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Hasan Mukhtar - One of the best experts on this subject based on the ideXlab platform.
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abstract 5422 Delphinidin dietary anthocyanidin modulates egfr her 2 signaling pathway in breast cancer cells
Cancer Research, 2011Co-Authors: Farrukh Afaq, Naghma Khan, Hasan MukhtarAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Breast cancer is the second leading cause of cancer deaths in women in the United States. The epidermal growth factor receptor (EGFR) and HER-2 are expressed in many breast cancer patients and are associated with poor prognosis. Over-expression of EGFR and HER-2 lead to resistance against tamoxifen, a selective estrogen receptor (ER) modulator. In addition, the efficacy of trastuzumab or lapatinib for the treatment of ER-negative breast cancer as a monotherapy or in combination with chemotherapy is limited in more advanced stages of HER-2 positive breast cancers by development of therapeutic resistance. Considerable attention has been devoted towards the development of dual inhibitors of EGFR and HER-2 for breast cancer treatment. Several of these inhibitors such as lapatinib have been tested preclinically and clinically, but their use is limited because of their unacceptable cytotoxic effects on normal cells or cancer cells acquire resistance to such treatment. Therefore, identification of a natural, nontoxic agent(s) capable of inhibiting both EGFR and HER-2 is of utmost importance. Delphinidin, an anthocyanidin, present in many pigmented fruits and vegetables possesses anti-oxidant and anti-proliferative properties. We showed that Delphinidin inhibits constitutive and EGF-induced kinase activities of EGFR (Afaq et. al., Int. J Cancer 2008; 123: 1508-1515) in breast cancer cell lines. Recently, we found that Delphinidin treatment also inhibits protein expression of HER-2 in breast cancer cells. The goal of the present study was to determine the antiproliferative and proapoptotic potentials of Delphinidin in ER-positive and ER-negative breast cancer cell lines that overexpress EGFR/HER2. We first determined whether blockade of EGFR/HER-2 signaling pathways by Delphinidin exhibits growth inhibitory effect. Delphinidin (5-60 μM; 72 hrs) treatment of ER-positive (BT-474 and MCF-7) and ER-negative (MDA-MB-231 and MDA-MB-468) breast cancer cells resulted in a dose-dependent decrease in cell viability but had only minimal effects on normal mammary epithelial cell line, 184A1. The signaling pathways induced by activated EGFR/HER-2 include the PI3K/AKT and MAPK, both of which play a role in the mitogenic and cell survival responses. Therefore, we analyzed the expression of these proteins and found that Delphinidin treatment of ER-positive and ER-negative breast cancer cells inhibited the activation of PI3K and phosphorylation of AKT and MAPKs. Treatment of BT-474 and MDA-MB-231 cells with delphindin (5-60 μM; 72 hrs) resulted in (i) cleavage of PARP protein, (ii) activation of caspase-3 and-9, (iii) downregulation of cyclin D1 and Bcl-2, and (iv) increased expression of p27 and Bax. Based on these observations, we suggest that Delphinidin, alone or as an adjuvant to current therapies, could be useful for the management of both ER-positive and ER-negative breast cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5422. doi:10.1158/1538-7445.AM2011-5422
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Delphinidin, a dietary anthocyanidin in pigmented fruits and vegetables: a new weapon to blunt prostate cancer growth.
Cell cycle (Georgetown Tex.), 2008Co-Authors: Bilal Bin Hafeez, Imtiaz A Siddiqui, Mohammad Asim, Vaqar M Adhami, Imtiyaz Murtaza, Hasan MukhtarAbstract:In a recent publication, we have shown that Delphinidin, an anthocyanidin induces apoptosis and cell cycle arrest in highly metastatic human prostate cancer (PCa) PC3 cells. Extending these studies, we provide additional evidence that Delphinidin induces apoptosis and cell cycle arrest in androgen refractory human PCa 22Rn1 cells and that these effects are concomitant with inhibition of NF-kB. We observed that Delphinidin treatment to 22Rn1 cells resulted in a dose-dependent (i) G2/M phase cell cycle arrest, (ii) induction of apoptosis (iii) and inhibition of NF-kB signaling. The induction of apoptosis by Delphinidin was mediated via activation of caspases since a general caspase inhibitor Z-VAD-FMK significantly reversed this effect. Delphinidin treatment to cells resulted in a dose-dependent decrease in (i) phosphorylation of IKKgamma (NEMO), (ii) phosphorylation of NF-kB inhibitory protein, (iii) phosphorylation of NF-kB/p65 at Ser536 and NF-kB/p50 at Ser529, (iv) NF-kB/p65 nuclear translocation, and (...
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a dietary anthocyanidin Delphinidin induces apoptosis of human prostate cancer pc3 cells in vitro and in vivo involvement of nuclear factor κb signaling
Cancer Research, 2008Co-Authors: Bilal Bin Hafeez, Farrukh Afaq, Imtiaz A Siddiqui, Mohammad Asim, Arshi Malik, Vaqar M Adhami, Mohammad Saleem, Maria Din, Hasan MukhtarAbstract:Delphinidin, a major anthocyanidin present in many pigmented fruits and vegetables, possesses antioxidant, anti-inflammatory, and antiangiogenic properties. In this study, we provide evidence that it could be developed as a novel agent against human prostate cancer (PCa). We observed that Delphinidin treatment to human PCa LNCaP, C4-2, 22Rnu1, and PC3 cells resulted in a dose-dependent inhibition of cell growth without having any substantial effect on normal human prostate epithelial cells. We selected PC3 cells as a test model system because of their highly aggressive proliferative nature. Delphinidin treatment of cells resulted in a dose-dependent induction of apoptosis and arrest of cells in G(2)-M phase. This induction of apoptosis seems to be mediated via activation of caspases because N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluromethylketone significantly reduced apoptosis induced by Delphinidin. We also observed that Delphinidin treatment of cells resulted in a dose-dependent decrease in (a) phosphorylation of IkappaB kinase gamma (NEMO), (b) phosphorylation of nuclear factor-kappaB (NF-kappaB) inhibitory protein IkappaBalpha, (c) phosphorylation of NF-kappaB/p65 at Ser(536) and NF-kappaB/p50 at Ser(529), (d) NF-kappaB/p65 nuclear translocation, and (e) NF-kappaB DNA binding activity. Delphinidin administration (2 mg, i.p. thrice weekly) to athymic nude mice implanted with PC3 cells resulted in a significant inhibition of tumor growth. Analysis of tumors from Delphinidin-treated mice showed significant decrease in the expression of NF-kappaB/p65, Bcl2, Ki67, and PCNA. Taken together, our data suggest that Delphinidin could be developed as an agent against human PCa.
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Inhibition of epidermal growth factor receptor signaling pathway by Delphinidin, an anthocyanidin in pigmented fruits and vegetables
International journal of cancer, 2008Co-Authors: Farrukh Afaq, Naghma Khan, Najia Zaman, Deeba N. Syed, Sami Sarfaraz, Mohammad Abu Zaid, Hasan MukhtarAbstract:Inhibitors of the epidermal growth factor receptor (EGFR) have generated considerable hope for cancer treatment, specifically for lung and breast cancers. Therefore, identification of a natural, nontoxic agent(s) as an inhibitor of EGFR is of considerable importance. Delphinidin, an anthocyanidin present in pigmented fruits and vegetables, possesses potent antioxidant and antiproliferative properties. In our study, employing EGFR positive breast cancer AU-565 cells and immortalized MCF-10A cells, we evaluated the effect of Delphinidin on EGFR and its downstream signaling pathways. Delphinidin (5–40 μM; 3 hr) treatment of both AU-565 cells and MCF-10A cells inhibited the (i) phosphorylation of EGFR, (ii) activation of PI3K, (iii) phosphorylation of AKT and MAPK. Further, Delphinidin treatment of AU-565 cells inhibited EGF-induced autophosphorylation of EGFR, AKT and MAPK, activation of PI3K and cell invasion. We then compared the growth inhibitory effects of Delphinidin (5–40 μM; 48 hr), and found that it resulted in a decrease in cell growth of AU-565 and MCF-10A cells but had only minimal effects on normal mammary epithelial 184A1 cells. Treatment of AU-565 cells with Delphinidin resulted in (i) induction of apoptosis, (ii) cleavage of PARP protein, (iii) activation of caspase-3 and (iv) downregulation of Bcl-2 with an increase in the expression of Bax. In summary, our study identifies a naturally occurring dietary agent Delphinidin as an effective inhibitor of EGFR signaling in breast cancer cells. We suggest that Delphinidin could be developed as an agent for the management of EGFR positive human cancers. © 2008 Wiley-Liss, Inc.
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Delphinidin, an Anthocyanidin in Pigmented Fruits and Vegetables, Induces Apoptosis and Cell Cycle Arrest in Human Colon Cancer HCT116 Cells
Molecular carcinogenesis, 2008Co-Authors: Jungmi Yun, Farrukh Afaq, Naghma Khan, Hasan MukhtarAbstract:Because of unsatisfactory treatment options for colon cancer, there is a need to develop novel preventive approaches for this malignancy. One such strategy is through chemoprevention by the use of non-toxic dietary substances and botanical products. Delphinidin, an anthocyanidin in pigmented fruits and vegetables, possesses strong anti-oxidant and anti-inflammatory properties. In the present study, we investigated the antiproliferative and proapoptotic properties of Delphinidin in human colon cancer HCT116 cells. We found that treatment of cells with Delphinidin (30-240 microM; 48 h) resulted in (i) decrease in cell viability (ii) induction of apoptosis, (iii) cleavage of PARP, (iv) activation of caspases-3, -8, and -9, (v) increase in Bax with a concomitant decrease in Bcl-2 protein, and (vi) G2/M phase cell cycle arrest. NF-kappaB provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of both pre-neoplastic and malignant cells to resist apoptosis-based tumor surveillance mechanisms. We therefore, determined the effect of Delphinidin on NF-kappaB signaling pathway. The immunoblot, ELISA and EMSA analysis demonstrated that the treatment of HCT116 cells with Delphinidin resulted in the inhibition of (i) IKKalpha, (ii) phosphorylation and degradation of IkappaBalpha, (iii) phosphorylation of NF-kappaB/p65 at Ser(536), (iv) nuclear translocation of NF-kappaB/p65, (v) NF-kappaB/p65 DNA binding activity, and (vi) transcriptional activation of NF-kappaB. Our results suggest that Delphinidin treatment of HCT116 cells suppressed NF-kappaB pathway, resulting in G2/M phase arrest and apoptosis. We suggest that Delphinidin could have potential in inhibiting colon cancer growth.
Farrukh Afaq - One of the best experts on this subject based on the ideXlab platform.
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Delphinidin reduces cell proliferation and induces apoptosis of non-small-cell lung cancer cells by targeting EGFR/VEGFR2 signaling pathways.
PloS one, 2013Co-Authors: Harish C. Pal, Samriti Sharma, Leah Ray Strickland, Jyoti Agarwal, Mohammad Athar, Craig A. Elmets, Farrukh AfaqAbstract:Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) have emerged as two effective clinical targets for non-small-cell lung cancer (NSCLC). In the present study, we found that Delphinidin, an anthocyanidin, present in pigmented fruits and vegetables, is a potent inhibitor of both EGFR and VEGFR2 in NSCLC cells that overexpress EGFR/VEGFR2. Using these cells, we next determined the effects of Delphinidin on cell growth and apoptosis in vitro and on tumor growth and angiogenesis in vivo. Delphinidin (5-60 µM) treatment of NSCLC cells inhibited the activation of PI3K, and phosphorylation of AKT and MAPKs. Additionally, treatment of NSCLC cells with Delphinidin resulted in inhibition of cell growth without having significant toxic effects on normal human bronchial epithelial cells. Specifically, treatment of NCI-H441 and SK-MES-1 cells with delphindin (5-60 µM) resulted in (i) cleavage of PARP protein, (ii) activation of caspase-3 and -9, (iii) downregulation of anti-apoptotic proteins (Bcl2, Bcl-xL and Mcl-1), (iv) upregulation of pro-apoptotic proteins (Bax and Bak), and (v) decreased expression of PCNA and cyclin D1. Furthermore, in athymic nude mice subcutaneously implanted with human NSCLC cells, Delphinidin treatment caused a (i) significant inhibition of tumor growth, (ii) decrease in the expression of markers for cell proliferation (Ki67 and PCNA) and angiogenesis (CD31 and VEGF), and (iii) induction of apoptosis, when compared with control mice. Based on these observations, we suggest that Delphinidin, alone or as an adjuvant to current therapies, could be used for the management of NSCLC, especially those that overexpress EGFR and VEGFR2.
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abstract 3666 Delphinidin reduces cell proliferation and induces apoptosis of non small cell lung cancer cellsin vitroandin vivo
Cancer Research, 2013Co-Authors: Harish C. Pal, Samriti Sharma, Craig A. Elmets, Farrukh AfaqAbstract:Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Lung cancer is a major health problem worldwide and accounts for approximately 28% of all cancer-related deaths in the USA. Like most cancers, lung cancer is a conglomeration of diseases of diverse etiology, broadly divided into small-cell lung cancer (SCLC, comprising 20% of lung cancers), and non-small-cell lung cancer (NSCLC, comprising 80% of lung cancers). Lung cancer has proven difficult to control with conventional therapeutic and surgical approaches, and the prognosis is poor with an overall 5-year survival rate of only 15% for NSCLC in the USA. The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2) have emerged as two clinically validated targets for NSCLC. The development of dietary agents which exhibit combined EGFR/VEGFR-2 inhibitory activities may be a step forward to improve antitumor efficacy and to broaden application possibilities. In our pursuit for the identification of non-toxic dietary ingredients for prevention and treatment of cancer, we found that Delphinidin, an anthocyanidin, present in pigmented fruits and vegetables, is a potent inhibitor of both EGFR and VEGFR-2 in NSCLC cells. In the present study, we determined the effects of Delphinidin on cell growth and apoptosis in vitro and on tumor growth and angiogenesis in vivo in NSCLC cells that overexpress EGFR/VEGFR-2. Delphinidin (5-60 μM) treatment of NSCLC cells inhibited the (i) activation of PI3K, and (ii) phosphorylation of AKT and MAPKs. We next determined whether inhibition of EGFR/VEGFR-2 signaling pathways by Delphinidin exhibits a growth inhibitory effect. We observed that Delphinidin treatment of NCI-H441, SK-MES-1 and A549 cells resulted in a dose-dependent inhibition of cell growth without having any substantial effects on normal human bronchial epithelial cells as assessed by MTT assay. Treatment of NCI-H441 and SK-MES-1 cells with delphindin (5-60 μM) resulted in (i) cleavage of PARP protein, (ii) activation of caspase-3 and -9, (iii) downregulation of anti-apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1), (iv) upregulation of pro-apoptotic proteins (Bax and Bak), and (v) decreased expression of PCNA and cyclin D1. In athymic nude mice implanted with human NSCLC cells (NCI-H441 or SK-MES-1), Delphinidin (1-2 mg, i.p. thrice-weekly) treatment caused a significant inhibition of tumor growth. There was also a decrease in the expression of markers for cell proliferation (Ki-67 and PCNA) and angiogenesis (CD31 and VEGF) as well as an induction of apoptosis in tumor tissues treated with Delphinidin, when compared with tumor tissues of control mice. Based on these observations, we suggest that Delphinidin, alone or as an adjuvant to current therapies, could be useful for the management of NSCLCs, especially those that overexpress EGFR and VEGFR-2. Citation Format: Harish C. Pal, Samriti Sharma, Craig A. Elmets, Farrukh Afaq. Delphinidin reduces cell proliferation and induces apoptosis of non-small cell lung cancer cells in vitro and in vivo . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3666. doi:10.1158/1538-7445.AM2013-3666
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abstract 2565 Delphinidin a dual tyrosine kinase inhibitor of egfr and vegfr 2 reduces cell proliferation and induces apoptosis of non small cell lung cancer cells
Cancer Research, 2012Co-Authors: Farrukh Afaq, Samriti Sharma, Harish C. PalAbstract:Lung cancer has proven difficult to control with conventional therapeutic and surgical approaches, and the prognosis is poor with an overall 5-year survival rate of only 15% for non-small-cell lung cancer (NSCLC) in the USA. Over the last decade, the notions of targeting tyrosine kinase receptors for prevention and treatment of cancers have gained considerable attention. The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2) have emerged as two clinically validated targets for NSCLC. Dual specific tyrosine kinase receptor inhibitors, which target two different classes of growth factor receptors, represent an elegant way to avoid multiple treatment modalities when used alone and in combination with various anti-signaling agents. The development of dietary agents with combined EGFR/VEGFR-2 inhibitory activities in the same molecule may be a step forward to improve antitumor efficacy and to broaden application possibilities. In our pursuit for identification of non-toxic dietary ingredients for prevention and treatment of cancer, we found that Delphinidin, an anthocyanidin, present in pigmented fruits (such as pomegranate, berries, and dark grapes) and vegetables (such as egg plant, tomato, carrot and red onion), is a potent inhibitor of EGFR and VEGFR-2 in NSCLC cells. Employing EGFR and VEGFR-2 over expressing NSCLC cells (NCI-H441 and SK-MES-1); we evaluated the effect of Delphinidin on EGFR/VEGFR-2 downstream signaling pathways. Delphinidin (5-60 μM) treatment of both NCI-H441 and SK-MES-1 cells inhibited the (i) activation of PI3K, and (ii) phosphorylation of AKT and mitogen activated protein kinases (such as ERK1/2, JNK1/2 and p38). We next determined whether inhibition of EGFR/VEGFR-2 signaling pathways by Delphinidin exhibits growth inhibitory effect. We observed that Delphinidin treatment of NCI-H441, SK-MES-1 and A-549 cells resulted in a dose-dependent inhibition of cell growth without having any substantial effect on normal human bronchial epithelial cells as assessed by an MTT assay. Treatment of NCI-H441 and SK-MES-1 cells with delphindin (5-60 μM) resulted in (i) cleavage of PARP protein, (ii) activation of caspase-3 and-9, (iii) downregulation of anti-apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1), (iv) upregulation of pro-apoptotic proteins (Bax, Bid and Bak), and (v) decrease expression of PCNA and cyclin D1. In addition, we found that Delphinidin was effective in reducing the invasive potential of NSCLC cells. This study identifies an abundant fruits and vegetables based anthocyanidin Delphinidin as an effective blocker of EGFR and VEGFR-2 in lung cancer cells. Based on these observations, we suggest that Delphinidin, alone or as an adjuvant to current therapies, could be useful for the management of NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2565. doi:1538-7445.AM2012-2565
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abstract 5422 Delphinidin dietary anthocyanidin modulates egfr her 2 signaling pathway in breast cancer cells
Cancer Research, 2011Co-Authors: Farrukh Afaq, Naghma Khan, Hasan MukhtarAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Breast cancer is the second leading cause of cancer deaths in women in the United States. The epidermal growth factor receptor (EGFR) and HER-2 are expressed in many breast cancer patients and are associated with poor prognosis. Over-expression of EGFR and HER-2 lead to resistance against tamoxifen, a selective estrogen receptor (ER) modulator. In addition, the efficacy of trastuzumab or lapatinib for the treatment of ER-negative breast cancer as a monotherapy or in combination with chemotherapy is limited in more advanced stages of HER-2 positive breast cancers by development of therapeutic resistance. Considerable attention has been devoted towards the development of dual inhibitors of EGFR and HER-2 for breast cancer treatment. Several of these inhibitors such as lapatinib have been tested preclinically and clinically, but their use is limited because of their unacceptable cytotoxic effects on normal cells or cancer cells acquire resistance to such treatment. Therefore, identification of a natural, nontoxic agent(s) capable of inhibiting both EGFR and HER-2 is of utmost importance. Delphinidin, an anthocyanidin, present in many pigmented fruits and vegetables possesses anti-oxidant and anti-proliferative properties. We showed that Delphinidin inhibits constitutive and EGF-induced kinase activities of EGFR (Afaq et. al., Int. J Cancer 2008; 123: 1508-1515) in breast cancer cell lines. Recently, we found that Delphinidin treatment also inhibits protein expression of HER-2 in breast cancer cells. The goal of the present study was to determine the antiproliferative and proapoptotic potentials of Delphinidin in ER-positive and ER-negative breast cancer cell lines that overexpress EGFR/HER2. We first determined whether blockade of EGFR/HER-2 signaling pathways by Delphinidin exhibits growth inhibitory effect. Delphinidin (5-60 μM; 72 hrs) treatment of ER-positive (BT-474 and MCF-7) and ER-negative (MDA-MB-231 and MDA-MB-468) breast cancer cells resulted in a dose-dependent decrease in cell viability but had only minimal effects on normal mammary epithelial cell line, 184A1. The signaling pathways induced by activated EGFR/HER-2 include the PI3K/AKT and MAPK, both of which play a role in the mitogenic and cell survival responses. Therefore, we analyzed the expression of these proteins and found that Delphinidin treatment of ER-positive and ER-negative breast cancer cells inhibited the activation of PI3K and phosphorylation of AKT and MAPKs. Treatment of BT-474 and MDA-MB-231 cells with delphindin (5-60 μM; 72 hrs) resulted in (i) cleavage of PARP protein, (ii) activation of caspase-3 and-9, (iii) downregulation of cyclin D1 and Bcl-2, and (iv) increased expression of p27 and Bax. Based on these observations, we suggest that Delphinidin, alone or as an adjuvant to current therapies, could be useful for the management of both ER-positive and ER-negative breast cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5422. doi:10.1158/1538-7445.AM2011-5422
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a dietary anthocyanidin Delphinidin induces apoptosis of human prostate cancer pc3 cells in vitro and in vivo involvement of nuclear factor κb signaling
Cancer Research, 2008Co-Authors: Bilal Bin Hafeez, Farrukh Afaq, Imtiaz A Siddiqui, Mohammad Asim, Arshi Malik, Vaqar M Adhami, Mohammad Saleem, Maria Din, Hasan MukhtarAbstract:Delphinidin, a major anthocyanidin present in many pigmented fruits and vegetables, possesses antioxidant, anti-inflammatory, and antiangiogenic properties. In this study, we provide evidence that it could be developed as a novel agent against human prostate cancer (PCa). We observed that Delphinidin treatment to human PCa LNCaP, C4-2, 22Rnu1, and PC3 cells resulted in a dose-dependent inhibition of cell growth without having any substantial effect on normal human prostate epithelial cells. We selected PC3 cells as a test model system because of their highly aggressive proliferative nature. Delphinidin treatment of cells resulted in a dose-dependent induction of apoptosis and arrest of cells in G(2)-M phase. This induction of apoptosis seems to be mediated via activation of caspases because N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluromethylketone significantly reduced apoptosis induced by Delphinidin. We also observed that Delphinidin treatment of cells resulted in a dose-dependent decrease in (a) phosphorylation of IkappaB kinase gamma (NEMO), (b) phosphorylation of nuclear factor-kappaB (NF-kappaB) inhibitory protein IkappaBalpha, (c) phosphorylation of NF-kappaB/p65 at Ser(536) and NF-kappaB/p50 at Ser(529), (d) NF-kappaB/p65 nuclear translocation, and (e) NF-kappaB DNA binding activity. Delphinidin administration (2 mg, i.p. thrice weekly) to athymic nude mice implanted with PC3 cells resulted in a significant inhibition of tumor growth. Analysis of tumors from Delphinidin-treated mice showed significant decrease in the expression of NF-kappaB/p65, Bcl2, Ki67, and PCNA. Taken together, our data suggest that Delphinidin could be developed as an agent against human PCa.
Ki Won Lee - One of the best experts on this subject based on the ideXlab platform.
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NADPH oxidase is a novel target of Delphinidin for the inhibition of UVB-induced MMP-1 expression in human dermal fibroblasts.
Experimental dermatology, 2013Co-Authors: Tae Gyu Lim, Jong-eun Kim, Sung Keun Jung, Hyong Joo Lee, Yoona Kim, Tae Su Jang, Ki Won LeeAbstract:We investigated the reported antiphotoaging effects of the major anthocyanidin delphidin and sought to identify its specific molecular target during UVB-induced MMP-1 expression. Delphinidin treatment significantly inhibited UVB-induced MMP-1 expression in primary cultured human dermal fibroblasts (HDF), an effect associated with the suppression of MKK4-JNK1/2, MKK3/6-p38 and MEK-ERK1/2 phosphorylation. Further investigation revealed that Delphinidin significantly inhibited UVB-induced ROS production and NOX activity. Interestingly, the inhibitory effect of Delphinidin on UVB-induced NOX activity was stronger than that of apocynin, a pharmaceutical NOX inhibitor. Fractioned cell analysis results using a Western blot assay showed that this effect occurred through the inhibition of UVB-induced P47phox (a NOX subunit) translocation from the cytosol to the membrane. Pull down assays demonstrated that Delphinidin binds directly to P47phox in vitro. Collectively, our results suggest that Delphinidin targets NOX, resulting in the suppression of UVB-induced MMP-1 expression in human dermal fibroblasts.
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Abstract LB-426: Delphinidin suppresses ultraviolet B-induced cyclooxygenases-2 expression through inhibition of MAPKK4 and PI-3 kinase
Prevention Research, 2010Co-Authors: Nam Joo Kang, Jung Yeon Kwon, Ki Won Lee, Jong-eun Kim, Sung Keun Jung, Mun Kyung Hwang, Yong-seok Heo, Ann M. Bode, Hyong Joo Lee, Zigang DongAbstract:Cyclooxygenase-2 (COX-2), a key mediator of inflammation, and its product, prostaglandin E2 (PGE2), enhance carcinogenesis, particularly in skin. Ultraviolet (UV) B is the most carcinogenic component of solar irradiation, and a crucial role of COX-2 in UVB-mediated skin carcinogenesis has been reported. Here, we investigated the effects of Delphinidin, an abundant dietary anthocyanin, on UVB-induced COX-2 upregulation and the underlying molecular mechanism. We found that Delphinidin suppressed UVB-induced COX-2 expression in JB6 P+ mouse epidermal cells. COX-2 promoter activity and PGE2 production were also suppressed by Delphinidin treatment within non-cytotoxic concentrations. Activator protein-1 and nuclear factor- B, crucial transcription factors involved in COX-2 expression, were activated by UVB and Delphinidin abolished this activation. UVB-induced phosphorylation of c-Jun N-terminal kinase, p38 kinase and Akt was inhibited by Delphinidin. The activities of mitogenactivated protein kinase kinase (MAPKK) 4 and phosphatidylinositol-3 kinase (PI-3K) were inhibited markedly by Delphinidin. A pull-down assay using Delphinidin-Sepharose beads revealed that Delphinidin binds directly with MAPKK4 or PI-3K in a manner that was competitive with adenosine triphosphate. Moreover, in vivo investigations using mouse skin revealed that the upregulation of COX-2 expression, MAPKK4 activity and PI-3K activity induced by UVB was abolished with Delphinidin treatment. Collectively, our results demonstrated that Delphinidin targets MAPKK4 and PI-3K directly to suppress COX-2 overexpression, suggesting a potential protective role for Delphinidin against UVB-mediated skin carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-426.
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Delphinidin suppresses ultraviolet B-induced cyclooxygenases-2 expression through inhibition of MAPKK4 and PI-3 kinase.
Carcinogenesis, 2009Co-Authors: Jung Yeon Kwon, Ki Won Lee, Jong-eun Kim, Sung Keun Jung, Nam Joo Kang, Mun Kyung Hwang, Yong-seok Heo, Ann M. Bode, Zigang Dong, Hyong Joo LeeAbstract:Cyclooxygenase-2 (COX-2), a key mediator of inflammation, and its product, prostaglandin E2 (PGE2), enhance carcinogenesis, particularly in skin. Ultraviolet (UV) B is the most carcinogenic component of solar irradiation, and a crucial role of COX-2 in UVB-mediated skin carcinogenesis has been reported. Here, we investigated the effects of Delphinidin, an abundant dietary anthocyanin, on UVB-induced COX-2 upregulation and the underlying molecular mechanism. We found that Delphinidin suppressed UVB-induced COX-2 expression in JB6 P+ mouse epidermal cells. COX-2 promoter activity and PGE2 production were also suppressed by Delphinidin treatment within non-cytotoxic concentrations. Activator protein-1 and nuclear factor-κB, crucial transcription factors involved in COX-2 expression, were activated by UVB and Delphinidin abolished this activation. UVB-induced phosphorylation of c-Jun N-terminal kinase, p38 kinase and Akt was inhibited by Delphinidin. The activities of mitogen-activated protein kinase kinase (MAPKK) 4 and phosphatidylinositol-3 kinase (PI-3K) were inhibited markedly by Delphinidin. A pull-down assay using Delphinidin–Sepharose beads revealed that Delphinidin binds directly with MAPKK4 or PI-3K in a manner that was competitive with adenosine triphosphate. Moreover, in vivo investigations using mouse skin revealed that the upregulation of COX-2 expression, MAPKK4 activity and PI-3K activity induced by UVB was abolished with Delphinidin treatment. Collectively, our results demonstrated that Delphinidin targets MAPKK4 and PI-3K directly to suppress COX-2 overexpression, suggesting a potential protective role for Delphinidin against UVB-mediated skin carcinogenesis.
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Delphinidin attenuates neoplastic transformation in jb6 cl41 mouse epidermal cells by blocking raf mitogen activated protein kinase kinase extracellular signal regulated kinase signaling
Cancer Prevention Research, 2008Co-Authors: Nam Joo Kang, Jung Yeon Kwon, Ki Won Lee, Mun Kyung Hwang, Yong-seok Heo, Evgeny A Rogozin, Ann M. BodeAbstract:Recent studies suggest that anthocyanidins play a pivotal role in the chemopreventive effects of fruits and vegetables. However, the underlying molecular mechanisms and cellular targets remain unknown. Neoplastic transformation of cells and inflammation are considered to be major events contributing to carcinogenesis. Here, we report that Delphinidin, a major dietary anthocyanidin, inhibits tumor promoter-induced transformation and cyclooxygenase-2 (COX-2) expression in JB6 promotion-sensitive mouse skin epidermal (JB6 P+) cells by directly targeting Raf and mitogen-activated protein kinase kinase (MEK). Delphinidin inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation and COX-2 expression at both the protein and transcriptional levels. The activation of activator protein-1 and nuclear factor-kappaB induced by TPA was dose dependently inhibited by Delphinidin treatment. Delphinidin strongly suppressed Raf1 and MEK1 kinase activities and subsequently attenuated TPA-induced phosphorylation of MEK, extracellular signal-regulated kinase (ERK), p90RSK, and MSK. Although Delphinidin suppressed ERK and c-Jun NH(2)-terminal kinase activities, it was more effective at inhibiting Raf1 or MEK1 activities. Pull-down and competition assays revealed that Delphinidin binds with Raf1 or MEK1 noncompetitively with ATP. Delphinidin also dose dependently suppressed JB6 P+ cell transformation induced by epidermal growth factor and H-Ras, both of which are involved in the activation of Raf/MEK/ERK signaling. Together, these findings suggested that the targeted inhibition of Raf1 and MEK activities and COX-2 expression by Delphinidin contribute to the chemopreventive potential of fruits and vegetables.
Tae Gyu Lim - One of the best experts on this subject based on the ideXlab platform.
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NADPH oxidase is a novel target of Delphinidin for the inhibition of UVB-induced MMP-1 expression in human dermal fibroblasts.
Experimental dermatology, 2013Co-Authors: Tae Gyu Lim, Jong-eun Kim, Sung Keun Jung, Hyong Joo Lee, Yoona Kim, Tae Su Jang, Ki Won LeeAbstract:We investigated the reported antiphotoaging effects of the major anthocyanidin delphidin and sought to identify its specific molecular target during UVB-induced MMP-1 expression. Delphinidin treatment significantly inhibited UVB-induced MMP-1 expression in primary cultured human dermal fibroblasts (HDF), an effect associated with the suppression of MKK4-JNK1/2, MKK3/6-p38 and MEK-ERK1/2 phosphorylation. Further investigation revealed that Delphinidin significantly inhibited UVB-induced ROS production and NOX activity. Interestingly, the inhibitory effect of Delphinidin on UVB-induced NOX activity was stronger than that of apocynin, a pharmaceutical NOX inhibitor. Fractioned cell analysis results using a Western blot assay showed that this effect occurred through the inhibition of UVB-induced P47phox (a NOX subunit) translocation from the cytosol to the membrane. Pull down assays demonstrated that Delphinidin binds directly to P47phox in vitro. Collectively, our results suggest that Delphinidin targets NOX, resulting in the suppression of UVB-induced MMP-1 expression in human dermal fibroblasts.
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Abstract 4981: NADPH oxidase is a novel target of Delphinidin to inhibits UVB-induced MMP-1 expression in human dermal fibroblasts
Molecular and Cellular Biology, 2012Co-Authors: Tae Gyu LimAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Ultraviolet (UV) induced ROS production is considered a major cause of photoaging via abnormal expression of matrix metalloproteinase (MMP)-1 and NADPH oxidase (NOX) is a key enzyme of endogenous ROS production. Here, we investigated the anti-photoaging effect of delphidin, a major anthocyanin found in berry, beans, and red wine, and its molecular target in UVB-induced MMP-1 expression using primary cultured human dermal fibroblast. Delphinidin inhibited UVB-induced MMP-1 expression in human dermal fibroblasts. UVB-induced MKK4-JNK1/2, MKK3/6-p38, and MEK-ERK1/2 phosphorylation were suppressed by Delphinidin. In addition, quantification of ROS stained with the 2′,7′-dichlorofluorescein diacetate (DCF-DA) dye showed that Delphinidin significantly inhibited UVB-induced ROS production. Delphinidin significantly inhibited UVB-induced NOX activity. Interestingly, the inhibitory effect of Delphinidin on UVB-induced NOX activity was stronger than apocynin, a pharmaceutical NOX inhibitor. Fractioned cell analysis results using a western blot assay showed that Delphinidin strongly suppressed UVB-induced P47phox, a NOX subunit, translocation from the cytosol to the membrane. Delphinidin produced similar effects with apocynin on UVB-induced MMP-1 expression. Pull down assays showed that Delphinidin directly bound to P47phox. Collectively, our results suggest that NOX is a potential target of Delphinidin in the suppression of UVB-induced MMP-1 expression in human dermal fibroblasts. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4981. doi:1538-7445.AM2012-4981
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NADPH oxidase is a novel target of Delphinidin for the inhibition of UVB-induced MMP-1 expression in human dermal fibroblasts.
Experimental dermatology, 2013Co-Authors: Tae Gyu Lim, Jong-eun Kim, Sung Keun Jung, Hyong Joo Lee, Yoona Kim, Tae Su Jang, Ki Won LeeAbstract:We investigated the reported antiphotoaging effects of the major anthocyanidin delphidin and sought to identify its specific molecular target during UVB-induced MMP-1 expression. Delphinidin treatment significantly inhibited UVB-induced MMP-1 expression in primary cultured human dermal fibroblasts (HDF), an effect associated with the suppression of MKK4-JNK1/2, MKK3/6-p38 and MEK-ERK1/2 phosphorylation. Further investigation revealed that Delphinidin significantly inhibited UVB-induced ROS production and NOX activity. Interestingly, the inhibitory effect of Delphinidin on UVB-induced NOX activity was stronger than that of apocynin, a pharmaceutical NOX inhibitor. Fractioned cell analysis results using a Western blot assay showed that this effect occurred through the inhibition of UVB-induced P47phox (a NOX subunit) translocation from the cytosol to the membrane. Pull down assays demonstrated that Delphinidin binds directly to P47phox in vitro. Collectively, our results suggest that Delphinidin targets NOX, resulting in the suppression of UVB-induced MMP-1 expression in human dermal fibroblasts.
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Abstract LB-426: Delphinidin suppresses ultraviolet B-induced cyclooxygenases-2 expression through inhibition of MAPKK4 and PI-3 kinase
Prevention Research, 2010Co-Authors: Nam Joo Kang, Jung Yeon Kwon, Ki Won Lee, Jong-eun Kim, Sung Keun Jung, Mun Kyung Hwang, Yong-seok Heo, Ann M. Bode, Hyong Joo Lee, Zigang DongAbstract:Cyclooxygenase-2 (COX-2), a key mediator of inflammation, and its product, prostaglandin E2 (PGE2), enhance carcinogenesis, particularly in skin. Ultraviolet (UV) B is the most carcinogenic component of solar irradiation, and a crucial role of COX-2 in UVB-mediated skin carcinogenesis has been reported. Here, we investigated the effects of Delphinidin, an abundant dietary anthocyanin, on UVB-induced COX-2 upregulation and the underlying molecular mechanism. We found that Delphinidin suppressed UVB-induced COX-2 expression in JB6 P+ mouse epidermal cells. COX-2 promoter activity and PGE2 production were also suppressed by Delphinidin treatment within non-cytotoxic concentrations. Activator protein-1 and nuclear factor- B, crucial transcription factors involved in COX-2 expression, were activated by UVB and Delphinidin abolished this activation. UVB-induced phosphorylation of c-Jun N-terminal kinase, p38 kinase and Akt was inhibited by Delphinidin. The activities of mitogenactivated protein kinase kinase (MAPKK) 4 and phosphatidylinositol-3 kinase (PI-3K) were inhibited markedly by Delphinidin. A pull-down assay using Delphinidin-Sepharose beads revealed that Delphinidin binds directly with MAPKK4 or PI-3K in a manner that was competitive with adenosine triphosphate. Moreover, in vivo investigations using mouse skin revealed that the upregulation of COX-2 expression, MAPKK4 activity and PI-3K activity induced by UVB was abolished with Delphinidin treatment. Collectively, our results demonstrated that Delphinidin targets MAPKK4 and PI-3K directly to suppress COX-2 overexpression, suggesting a potential protective role for Delphinidin against UVB-mediated skin carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-426.
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Delphinidin suppresses ultraviolet B-induced cyclooxygenases-2 expression through inhibition of MAPKK4 and PI-3 kinase.
Carcinogenesis, 2009Co-Authors: Jung Yeon Kwon, Ki Won Lee, Jong-eun Kim, Sung Keun Jung, Nam Joo Kang, Mun Kyung Hwang, Yong-seok Heo, Ann M. Bode, Zigang Dong, Hyong Joo LeeAbstract:Cyclooxygenase-2 (COX-2), a key mediator of inflammation, and its product, prostaglandin E2 (PGE2), enhance carcinogenesis, particularly in skin. Ultraviolet (UV) B is the most carcinogenic component of solar irradiation, and a crucial role of COX-2 in UVB-mediated skin carcinogenesis has been reported. Here, we investigated the effects of Delphinidin, an abundant dietary anthocyanin, on UVB-induced COX-2 upregulation and the underlying molecular mechanism. We found that Delphinidin suppressed UVB-induced COX-2 expression in JB6 P+ mouse epidermal cells. COX-2 promoter activity and PGE2 production were also suppressed by Delphinidin treatment within non-cytotoxic concentrations. Activator protein-1 and nuclear factor-κB, crucial transcription factors involved in COX-2 expression, were activated by UVB and Delphinidin abolished this activation. UVB-induced phosphorylation of c-Jun N-terminal kinase, p38 kinase and Akt was inhibited by Delphinidin. The activities of mitogen-activated protein kinase kinase (MAPKK) 4 and phosphatidylinositol-3 kinase (PI-3K) were inhibited markedly by Delphinidin. A pull-down assay using Delphinidin–Sepharose beads revealed that Delphinidin binds directly with MAPKK4 or PI-3K in a manner that was competitive with adenosine triphosphate. Moreover, in vivo investigations using mouse skin revealed that the upregulation of COX-2 expression, MAPKK4 activity and PI-3K activity induced by UVB was abolished with Delphinidin treatment. Collectively, our results demonstrated that Delphinidin targets MAPKK4 and PI-3K directly to suppress COX-2 overexpression, suggesting a potential protective role for Delphinidin against UVB-mediated skin carcinogenesis.