Abstract
Abstract 2560: The cisplatin and Chal-24 combination synergistically kills cancer cells through IAP and c-FLIP degradation, Ripoptosome formation and autophagy-mediated apoptosis
Cancer research (Chicago, Ill.), Vol.75(15_Supplement), pp.2560-2560
08/01/2015
DOI: 10.1158/1538-7445.AM2015-2560
Abstract
Because chemoresistance is the major hurdle of anticancer therapy, sensitizing cancer cells to chemotherapy is a main challenge for improving survival in cancer patients. Combined therapy by using drugs with distinct functioning mechanisms may increase anticancer efficacy. We have recently identified the novel chalcone derivative chalcone-24 (Chal-24) as a potential therapeutic that kills cancer cells through activation of an autophagy-mediated necroptosis pathway. In this study, we investigated if Chal-24 can be combined with the frontline genotoxic anticancer drug cisplatin for cancer therapy. The combination of Chal-24 and cisplatin synergistically induced apoptotic cytotoxicity in lung cancer cell lines, which was dependent on Chal-24-induced autophagy. While cisplatin slightly potentiated the JNK/Bcl2/Beklin1 pathway for autophagy activation, it strongly triggered Chal-24-induced proteasomal degradation of the cellular inhibitor of apoptosis proteins (c-IAPs) and formation of the Ripoptosome complex that contains RIP1, FADD and caspase 8. Furthermore, cisplatin induced dramatic degradation of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein large (cFLIPL) which suppresses Ripoptosome-mediated apoptosis activation. These results establish a dual mechanism for potentiation of anticancer activity with combination of Chal-24 and cisplatin: to enhance apoptosis signaling through Ripoptosome formation and to release the apoptosis brake through c-FLIP degradation. Altogether, our work suggests that combination of Chal-24 and cisplatin could be employed for improving chemotherapy efficacy. (Supported by R01ES017328 (NIEHS/NIH) and DE-FG02-09ER64783 (DOE). Citation Format: Shaoqing Shi, Qiong Wang, Jennings Xu, Mabel T. Padilla, Toru Nyunoya, Chengguo Xing, Lin Zhang, Yong Lin. The cisplatin and Chal-24 combination synergistically kills cancer cells through IAP and c-FLIP degradation, Ripoptosome formation and autophagy-mediated apoptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2560. doi:10.1158/1538-7445.AM2015-2560
Details
- Title: Subtitle
- Abstract 2560: The cisplatin and Chal-24 combination synergistically kills cancer cells through IAP and c-FLIP degradation, Ripoptosome formation and autophagy-mediated apoptosis
- Creators
- Shaoqing Shi - Lovelace Respiratory Research InstituteQiong Wang - Lovelace Respiratory Research InstituteJennings Xu - Lovelace Respiratory Research InstituteMabel T. Padilla - Lovelace Respiratory Research InstituteToru Nyunoya - Lovelace Respiratory Research InstituteChengguo Xing - University of MinnesotaLin Zhang - Sichuan UniversityYong Lin - Lovelace Respiratory Research Institute
- Resource Type
- Abstract
- Publication Details
- Cancer research (Chicago, Ill.), Vol.75(15_Supplement), pp.2560-2560
- DOI
- 10.1158/1538-7445.AM2015-2560
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Publisher
- AMER ASSOC CANCER RESEARCH
- Language
- English
- Date published
- 08/01/2015
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985217040102771
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