Amer Ali Abd El-Hafeez1, Hazim O Khalifa2, Elham A M Mahdy3, Vikas Sharma4, Toru Hosoi5, Pradipta Ghosh6, Koichiro Ozawa5, Monica M Montano4, Takashi Fujimura7, Ahmed R N Ibrahim8, Mohamed A A Abdelhamid9, Seung Pil Pack10, Samia A Shouman11, Seiji Kawamoto7. 1. Pharmacotherapy Department, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; Global Career Design Center, Hiroshima University, Hiroshima, Japan; Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt. Electronic address: amer.ali@nci.cu.edu.eg. 2. Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt; Department of Infectious Diseases, Graduate School of Medicine, International University of Health and Welfare, Narita, Japan. 3. Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt. 4. Pharmacology Department, Case Western Reserve University School of Medicine, Cleveland, OH, USA. 5. Pharmacotherapy Department, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. 6. Department of Medicine, University of California, San Diego, La Jolla, CA,USA; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. 7. Hiroshima Research Center for Healthy Aging (HiHA), Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Hiroshima, Japan. 8. Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, Egypt. 9. Department of Botany and Microbiology, Faculty of Science, Minia University, Minia Egypt; Department of Biotechnology and Bioinformatics, Korea University, Sejong, Republic of Korea. 10. Department of Biotechnology and Bioinformatics, Korea University, Sejong, Republic of Korea. 11. Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
Abstract
BACKGROUND: Nor-wogonin, a polyhydroxy flavone, has been shown to possess antitumor activity. However, the mechanisms responsible for its antitumor activity are poorly studied. Herein, we investigated the mechanisms of nor-wogonin actions in triple-negative breast cancer (TNBC) cells. METHODS: Effects of nor-wogonin on cell proliferation and viability of four TNBC cell lines (MDA-MB-231, BT-549, HCC70, and HCC1806) and two non-tumorigenic breast cell lines (MCF-10A and AG11132) were assessed by BrdU incorporation assays and trypan blue dye exclusion tests. Cell cycle and apoptosis analyses were carried out by flow cytometry. Protein expression was analyzed by immunoblotting. RESULTS: Nor-wogonin significantly inhibited the growth and decreased the viability of TNBC cells; however, it exhibited no or minimal effects in non-tumorigenic breast cells. Nor-wogonin (40 μM) was a more potent anti-proliferative and cytotoxic agent than wogonin (100 μM) and wogonoside (100 μM), which are structurally related to nor-wogonin. The antitumor effects of nor-wogonin can be attributed to cell cycle arrest via reduction of the expression of cyclin D1, cyclin B1, and CDK1. Furthermore, nor-wogonin induced mitochondrial apoptosis, (as evidenced by the increase in % of cells that are apoptotic), decreases in the mitochondrial membrane potential (ΔΨm), increases in Bax/Bcl-2 ratio, and caspase-3 cleavage. Moreover, nor-wogonin attenuated the expression of the nuclear factor kappa-B and activation of signal transducer and activator of transcription 3 pathways, which can be correlated with suppression of transforming growth factor-β-activated kinase 1 in TNBC cells. CONCLUSION: These results showed that nor-wogonin might be a potential multi-target agent for TNBC treatment.
BACKGROUND:Nor-wogonin, a polyhydroxy flavone, has been shown to possess antitumor activity. However, the mechanisms responsible for its antitumor activity are poorly studied. Herein, we investigated the mechanisms of nor-wogonin actions in triple-negative breast cancer (TNBC) cells. METHODS: Effects of nor-wogonin on cell proliferation and viability of four TNBC cell lines (MDA-MB-231, BT-549, HCC70, and HCC1806) and two non-tumorigenic breast cell lines (MCF-10A and AG11132) were assessed by BrdU incorporation assays and trypan blue dye exclusion tests. Cell cycle and apoptosis analyses were carried out by flow cytometry. Protein expression was analyzed by immunoblotting. RESULTS:Nor-wogonin significantly inhibited the growth and decreased the viability of TNBC cells; however, it exhibited no or minimal effects in non-tumorigenic breast cells. Nor-wogonin (40 μM) was a more potent anti-proliferative and cytotoxic agent than wogonin (100 μM) and wogonoside (100 μM), which are structurally related to nor-wogonin. The antitumor effects of nor-wogonin can be attributed to cell cycle arrest via reduction of the expression of cyclin D1, cyclin B1, and CDK1. Furthermore, nor-wogonin induced mitochondrial apoptosis, (as evidenced by the increase in % of cells that are apoptotic), decreases in the mitochondrial membrane potential (ΔΨm), increases in Bax/Bcl-2 ratio, and caspase-3 cleavage. Moreover, nor-wogonin attenuated the expression of the nuclear factor kappa-B and activation of signal transducer and activator of transcription 3 pathways, which can be correlated with suppression of transforming growth factor-β-activated kinase 1 in TNBC cells. CONCLUSION: These results showed that nor-wogonin might be a potential multi-target agent for TNBC treatment.
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