Journal of biochemical and molecular toxicology, 2018
The objective of the present study was to characterize the role of novel resveratrol (Res) analog... more The objective of the present study was to characterize the role of novel resveratrol (Res) analogs: 4-(E)-{(4-hydroxyphenylimino)-methylbenzene, 1, 2-diol} (HPIMBD) and 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) as potent antioxidants against breast cancer. Non-neoplastic breast epithelial cell lines MCF-10A and MCF-10F were treated with 17β-estradiol (E2), Res, HPIMBD, and TIMBD for up to 72 h. mRNA and protein levels of antioxidant genes, superoxide dismutase 3 (SOD3) and N-quinoneoxidoreductase-1 (NQO1) and transcription factors, nuclear factor erythroid 2-related factor (Nrf) 1, 2 and 3 were quantified after the above treatments. Generation of reactive oxygen species (ROS) was measured by CM-H2-DCFDA and oxidative-DNA damage was determined by measuring 8-hydroxy-2-deoxyguanosine (8-OHdG). HPIMBD and TIMBD scavenged cellular ROS production, attenuated oxidative DNA damage, increased mRNA and protein expression levels of SOD3 and NQO1 and activated Nrf signaling pathway...
Breast cancer is a public health concern worldwide. Prolonged exposure to estrogens has been impl... more Breast cancer is a public health concern worldwide. Prolonged exposure to estrogens has been implicated in the development of breast neoplasms. Epidemiologic and experimental evidence suggest a chemopreventive role of phytoestrogens in breast cancers. Resveratrol, a naturally occurring phytoestrogen, has been shown to have potent anti-cancer properties. However, poor efficacy and bioavailability have prevented the use of resveratrol in clinics. In order to address these problems, we have synthesized a combinatorial library of azaresveratrol analogs and tested them for their ability to inhibit the proliferation of breast cancer cells. We have recently shown that 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD), has better anti-cancer properties than resveratrol and any other resveratrol analog we have synthesized so far. The objective of this study was to investigate the regulation of estrogen receptors (ERs) α and β by TIMBD in breast cancer cell lines. We demonstrate that TIMB...
Epithelial-mesenchymal transition (EMT) is a biological process that mediates a phenotypical chan... more Epithelial-mesenchymal transition (EMT) is a biological process that mediates a phenotypical change in the polarized epithelial cells to mesenchymal cells. The process of EMT increases a cell's migratory and invasive properties. It is well documented that the process of EMT plays a very critical role in cancer metastasis. The objective of this study was to characterize the role of a novel Resveratrol analog 4-(E)-{4-hydroxyphenylimino)-methylbenzene, 1,2-diol} (HPIMBD) on EMT in human breast cancer cells. Human breast cancer cells MDA-MB-231 were treated with Resveratrol (Res) and HPIMBD for up to 48 hours. Protein expression levels of E-cadherin, matrix metalloproteases (MMPs), snail, slug, zeb1/2 and nuclear migration of β-catenin were quantified after treatment with Res or HPIMBD and compared with that of the vehicle-treated control cells. mRNA expression levels of β-catenin and wnt-7b were also quantified. Migration MDA-MB-231 cells was determined after treatment with Res or...
Evidence from epidemiological and experimental studies suggest an association between diets rich ... more Evidence from epidemiological and experimental studies suggest an association between diets rich in phytoestrogens and reduced risk of breast cancer. Resveratrol, a bioflavonoid, found naturally in grapes, fruits and nuts, has been shown to be a potent chemopreventive agent in vitro. However, poor bioavailability, rapid metabolism and poor specificity limit its use as the preferred anticancer agent. In an attempt to improve the anticancer properties of resveratrol, we synthesized several analogs of resveratrol with appropriate chemical modifications. Of the compounds that were screened for anticancer activity towards breast cancer cells, two analogs, namely, HPIMBD and TIMBD showed better potency and selectivity in inhibiting the growth of breast cancer cell lines while they did not significantly affect the growth of non-neoplastic breast epithelial cell lines. In this study, we investigated the ability of resveratrol and resveratrol analogs in the regulation of estrogen metabolizin...
Epidemiological data and studies in rodent models strongly support the role of estrogens in the d... more Epidemiological data and studies in rodent models strongly support the role of estrogens in the development of breast cancers. Exact mechanisms underlying the initiation and progression of estrogen-related cancers are not clear. Literature evidence and our studies strongly support the role of estrogen metabolism mediated oxidative stress in estrogen-induced breast carcinogenesis. We have recently demonstrated that antioxidants vitamin C (VC) or butylated hydroxyanisole (BHA) severely inhibit 17β-estradiol (E2)-induced breast tumor development in female ACI rats. The objective of this study was to characterize the role of CNC b-zip transcription factors in antioxidant-mediated prevention of breast cancer. Human non-neoplastic breast epithelial cell line MCF-10A was treated with E2, VC, VC + E2, Resveratrol (Res) and Res + E2 for up to 72 hrs. mRNA and protein expression levels of phase-II detoxifying enzymes SOD1, SOD2, SOD3, GPx, NQO1 and transcription factors from CNC b-zip family:...
Tamoxifen is currently the first line of therapy against estrogen receptor (ER)-positive breast c... more Tamoxifen is currently the first line of therapy against estrogen receptor (ER)-positive breast cancers. Prolonged treatment with tamoxifen has been associated with the development of resistant tumor phenotypes. Moreover, this treatment strategy is ineffective against ER-negative breast cancers. In this study, we have investigated the role of 4-(E)-{(4-hydroxyphenylimino)-methylbenzene, 1,2-diol} (HPIMBD), a novel analog of resveratrol, either alone or in combination with tamoxifen on the growth inhibition of breast cancer cells. Breast cancer cell lines MCF-7, T47D, MDA-MB-231 and MDA-MB-468 as well as non-neoplastic breast epithelial cell lines MCF-10A, MCF-10F and HMEC were treated with different doses of HPIMBD or a combination of tamoxifen (2µM) and HPIMBD (at its IC50 dose). Cell proliferation was determined by MTT assays. No effect on cell proliferation was observed upon treatment of non-neoplastic breast cells with HPIMBD. A dose dependent growth inhibition was demonstrated ...
The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induc... more The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induced oxidative stress has been implicated in this carcinogenic process. Resveratrol, a natural antioxidant phytoestrogen has chemopreventive effects against a variety of illnesses including cancer. The objective of the present study was to characterize the mechanism of resveratrol-mediated protection against estrogen-induced breast carcinogenesis. Female ACI rats were treated with 17β-estradiol (E2), resveratrol, and resveratrol + E2 for 8 months. Co-treatment of rats with resveratrol + E2 significantly increased tumor latency and reduced E2-induced breast tumor development. Resveratrol treatment upregulated nuclear factor erythroid 2-related factor 2 (NRF2) expression and inhibited E2-mediated changes in activities of antioxidant enzymes in the mammary tissues. Resveratrol upregulated NRF2-regulated antioxidant genes NQO1, SOD3, and OGG1 a gene involved in protection against oxidative DNA...
Resveratrol (Res) (3, 5, 4’-trihydroxystilbene) is a well known naturally occurring polyphenol th... more Resveratrol (Res) (3, 5, 4’-trihydroxystilbene) is a well known naturally occurring polyphenol that exhibits anti-tumor activity. However, its poor bioavailability and rapid metabolism limits its use as a preferred anticancer agent. In an attempt to improve the bioavailability and anticancer potential of Res, we have synthesized five new Res analogs. We then tested the ability of these analogs to inhibit the proliferation of 5 breast cancer cell lines and 3 non-neoplastic breast epithelial cell lines and compared their inhibition potential with Res. MTT assay for cell proliferation was carried out in human breast cancer and non-neoplastic breast epithelial cell lines. The breast cancer cell lines tested were MCF-7, T47D, MDA-MB-231, MDA-MB-468 and BT-20. The non-neoplastic breast cell lines tested were MCF-10A, MCF-10F and HMLE. Of all the analogs tested, one namely ARSHA showed higher potency for inhibiting the proliferation of breast cancer cells compared to Res. Furthermore, ARSH...
Journal of biochemical and molecular toxicology, 2014
The objective of the present study was to characterize the role of resveratrol (Res) and vitamin ... more The objective of the present study was to characterize the role of resveratrol (Res) and vitamin C (VC) in prevention of estrogen-induced breast cancer through regulation of cap "n"collar (CNC) b-zip transcription factors. Human breast epithelial cell line MCF-10A was treated with 17β-estradiol (E2) and VC or Res with or without E2. mRNA and protein expression levels of CNC b-zip transcription factors nuclear factor erythroid 2-related factor 1 (Nrf1), nuclear factor erythroid 2 related factor 2 (Nrf2), nuclear factor erythroid 2 related factor 3 (Nrf3), and Nrf2-regulated antioxidant enzymes superoxide dismutase 3 (SOD3) and quinone oxidoreductase 1 (NQO1) were quantified. The treatment with E2 suppressed, whereas VC and Res prevented E2-mediated decrease in the expression levels of SOD3, NQO1, Nrf2 mRNA, and protein in MCF-10A cells. The treatment with E2, Res, or VC significantly increased mRNA and protein expression levels of Nrf1. 17β-Estradiol treatment significantly...
Epidemiologic evidence suggests that diets rich in phytoestrogens are associated with a reduced r... more Epidemiologic evidence suggests that diets rich in phytoestrogens are associated with a reduced risk of breast cancer. Resveratrol, a bioflavonoid found naturally in grapes, has been very effective as an antiproliferative agent in vitro. However, its poor bioavailability and rapid metabolism limits its use as a preferred anticancer agent. The problem of poor bioavailability of resveratrol can be solved by the synthesis of its analogs with appropriate chemical modifications that would enhance the stability and anticancer potency of resveratrol. To achieve this objective, we have synthesized a library of resveratrol analogs that resemble the basic skeleton of resveratrol but have structural modifications. These novel analogs were screened for their potential to inhibit growth of breast cancer cells. One analog, namely, ARSHA showed better potential and selectivity in inhibiting the proliferation of breast cancer cells. Our next goal was to identify the mechanism by which ARSHA specifi...
Background Estrogen metabolism-mediated oxidative stress is suggested to play an important role i... more Background Estrogen metabolism-mediated oxidative stress is suggested to play an important role in estrogen-induced breast carcinogenesis. We have earlier demonstrated that antioxidants, vitamin C (Vit C) and butylated hydroxyanisole (BHA) inhibit 17β-estradiol (E2)-mediated oxidative stress and oxidative DNA damage, and breast carcinogenesis in female August Copenhagen Irish (ACI) rats. The objective of the present study was to characterize the mechanism by which above antioxidants prevent DNA damage during breast carcinogenesis. Methods Female ACI rats were treated with E2; Vit C; Vit C + E2; BHA; and BHA + E2 for up to 240 days. mRNA and protein levels of a DNA repair enzyme 8-Oxoguanine DNA glycosylase (OGG1) and a transcription factor NRF2 were quantified in the mammary and mammary tumor tissues of rats after treatment with E2 and compared with that of rats treated with antioxidants either alone or in combination with E2. Results The expression of OGG1 was suppressed in mammary...
The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induc... more The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induced oxidative stress has been implicated in this carcinogenic process. Resveratrol (Res), a natural antioxidant phytoestrogen has chemopreventive effects against a variety of illnesses including cancer. The objective of the present study was to characterize the mechanism(s) of Res-mediated protection against estrogen-induced breast carcinogenesis. Female August Copenhagen Irish rats were treated with 17β-estradiol (E2), Res and Res + E2 for 8 months. Cotreatment of rats with Res and E2 inhibited E2-mediated proliferative changes in mammary tissues and significantly increased tumor latency and reduced E2-induced breast tumor development. Resveratrol treatment alone or in combination with E2 significantly upregulated expression of nuclear factor erythroid 2-related factor 2 (NRF2) in mammary tissues. Expression of NRF2-regulated antioxidant genes NQO1, SOD3 and OGG1 that are involved in pro...
Journal of biochemical and molecular toxicology, 2018
The objective of the present study was to characterize the role of novel resveratrol (Res) analog... more The objective of the present study was to characterize the role of novel resveratrol (Res) analogs: 4-(E)-{(4-hydroxyphenylimino)-methylbenzene, 1, 2-diol} (HPIMBD) and 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) as potent antioxidants against breast cancer. Non-neoplastic breast epithelial cell lines MCF-10A and MCF-10F were treated with 17β-estradiol (E2), Res, HPIMBD, and TIMBD for up to 72 h. mRNA and protein levels of antioxidant genes, superoxide dismutase 3 (SOD3) and N-quinoneoxidoreductase-1 (NQO1) and transcription factors, nuclear factor erythroid 2-related factor (Nrf) 1, 2 and 3 were quantified after the above treatments. Generation of reactive oxygen species (ROS) was measured by CM-H2-DCFDA and oxidative-DNA damage was determined by measuring 8-hydroxy-2-deoxyguanosine (8-OHdG). HPIMBD and TIMBD scavenged cellular ROS production, attenuated oxidative DNA damage, increased mRNA and protein expression levels of SOD3 and NQO1 and activated Nrf signaling pathway...
Breast cancer is a public health concern worldwide. Prolonged exposure to estrogens has been impl... more Breast cancer is a public health concern worldwide. Prolonged exposure to estrogens has been implicated in the development of breast neoplasms. Epidemiologic and experimental evidence suggest a chemopreventive role of phytoestrogens in breast cancers. Resveratrol, a naturally occurring phytoestrogen, has been shown to have potent anti-cancer properties. However, poor efficacy and bioavailability have prevented the use of resveratrol in clinics. In order to address these problems, we have synthesized a combinatorial library of azaresveratrol analogs and tested them for their ability to inhibit the proliferation of breast cancer cells. We have recently shown that 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD), has better anti-cancer properties than resveratrol and any other resveratrol analog we have synthesized so far. The objective of this study was to investigate the regulation of estrogen receptors (ERs) α and β by TIMBD in breast cancer cell lines. We demonstrate that TIMB...
Epithelial-mesenchymal transition (EMT) is a biological process that mediates a phenotypical chan... more Epithelial-mesenchymal transition (EMT) is a biological process that mediates a phenotypical change in the polarized epithelial cells to mesenchymal cells. The process of EMT increases a cell's migratory and invasive properties. It is well documented that the process of EMT plays a very critical role in cancer metastasis. The objective of this study was to characterize the role of a novel Resveratrol analog 4-(E)-{4-hydroxyphenylimino)-methylbenzene, 1,2-diol} (HPIMBD) on EMT in human breast cancer cells. Human breast cancer cells MDA-MB-231 were treated with Resveratrol (Res) and HPIMBD for up to 48 hours. Protein expression levels of E-cadherin, matrix metalloproteases (MMPs), snail, slug, zeb1/2 and nuclear migration of β-catenin were quantified after treatment with Res or HPIMBD and compared with that of the vehicle-treated control cells. mRNA expression levels of β-catenin and wnt-7b were also quantified. Migration MDA-MB-231 cells was determined after treatment with Res or...
Evidence from epidemiological and experimental studies suggest an association between diets rich ... more Evidence from epidemiological and experimental studies suggest an association between diets rich in phytoestrogens and reduced risk of breast cancer. Resveratrol, a bioflavonoid, found naturally in grapes, fruits and nuts, has been shown to be a potent chemopreventive agent in vitro. However, poor bioavailability, rapid metabolism and poor specificity limit its use as the preferred anticancer agent. In an attempt to improve the anticancer properties of resveratrol, we synthesized several analogs of resveratrol with appropriate chemical modifications. Of the compounds that were screened for anticancer activity towards breast cancer cells, two analogs, namely, HPIMBD and TIMBD showed better potency and selectivity in inhibiting the growth of breast cancer cell lines while they did not significantly affect the growth of non-neoplastic breast epithelial cell lines. In this study, we investigated the ability of resveratrol and resveratrol analogs in the regulation of estrogen metabolizin...
Epidemiological data and studies in rodent models strongly support the role of estrogens in the d... more Epidemiological data and studies in rodent models strongly support the role of estrogens in the development of breast cancers. Exact mechanisms underlying the initiation and progression of estrogen-related cancers are not clear. Literature evidence and our studies strongly support the role of estrogen metabolism mediated oxidative stress in estrogen-induced breast carcinogenesis. We have recently demonstrated that antioxidants vitamin C (VC) or butylated hydroxyanisole (BHA) severely inhibit 17β-estradiol (E2)-induced breast tumor development in female ACI rats. The objective of this study was to characterize the role of CNC b-zip transcription factors in antioxidant-mediated prevention of breast cancer. Human non-neoplastic breast epithelial cell line MCF-10A was treated with E2, VC, VC + E2, Resveratrol (Res) and Res + E2 for up to 72 hrs. mRNA and protein expression levels of phase-II detoxifying enzymes SOD1, SOD2, SOD3, GPx, NQO1 and transcription factors from CNC b-zip family:...
Tamoxifen is currently the first line of therapy against estrogen receptor (ER)-positive breast c... more Tamoxifen is currently the first line of therapy against estrogen receptor (ER)-positive breast cancers. Prolonged treatment with tamoxifen has been associated with the development of resistant tumor phenotypes. Moreover, this treatment strategy is ineffective against ER-negative breast cancers. In this study, we have investigated the role of 4-(E)-{(4-hydroxyphenylimino)-methylbenzene, 1,2-diol} (HPIMBD), a novel analog of resveratrol, either alone or in combination with tamoxifen on the growth inhibition of breast cancer cells. Breast cancer cell lines MCF-7, T47D, MDA-MB-231 and MDA-MB-468 as well as non-neoplastic breast epithelial cell lines MCF-10A, MCF-10F and HMEC were treated with different doses of HPIMBD or a combination of tamoxifen (2µM) and HPIMBD (at its IC50 dose). Cell proliferation was determined by MTT assays. No effect on cell proliferation was observed upon treatment of non-neoplastic breast cells with HPIMBD. A dose dependent growth inhibition was demonstrated ...
The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induc... more The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induced oxidative stress has been implicated in this carcinogenic process. Resveratrol, a natural antioxidant phytoestrogen has chemopreventive effects against a variety of illnesses including cancer. The objective of the present study was to characterize the mechanism of resveratrol-mediated protection against estrogen-induced breast carcinogenesis. Female ACI rats were treated with 17β-estradiol (E2), resveratrol, and resveratrol + E2 for 8 months. Co-treatment of rats with resveratrol + E2 significantly increased tumor latency and reduced E2-induced breast tumor development. Resveratrol treatment upregulated nuclear factor erythroid 2-related factor 2 (NRF2) expression and inhibited E2-mediated changes in activities of antioxidant enzymes in the mammary tissues. Resveratrol upregulated NRF2-regulated antioxidant genes NQO1, SOD3, and OGG1 a gene involved in protection against oxidative DNA...
Resveratrol (Res) (3, 5, 4’-trihydroxystilbene) is a well known naturally occurring polyphenol th... more Resveratrol (Res) (3, 5, 4’-trihydroxystilbene) is a well known naturally occurring polyphenol that exhibits anti-tumor activity. However, its poor bioavailability and rapid metabolism limits its use as a preferred anticancer agent. In an attempt to improve the bioavailability and anticancer potential of Res, we have synthesized five new Res analogs. We then tested the ability of these analogs to inhibit the proliferation of 5 breast cancer cell lines and 3 non-neoplastic breast epithelial cell lines and compared their inhibition potential with Res. MTT assay for cell proliferation was carried out in human breast cancer and non-neoplastic breast epithelial cell lines. The breast cancer cell lines tested were MCF-7, T47D, MDA-MB-231, MDA-MB-468 and BT-20. The non-neoplastic breast cell lines tested were MCF-10A, MCF-10F and HMLE. Of all the analogs tested, one namely ARSHA showed higher potency for inhibiting the proliferation of breast cancer cells compared to Res. Furthermore, ARSH...
Journal of biochemical and molecular toxicology, 2014
The objective of the present study was to characterize the role of resveratrol (Res) and vitamin ... more The objective of the present study was to characterize the role of resveratrol (Res) and vitamin C (VC) in prevention of estrogen-induced breast cancer through regulation of cap "n"collar (CNC) b-zip transcription factors. Human breast epithelial cell line MCF-10A was treated with 17β-estradiol (E2) and VC or Res with or without E2. mRNA and protein expression levels of CNC b-zip transcription factors nuclear factor erythroid 2-related factor 1 (Nrf1), nuclear factor erythroid 2 related factor 2 (Nrf2), nuclear factor erythroid 2 related factor 3 (Nrf3), and Nrf2-regulated antioxidant enzymes superoxide dismutase 3 (SOD3) and quinone oxidoreductase 1 (NQO1) were quantified. The treatment with E2 suppressed, whereas VC and Res prevented E2-mediated decrease in the expression levels of SOD3, NQO1, Nrf2 mRNA, and protein in MCF-10A cells. The treatment with E2, Res, or VC significantly increased mRNA and protein expression levels of Nrf1. 17β-Estradiol treatment significantly...
Epidemiologic evidence suggests that diets rich in phytoestrogens are associated with a reduced r... more Epidemiologic evidence suggests that diets rich in phytoestrogens are associated with a reduced risk of breast cancer. Resveratrol, a bioflavonoid found naturally in grapes, has been very effective as an antiproliferative agent in vitro. However, its poor bioavailability and rapid metabolism limits its use as a preferred anticancer agent. The problem of poor bioavailability of resveratrol can be solved by the synthesis of its analogs with appropriate chemical modifications that would enhance the stability and anticancer potency of resveratrol. To achieve this objective, we have synthesized a library of resveratrol analogs that resemble the basic skeleton of resveratrol but have structural modifications. These novel analogs were screened for their potential to inhibit growth of breast cancer cells. One analog, namely, ARSHA showed better potential and selectivity in inhibiting the proliferation of breast cancer cells. Our next goal was to identify the mechanism by which ARSHA specifi...
Background Estrogen metabolism-mediated oxidative stress is suggested to play an important role i... more Background Estrogen metabolism-mediated oxidative stress is suggested to play an important role in estrogen-induced breast carcinogenesis. We have earlier demonstrated that antioxidants, vitamin C (Vit C) and butylated hydroxyanisole (BHA) inhibit 17β-estradiol (E2)-mediated oxidative stress and oxidative DNA damage, and breast carcinogenesis in female August Copenhagen Irish (ACI) rats. The objective of the present study was to characterize the mechanism by which above antioxidants prevent DNA damage during breast carcinogenesis. Methods Female ACI rats were treated with E2; Vit C; Vit C + E2; BHA; and BHA + E2 for up to 240 days. mRNA and protein levels of a DNA repair enzyme 8-Oxoguanine DNA glycosylase (OGG1) and a transcription factor NRF2 were quantified in the mammary and mammary tumor tissues of rats after treatment with E2 and compared with that of rats treated with antioxidants either alone or in combination with E2. Results The expression of OGG1 was suppressed in mammary...
The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induc... more The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induced oxidative stress has been implicated in this carcinogenic process. Resveratrol (Res), a natural antioxidant phytoestrogen has chemopreventive effects against a variety of illnesses including cancer. The objective of the present study was to characterize the mechanism(s) of Res-mediated protection against estrogen-induced breast carcinogenesis. Female August Copenhagen Irish rats were treated with 17β-estradiol (E2), Res and Res + E2 for 8 months. Cotreatment of rats with Res and E2 inhibited E2-mediated proliferative changes in mammary tissues and significantly increased tumor latency and reduced E2-induced breast tumor development. Resveratrol treatment alone or in combination with E2 significantly upregulated expression of nuclear factor erythroid 2-related factor 2 (NRF2) in mammary tissues. Expression of NRF2-regulated antioxidant genes NQO1, SOD3 and OGG1 that are involved in pro...
Uploads
Papers