Bowen Yu1,2, Bo Yuan1,3, Anna Kiyomi4, Hidetomo Kikuchi5, Hideki Hayashi1, Xiaomei Hu6, Mari Okazaki3, Munetoshi Sugiura4, Toshihiko Hirano7, Xiaohua Pei2, Norio Takagi1. 1. Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy & Life Sciences 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. 2. Beijing University of Chinese Medicine Third Affiliated Hospital Beijing 100029, P. R. China. 3. Laboratory of Pharmacology, School of Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan. 4. Department of Drug Safety and Risk Management, School of Pharmacy, Tokyo University of Pharmacy & Life Sciences 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. 5. Laboratory of Pharmacotherapy, Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan. 6. Xiyuan Hospital, China Academy of Chinese Medical Sciences Beijing 100091, P. R. China. 7. Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy & Life Sciences 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Abstract
BACKGROUND: To provide novel insight into the development of new therapeutic strategies to combat breast cancer, differentiation-inducing activity of clinically achievable concentrations of arsenite (AsIII) and tetrandrine (Tetra) was investigated in breast cancer cell lines MDA-MB-231 and MCF-7. METHODS: Differentiation induction of cancer cells was analyzed by flow cytometer. Alterations of genes related to differentiation, and proliferation of human normal peripheral blood mononuclear cells (PBMCs) were analyzed using western blotting and cell viability assay, respectively. RESULTS: Exposure to Tetra alone or in combination with AsIII induced differentiation of both cells characterized by upregulation of ICAM-1, downregulation of Her2/neu. In comparison with MCF-7, the combination of lower concentrations of AsIII and Tetra induced differentiation of MDA-MB-231, indicating that MDA-MB-231 cells were highly susceptible to differentiation. The differentiation occurred in parallel with activation of Erk signaling pathway, and was abolished by PD98059, a potent Erk inhibitor. Consistent with in vitro experimental results, the upregulation of ICAM-1 and the activation of Erk signaling pathway were also observed in MDA-MB-231 breast tumors in xenograft mouse obtained from our previous study. No obvious proliferation inhibition of PBMCs was observed following the exposure to AsIII combined with Tetra at the concentrations capable of inducing differentiation of MDA-MB-231 cells. CONCLUSION: The Erk signaling pathway may be crucially involved in the differentiation induction of breast cancer cells in vitro and in vivo. Collectively, our results suggest that the combination can probably serve as promising candidates for the development of novel therapeutic approaches for different types of breast cancer. AJTR
BACKGROUND: To provide novel insight into the development of new therapeutic strategies to combat breast cancer, differentiation-inducing activity of clinically achievable concentrations of arsenite (AsIII) and tetrandrine (Tetra) was investigated in breast cancer cell lines MDA-MB-231 and MCF-7. METHODS: Differentiation induction of cancer cells was analyzed by flow cytometer. Alterations of genes related to differentiation, and proliferation of human normal peripheral blood mononuclear cells (PBMCs) were analyzed using western blotting and cell viability assay, respectively. RESULTS: Exposure to Tetra alone or in combination with AsIII induced differentiation of both cells characterized by upregulation of ICAM-1, downregulation of Her2/neu. In comparison with MCF-7, the combination of lower concentrations of AsIII and Tetra induced differentiation of MDA-MB-231, indicating that MDA-MB-231 cells were highly susceptible to differentiation. The differentiation occurred in parallel with activation of Erk signaling pathway, and was abolished by PD98059, a potent Erk inhibitor. Consistent with in vitro experimental results, the upregulation of ICAM-1 and the activation of Erk signaling pathway were also observed in MDA-MB-231breast tumors in xenograft mouse obtained from our previous study. No obvious proliferation inhibition of PBMCs was observed following the exposure to AsIII combined with Tetra at the concentrations capable of inducing differentiation of MDA-MB-231 cells. CONCLUSION: The Erk signaling pathway may be crucially involved in the differentiation induction of breast cancer cells in vitro and in vivo. Collectively, our results suggest that the combination can probably serve as promising candidates for the development of novel therapeutic approaches for different types of breast cancer. AJTR
Authors: Jiameng Yin; Yajun Lin; Weiwei Fang; Xin Zhang; Jie Wei; Gang Hu; Pu Liu; Jie Niu; Jun Guo; Yongzhan Zhen; Jian Li Journal: Front Pharmacol Date: 2022-05-09 Impact factor: 5.988