shown in 2004 that such low doses have no preventive value for colorectal cancer. 5 Nonetheless, participants in the WHI study who had serum 25-hydroxyvitamin D [25(OH)D] levels <12 ng/ml at the beginning of the 8 year study had a 253% increased risk of colorectal cancer at the end of the study compared to women who had a 25(OH)D > 23 ng/ml. -The IARC report makes too little use of the results of distinguished cohort studies such as the Nurses' Health Study and the Male Health Professionals Study cohorts 7 and others. -The report did not make adequate use of the results of modern ecological studies, including studies that used multiple regression analysis to control for confounders. For example, one study of cancer mortality rates in the United States that included indices for numerous cancer risk-modifying factors (summertime solar ultraviolet-B, smoking, alcohol consumption, ethnic background, socioeconomic status, urban/rural residence) 10 was omitted from the IARC report, yet the report claimed that confounding factors were generally 'not included' in ecological studies. Solar UVB irradiance is the primary source of vitamin D for most people. Casual exposure to UVB in summer in the UK increases serum 25-hydroxyvitamin D levels by about 15 ng/mL (~38 nmol/l). 11 It has been established that +15 ng/mL would reduce the risk of colorectal cancer by about 25% 12 and that mortality rates for many types of cancer are inversely correlated with July solar UVB doses in the United States. The use of ecological studies to link solar UVB and vitamin D to cancer risk reduction is reviewed in two recent papers. 13,14 -There were no clearly stated criteria developed, a priori, upon which the committee was to evaluate the large and rapidly increasing literature on vitamin D and cancer. However, one recent report on risk factors for cancer did do so. In Box 3.8 of Food, Nutrition, Physical Activity, and the prevention of Cancer: a Global Perspective 15 the evidence was graded in five categories: 'convincing', 'probable', 'limited-suggestive', 'limited-no conclusion' and 'substantial effect on risk unlikely'.
Chick intestine maintained in organ culture at day 20 of embryonic life responds to appropriate d... more Chick intestine maintained in organ culture at day 20 of embryonic life responds to appropriate dose levels of 1,25dihydroxyvitamin D3 or vitamin D3 in the culture medium by stimulation of Na + -dependent uptake of inorganic phosphate (Pi) and D-glucose as well as by increased calcium absorption. The intensity of each single response to vitamin D varies along the small intestine: Only the jejunum shows high vitamin D increments of all three transport systems under investigation. Inhibition of vitamin D responses by actinomycin D suggests the involvement of gene activation in the sterol's action of raising intestinal transport activities. Determination of the developmental pattern of each vitamin D-dependent transport system showed that only calcium absorption could be induced in undifferentiated cells on day 15, while complete expression of vitamin D action, including elevation of Nadependent uptake of D-glucose and Pi, required a fairly advanced state of epithelial maturation and was thus not observed before the final day 20 of embryonic development. This indicates a progressive change of hormone sensitivity of absorptive cells during differentiation.
Epidemiologic studies suggest that nutritional phytoestrogens contained in soy are causally relat... more Epidemiologic studies suggest that nutritional phytoestrogens contained in soy are causally related to protection against hormone-dependent cancers. The incidence of colorectal cancer is at least 30% lower in women than in men in the United States. This suggests that estrogen and, conceivably, nutritional phytoestrogens are protective compounds against colorectal cancer for both sexes. Prevention of colorectal, mammary, and prostate cancer may also depend on optimal synthesis of the antimitotic prodifferentiating vitamin D hormonal metabolite 1,25-(OH) 2 -cholecalciferol (1,25-D3). Cytochrome-P450-hydroxylases responsible for synthesis (CYP27B1; 25-D3-1␣-hydroxylase) and catabolism (CYP24; 1,25-D3-24-hydroxylase) of 1,25-D3 are not only present in the kidney but are also expressed in human colonocytes, prostate cells, and mammary cells. In addition, levels of CYP27B1, vitamin D receptor, and estrogen receptor- (the high-affinity receptor for phytoestrogens) are enhanced early during human colorectal cancer, which suggests an interactive physiological defense against tumor progression. We demonstrate in human mammary and prostate cells concentration-dependent regulation of CYP27B1 and of CYP24 by genistein at 0.05-50 mol/L. The high concentration of 50 mol/L is very effective in eliminating CYP24 expression in prostate cancer cells. This high concentration can be achieved in vivo in the prostate by an as-yet-unknown concentrative mechanism. Soy feeding, or more effectively genistein feeding, elevates CYP27B1 and reduces CYP24 expression in the mouse colon. In mice fed low nutritional calcium, CYP24 rises in parallel to enhanced colonic proliferation, and genistein counteracts both. We suggest that nutritional soy or genistein can optimize extrarenal 1,25-D3 synthesis, which could result in growth control and, conceivably, in inhibition of tumor progression.
Sporadic colorectal cancer develops as a multistep process during decades of latency. Multiple fa... more Sporadic colorectal cancer develops as a multistep process during decades of latency. Multiple factors, in particular nutrition, influence progression. Both nutritional calcium and soy are known to reduce sporadic cancer incidence. Soy contains high levels of phytoestrogens. Among them genistein is recognized as an antioxidant and cell-cycle inhibitor.
Background: Epidemiology suggests that nutritional calcium and vitamin D together prevent colorec... more Background: Epidemiology suggests that nutritional calcium and vitamin D together prevent colorectal tumor progression. 1,25(OH) 2 D 3 is synthesized and degraded in colonocytes and, when bound to its receptor, has antiproliferative activity. Materials and Methods: 1,25(OH) 2 D 3 levels have been successfully measured in cell culture, but this is technically difficult in tissues. Double extraction coupled to an enzyme immunoassay was used to determine 1,25(OH) 2 D 3 concentration in colon mucosa. Results: In a mouse model fed low (0.04% ) nutritional calcium, expression of the vitamin D catabolizing CYP24A1, of the synthesizing CYP27B1 hydroxylase and of the vitamin D receptor was induced in the right colon only. While CYP24A1 mRNA was raised in both genders, raised CYP27B1 and VDR was found in females only. Levels of 1,25(OH) 2 D 3 were significantly higher in the right colon of females fed 0.04% calcium compared with the control group on 0.9% calcium, and with males fed either diet. Parallel to increased 1,25(OH) 2 D 3 , the intrinsic apoptotic pathway was enhanced in the right colon of females only. Conclusion: This demonstrates the significance of high nutritional calcium for colonic accumulation of 1,25(OH) 2 D 3 and suggests that female sex hormones may protect against mitotic action of low nutritional calcium by inducing 1,25(OH) 2 D 3 synthesis.
There is growing evidence that vitamin D exerts anticarcinogenic effects. Ultraviolet-B (UV-B) ra... more There is growing evidence that vitamin D exerts anticarcinogenic effects. Ultraviolet-B (UV-B) radiation, which is required for vitamin D production in the skin, was found to be inversely associated with cancer incidence and mortality. Recent studies have largely but not consistently shown that low 25-hydroxyvitamin D (25(OH)D) levels, which are considered to be the best indicator of vitamin D status, are a significant risk factor for cancer mortality. Circulating 25(OH)D levels were also associated with improved survival in colorectal and lung cancer patients and vitamin D insufficiency was observed in various other diseases such as autoimmune, infectious, musculoskeletal, neurological and cardiovascular diseases. In conclusion, we still need further studies to evaluate the association of vitamin D insufficiency and cancer incidence and mortality, but the multiple health benefits of vitamin D and the easy, safe and inexpensive way by which vitamin D can be supplemented should already guide current public health strategies to achieve 25(OH)D levels of at least 75 nmol/l (30 ng/ml) in the general population.
Although embryonic chick small intestinal segments provide a very limited amount of tissue for pr... more Although embryonic chick small intestinal segments provide a very limited amount of tissue for preparation of enterocyte brush border membrane vesicles (BBMV), we were able to develop a procedure for isolation of BBMV from cultured 20-d-old embryonic chick jejunum in high yield by modifying a divalent cation precipitation method. Total yield of the brush border marker enzyme alkaline phosphatase in the vesicle fraction as compared to the crude homogenate was approximately 40%, and the specific activity of the enzyme was increased 25-fold on the average. The brush border membrane vesicle fraction was only contaminated with other cellular organelles (basolateral membranes, mitochondria, lysosomes or endoplasmic reticulum) to a minor extent. Functional integrity of the brush border vesicles was indicated by Na+ gradient-driven electrogenic D-glucose transport leading to concentrative transfer (overshoot) of the sugar into an osmotically active intravesicular space. When jejuna were cul...
Uploads
Papers by Heide Cross