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A Plant Natural Compound(Shikonin) with 4-Hydroxytamoxifen Synergistically Inhibits the Proliferation of Breast Cancer Cells through Activating Apoptosis Signaling Pathway in Vitro and in Vivo

LIN Hongyan  HE Deliu  HAN Hongwei  SUN Wenxue  FENG Lu  MA Yingying  YANG Minkai  LU Guihua  WANG Xiaoming  LU Guihua  QI Jinliang  YANG Yonghua  
【摘要】:4-Hydroxytamoxifen(4-OHT) is the first line of endocrine therapy for estrogen receptor positive(ER+) breast cancer patients. However, its efficacy was greatly reduced by triggering drug resistance to ER+ patients and insensitivity to estrogen receptor negative(ER-) patients, which reinforcing the need for discovery of new effective chemosensitization agents to 4-OHT. Shikonin(SK) is a plant natural product broadly explored in cancer therapy. In the current study, we are aiming to assess the combination effects of SK and 4-OHT on human breast cancer cells in vitro and in vivo, and investigate the underlying mechanisms. Through in vitro experiment, we found that SK and 4-OHT synergistically inhibited cell proliferation in both MCF-7 and MDA-MB-435 S cells and promoted apoptosis by reducing mitochondrial membrane potential and increasing intracellular reaction oxygen species(ROS) level. Western blot results demonstrated that the combination of SK and 4-OHT activated both the mitochondrial-dependent apoptosis and the death receptor pathway, significantly regulating the PI3 K/AKT/Caspase 9 signaling pathway. Further, compared with SK and 4-OHT alone, the combination of SK and 4-OHT could better inhibit the tumor growth in the xenograft model of nude mice. Our findings suggest that the combination of SK and 4-OHT is of great potential to achieve a more highly efficient anticancer effect in breast cancer therapy. SK may be a promising candidate as an adjuvant agent to 4-OHT for breast cancer treatments.

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