Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan, Republic of Korea.
Oncol Rep. 2013 Mar;29(3):917-24. doi: 10.3892/or.2013.2228. Epub 2013 Jan 8.
The importance of anticancer stem cell research for breast cancer lies in the possibility of providing new approaches for an improved understanding of anticancer activity and cancer treatment. In this study, we demonstrated that the preclinical therapeutic efficacy of combining the multikinase inhibitor sorafenib with radiation was more effective in hypoxia-exposed breast cancer stem cells. We assessed cell viability and Annexin V to evaluate the combined effect of sorafenib and radiation following exposure to hypoxia. Our results showed that the synergistic cytotoxicity increased tumor cell apoptosis significantly and reduced cell proliferation in MDA-MB-231 and MCF-7 cells under hypoxic conditions compared to sorafenib or radiation alone in vitro. Additionally, the combined treatment induced G2/M cell cycle arrest. Notably, the combination of sorafenib and radiation eliminated CD44+CD24-/low cells preferentially, which highly expressed hypoxia-inducible factor (HIF)-1α and effectively inhibited primary and secondary mammosphere formation in MDA-MB-231 cells. A combined effect on MDA-MB‑231 cells in response to hypoxia was shown by inhibiting angiogenesis and metastasis by suppression of HIF-1α and matrix metalloproteinase-2 (MMP-2). Collectively, these results indicate that the efficacy of sorafenib combined with radiation for treating human breast cancer cells is synergistic and suggest a new therapeutic approach to prevent breast cancer progression by eliminating breast cancer stem cells.
抗癌干细胞研究对乳腺癌的重要性在于为提高对抗癌活性和癌症治疗的理解提供新的方法。在这项研究中，我们证明了多激酶抑制剂索拉非尼与放射联合应用的临床前治疗效果在暴露于缺氧环境的乳腺癌干细胞中更为有效。我们评估了细胞活力和 Annexin V，以评估在缺氧暴露下索拉非尼和放射联合应用的效果。我们的结果表明，与索拉非尼或放射单独作用相比，协同细胞毒性显著增加了肿瘤细胞凋亡，降低了 MDA-MB-231 和 MCF-7 细胞在缺氧条件下的细胞增殖。此外，联合治疗诱导 G2/M 细胞周期阻滞。值得注意的是，索拉非尼和放射的联合治疗优先消除 CD44+CD24-/low 细胞，这些细胞高度表达缺氧诱导因子 (HIF)-1α，并有效抑制 MDA-MB-231 细胞中的原发性和继发性类器官形成。通过抑制 HIF-1α 和基质金属蛋白酶-2 (MMP-2) 抑制血管生成和转移，对 MDA-MB-231 细胞在缺氧下的联合作用进行了显示。总之，这些结果表明，索拉非尼联合放射治疗人乳腺癌细胞的疗效具有协同作用，并提出了一种通过消除乳腺癌干细胞来预防乳腺癌进展的新治疗方法。
