Cotylenin A and arsenic trioxide cooperatively suppress cell proliferation and cell invasion activity in human breast cancer cells
Cotylenin A and arsenic trioxide cooperatively suppress cell proliferation and cell invasion activity in human breast cancer cells
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DOI：
10.3892/ijo.2014.2760
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发表时间：
2015-02-01
影响因子：
5.2
通讯作者：
Kumakura, Shunichi
中科院分区：
文献类型：
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作者：
Kasukabe, Takashi;Okabe-Kado, Junko;Kumakura, Shunichi
三氧化二砷 (ATO) 是一种经批准的治疗急性早幼粒细胞白血病 (APL) 的药物。它还显示出治疗多发性骨髓瘤和包括乳腺癌在内的各种实体瘤的潜力。在非 APL 和实体瘤细胞中诱导细胞凋亡需要高毒性浓度，这是其在其他血液恶性肿瘤和实体瘤中使用的主要限制。我们研究了白血病细胞分化诱导剂是否可以控制实体瘤细胞的生长。在本研究中，我们发现子叶素 A（一种植物生长调节剂和骨髓白血病细胞分化的有效诱导剂）显着增强了 ATO 诱导的对液体培养物中细胞生长的抑制，以及 ATO 诱导的对人乳腺癌 MCF-7 和 MDA-MB-231 细胞半固体培养物中贴壁独立生长的抑制。 ISIR-005（一种合成的子叶素 A 衍生物）也能够增强 ATO 诱导的生长抑制。子叶蛋白A和ATO的联合处理在MCF-7细胞中诱导裂解的caspase-7，其浓度是单独的ATO几乎不诱导且单独的子叶蛋白A仅微弱诱导的浓度。当cotylenin A和ATO同时存在时，MCF-7细胞中survivin的表达显着降低，尽管单独的cotylenin A或ATO仅轻微降低survivin的表达。 N:乙酰半胱氨酸预处理显着降低了联合治疗诱导的细胞生长抑制。这些数据表明，诱导裂解的 caspase-7、抑制生存素和氧化反应是子叶蛋白 A 和 ATO 诱导的 MCF-7 细胞生长协同抑制中的重要事件。此外，我们发现利用基于阻抗的 xCELLigence 实时细胞分析技术确定，cotylenin A 和 ATO 联合治疗也可以有效抑制 MDA-MB-231 细胞的侵袭能力。这些结果表明，cotylenin A 是 ATO 诱导的人类乳腺癌抗癌活性的有吸引力的增强剂。
Arsenic trioxide (ATO) is an approved treatment for acute promyelocytic leukemia (APL). It has also shown potential for treatment of multiple myeloma and various solid tumors including breast cancer. The requirement of high, toxic concentrations for the induction of apoptosis in non-APL and solid tumor cells is a major limitation for its use in other hematological malignancies and solid tumors. We have examined whether inducers of differentiation of leukemia cells can control the growth of solid tumor cells. In the present study, we found that cotylenin A, a plant growth regulator and a potent inducer of differentiation in myeloid leukemia cells, significantly potentiated both ATO-induced inhibition of cell growth in a liquid culture, and ATO-induced inhibition of anchorage-independent growth in a semi-solid culture in human breast cancer MCF-7 and MDA-MB-231 cells. ISIR-005 (a synthetic cotylenin A-derivative) was also able to enhance ATO-induced growth inhibition. The combined treatment with cotylenin A and ATO induced cleaved caspase-7 in MCF-7 cells at the concentrations which ATO alone scarcely induced and cotylenin A alone only weakly induced. Expression of survivin in MCF-7 cells was Markedly decreased with the presence of both cotylenin A and ATO, although the expression of survivin was only slightly decreased by cotylenin A or ATO alone. The pretreatment with N:acetylcysteine significantly reduced the combination treatment-induced cell growth inhibition. These data suggest that induction of cleaved caspase-7, inhibition of survivin and oxidative responses are important events in the corporative inhibition in the growth of MCF-7 cells induced by both cotylenin A and ATO. Furthermore, we found that the combined treatment with cotylenin A and ATO also could be effective in suppressing the invasive capacity of MDA-MB-231 cells determined with the impedance-based xCELLigence Real-Time Cell Analysis technology. These results suggest that cotylenin A is an attractive enhancer for the ATO-induced anticancer activities in human breast cancer.