Anticancer activity in human multiple myeloma U266 cells: synergy between cryptotanshinone and arsenic trioxide
Anticancer activity in human multiple myeloma U266 cells: synergy between cryptotanshinone and arsenic trioxide
复制标题
人多发性骨髓瘤 U266 细胞的抗癌活性：隐丹参酮与三氧化二砷的协同作用
DOI：
10.1039/c3mt20272k
复制
发表时间：
2013-01-01
期刊：
影响因子：
3.4
通讯作者：
Chen, Zhe
中科院分区：
文献类型：
--
作者：
Liu, Pei;Xu, Shi;Chen, Zhe
三氧化二砷（As2O3）最近被确定为治疗急性早幼粒细胞白血病最有效的药物之一。然而，它对非早幼粒细胞白血病或其他类型的恶性肿瘤的疗效较低。本研究的目的是探索基于As2O3治疗人类多发性骨髓瘤的新策略。在这里，我们首次报道了隐丹参酮（CPT）和As2O3协同作用增强人类多发性骨髓瘤U266细胞的细胞毒性。特别是，iAs(III) + CPT联合处理后，凋亡相关蛋白（如cleaved poly （adp -核糖）聚合酶（PARP）、caspase-3和-9）显著增加，而存活蛋白（如Bcl-2和survivin）的表达受到抑制，提示凋亡是通过线粒体介导的凋亡途径诱导的。此外，单独暴露于As2O3或CPT后，在细胞中没有观察到明显的影响。为了更好地了解分子机制，我们进一步测定了STAT3、JNK、ERK和p38的磷酸化水平。有趣的是，联合治疗显著诱导JNK和p38的磷酸化，而未观察到STAT3或ERK的明显抑制。此外，仅JNK抑制剂预处理能部分消除人多发性骨髓瘤细胞的凋亡诱导作用，而p38抑制剂未起作用，提示JNK途径可能通过iAs（III）和CPT联合作用在诱导细胞凋亡中发挥重要作用。需要进一步的研究来评估这种体内协同抗癌作用。在不久的将来，这种新方法可能用于多发性骨髓瘤（MM）的临床治疗。
Arsenic trioxide (As2O3) has been recently established as one of the most effective drugs for the treatment of patients with acute promyelocytic leukemia. However, it has exhibited to be less efficient for the non-promyelocytic leukaemia or other types of malignant tumors. The purpose of the present study was to explore new therapeutic strategies based on As2O3 for human multiple myeloma. Here, we first report cryptotanshinone (CPT) and As2O3 synergy for enhanced cytotoxicity in human multiple myeloma U266 cells. In particular, the apoptosis related proteins (e.g., cleaved poly (ADP-ribose) polymerase (PARP), caspase-3 and -9) were significantly increased by the combination treatment (iAs(III) + CPT), whereas, the expression of survival proteins such as Bcl-2 and survivin was suppressed, suggesting that the induction of apoptosis through mitochondrial-mediated apoptotic pathway. In addition, there were no appreciable effects observed in cells after exposure to either As2O3 or CPT alone. In order to better understand the molecular mechanism, we further determined the phosphorylation of STAT3, JNK, ERK and p38. Interestingly, phosphorylation of JNK and p38 were remarkably induced by combination treatment, and no significant inhibition of STAT3 or ERK was observed. In addition, induction of apoptosis in human multiple myeloma cells was partially abrogated only by pretreatment with JNK inhibitor and not by p38 inhibitor, suggesting that JNK pathway may play an important role in induction of apoptosis by the combination of iAs(III) and CPT. Further studies are needed to evaluate this synergistic anticancer effect in vivo. In the near future, this new approach might be used clinically for multiple myeloma (MM) treatment.