The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis

• Published in: Cancer biology & therapy 2017-08, Vol.18 (8), p.584-595
• Main Authors: Wang, Gaoxiang, Zhou, Pan, Chen, Xing, Zhao, Lei, Tan, Jiaqi, Yang, Yang, Fang, Yong, Zhou, Jianfeng
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; antitumor; Apoptosis; Apoptosis - drug effects; autophagy; Autophagy - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; elaiophylin; endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Female; Humans; Macrolides - pharmacology; Macrolides - therapeutic use; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Mutation; Research Paper; Signal Transduction; Taurochenodeoxycholic Acid - pharmacology; Tumor Suppressor Protein p53 - genetics; xenograft model; Xenograft Model Antitumor Assays; Zebrafish
• ISSN: 1538-4047; 1555-8576
• DOI: 10.1080/15384047.2017.1345386

Elaiophylin is a natural compound and a novel and potent inhibitor of late stage autophagy with outstanding antitumor activity in human ovarian cancer cells. However, the possible biologic effects and functional linkage between elaiophylin and multiple myeloma (MM) have not been explored. This study aimed to assess the effect of elaiophylin on MM cells with mutant TP53 and the possible molecular mechanism. The results suggested that elaiophylin exerted anti-myeloma activity by inducing apoptosis and proliferation arrest. As expected, elaiophylin blocked autophagy flux in MM cells. Subsequently, persistent activation of endoplasmic reticulum (ER) stress was induced. Moreover, the apoptotic effect was to some extent attenuated by the ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Further studies indicated that elaiophylin effectively suppressed MM cell growth without obvious side effects in zebrafish embryo and mouse xenograft models. Taken together, our data are the first to demonstrate that exposure of human MM cells with mutant TP53 to elaiophylin blocked autophagy flux and thus induced cell death, which partially involved ER stress-associated apoptosis. Targeted disruption of the cellular protein handling system by elaiophylin is therefore a promising therapeutic strategy for overcoming incurable MM, even when TP53 mutations are present.