Alantolactone induces G1 phase arrest and apoptosis of multiple myeloma cells and overcomes bortezomib resistance
Alantolactone induces G1 phase arrest and apoptosis of multiple myeloma cells and overcomes bortezomib resistance
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DOI：
10.1007/s10495-015-1140-2
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发表时间：
2015-06
期刊：
影响因子：
7.2
通讯作者：
Yao Yao-Yao;Dandan Xia;Yueping Bian;Yueyue Sun;F. Zhu;B. Pan;Mingshan Niu;K. Zhao;Qingyun Wu;J. Qiao;Chunling Fu;Zhenyu Li;K. Xu
中科院分区：
文献类型：
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作者：
Yao Yao-Yao;Dandan Xia;Yueping Bian;Yueyue Sun;F. Zhu;B. Pan;Mingshan Niu;K. Zhao;Qingyun Wu;J. Qiao;Chunling Fu;Zhenyu Li;K. Xu
已经提取了几种倍半萜内酯，并证明其在多种癌症中发挥各种药理学功能。在这里，我们研究了土荆芥内酯（一种变应原性倍半萜内酯）对人多发性骨髓瘤（MM）的抗肿瘤作用，并显示土荆芥内酯在存在或不存在骨髓（BM）来源的基质细胞（HS-5）的情况下抑制MM细胞的生长，随后抑制G1期阻滞，并通过增加Annexin-V/7-AAD结合证明细胞凋亡，半胱天冬酶-3或半胱天冬酶-9活化和下调细胞外信号调节激酶1/2的活化。此外，土木香内酯减少MM细胞或HS-5细胞分泌MM存活和生长相关细胞因子、血管内皮生长因子，并抑制马槟榔碱诱导的破骨细胞生成。值得注意的是，土木香内酯还抑制硼替佐米耐药MM细胞的细胞增殖。综上所述，土木香内酯通过抑制细胞增殖、触发细胞凋亡、部分破坏骨髓微环境和克服蛋白酶体抑制剂耐药性等途径对MM发挥抗肿瘤作用，提示土木香内酯可能是治疗人类MM的一种新的治疗方法。
Several sesquiterpene lactones have been extracted and demonstrated to exert various pharmacological functions in a variety of cancers. Here, we investigated anti-tumor effect of alantolactone, an allergenic sesquiterpene lactone, on human multiple myeloma (MM) and showed alantolactone inhibited growth of MM cells, both in the presence or absence of bone marrow (BM)-derived stromal cells (HS-5), and subsequent G1 phase arrest, and apoptosis as demonstrated by increased Annexin-V/7-AAD binding, caspase-3 or caspase-9 activation and down-modulation of activation of extracellular signal-regulated kinases 1/2. In addition, alantolactone reduced the secretion of MM survival and growth-related cytokines, vascular endothelial growth factor, from MM cells or HS-5 cells, and inhibited cytokine-induced osteoclastogenesis. Notably, alantolactone also inhibited cell proliferation in bortezomib-resistant MM cells. Taken together, alantolactone exerted anti-tumor effect on MM by suppressing cell proliferation, triggering apoptosis, partly damaging the BM microenvironment and overcoming proteasome inhibitor resistance, suggesting alantolactone may be a novel therapeutic approach for the treatment of human MM.