Journal article
Synergistic anticancer effect of cisplatin and Chal-24 combination through IAP and c-FLIPL degradation, Ripoptosome formation and autophagy-mediated apoptosis
Oncotarget, Vol.6(3), pp.1640-1651
01/30/2015
DOI: 10.18632/oncotarget.2746
PMID: 25682199
Abstract
Drug resistance is a major hurdle in anticancer chemotherapy. Combined therapy using drugs with distinct mechanisms of function 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 report, 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/Beclin1 pathway for autophagy activation, its combination with Chal-24 strongly triggered 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, the cisplatin and Chal-24 combination induced dramatic degradation of cellular FLICE (FADD-like IL-1 beta-converting enzyme)inhibitory protein large (cFLIPL) which suppresses Ripoptosome-mediated apoptosis activation. These results establish a novel mechanism for potentiation of anticancer activity with the combination of Chal-24 and cisplatin: to enhance apoptosis signaling through Ripoptosome formation and to release the apoptosis brake through c-FLIPL degradation. Altogether, our work suggests that the combination of Chal-24 and cisplatin could be employed to improve chemotherapy efficacy.
Details
- Title: Subtitle
- Synergistic anticancer effect of cisplatin and Chal-24 combination through IAP and c-FLIPL degradation, Ripoptosome formation and autophagy-mediated apoptosis
- Creators
- Shaoqing Shi - Lovelace Respiratory Research InstituteQiong Wang - Lovelace Respiratory Research InstituteJennings Xu - Lovelace Respiratory Research InstituteJun-Ho Jang - 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 InstituteLovelace Biomedical and Environmental Research Institute, Albuquerque, NM (United States)
- Resource Type
- Journal article
- Publication Details
- Oncotarget, Vol.6(3), pp.1640-1651
- DOI
- 10.18632/oncotarget.2746
- PMID
- 25682199
- ISSN
- 1949-2553
- eISSN
- 1949-2553
- Publisher
- Impact Journals Llc
- Number of pages
- 12
- Grant note
- China Scholarship Council R01ES017328 / NIEHS/NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) R01CA142649 / NCI/NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 81272821 / National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) DE-FG02-09ER64783 / Office of Science (BER), U.S. Department of Energy; United States Department of Energy (DOE)
- Language
- English
- Date published
- 01/30/2015
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985214104202771
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