Chen Runzhe, Zhang Hongming, Liu Ping, Wu Xue, Chen Baoan
Department of Hematology and Oncology (Key Discipline of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing 210009, Jiangsu Province, P.R. China.
J Cancer. 2017 Mar 7;8(5):839-851. doi: 10.7150/jca.17657. eCollection 2017.
Although the introduction of protease inhibitor bortezomib (BTZ) and immunomodulatory agent lenalidomide has led to improved outcomes in patients with multiple myeloma (MM), the disease remains incurable. Gambogenic acid (GNA), a polyprenylated xanthone isolated from the traditional Chinese medicine gamboge, has been reported to have potent antitumor activity and can effectively inhibit the survival and proliferation of cancer. In this study, we hypothesized that GNA could synergistically potentiate BTZ-induced apoptosis of MM cells and that combining BTZ and GNA may provide a more effective approach to treat MM. Hence, we investigate the and effects of BTZ and GNA, alone or in combination, against myeloma MM.1S cells. Cell counting kit-8 (CCK-8) assay, combination index (CI) isobologram, flow cytometry, western blot, xenograft tumor models, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and immunochemistry were used in this study. The results showed that BTZ and GNA combination treatment resulted in a strong synergistic action against the MM.1S cell line. Increased G2/M phase cells were triggered by BTZ, GNA and the combined treatment. The combined treatment could induce more markedly apoptosis of MM.1S cells via the activation of PARP cleavage, P53, Caspase-3 cleavage and Bax and inhibition of Bcl-2 expression. An increased antitumor effects of combination therapy of BTZ and GNA on MM.1S xenograft models were observed, and combining BTZ and GNA was found to be superior to a single agent. Our data support that a synergistic antitumor activity exists between BTZ and GNA, and provide a rationale for successful utilization of dual BTZ and GNA in MM chemotherapy in the future.
尽管蛋白酶体抑制剂硼替佐米（BTZ）和免疫调节剂来那度胺的引入已使多发性骨髓瘤（MM）患者的预后得到改善，但该疾病仍无法治愈。藤黄酸（GNA）是从传统中药藤黄中分离出的一种多异戊烯基呫吨酮，据报道具有强大的抗肿瘤活性，可有效抑制癌细胞的存活和增殖。在本研究中，我们假设GNA可协同增强BTZ诱导的MM细胞凋亡，且联合使用BTZ和GNA可能为治疗MM提供更有效的方法。因此，我们研究了BTZ和GNA单独或联合使用对骨髓瘤MM.1S细胞的作用及影响。本研究采用细胞计数试剂盒-8（CCK-8）检测、联合指数（CI）等效线图、流式细胞术、蛋白质印迹法、异种移植瘤模型、末端脱氧核苷酸转移酶dUTP缺口末端标记法（TUNEL）和免疫化学法。结果表明，BTZ和GNA联合治疗对MM.1S细胞系产生了强烈的协同作用。BTZ、GNA及联合治疗均引发了G2/M期细胞增加。联合治疗可通过激活PARP裂解、P53、Caspase-3裂解和Bax并抑制Bcl-2表达，更显著地诱导MM.1S细胞凋亡。观察到BTZ和GNA联合治疗对MM.1S异种移植模型的抗肿瘤作用增强，且发现联合使用BTZ和GNA优于单一药物。我们的数据支持BTZ和GNA之间存在协同抗肿瘤活性，并为未来在MM化疗中成功联合使用BTZ和GNA提供了理论依据。
