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Oncotarget ; 6(18): 16623-37, 2015 Jun 30.
Article in English | MEDLINE | ID: mdl-26009874

ABSTRACT

Oral and oropharyngeal cancers are the sixth most common cancers worldwide. Despite intensive investigation, oral squamous cell carcinomas (OSCC) represent a clinical challenge resulting in significant morbidity and mortality. Resistance to cell death is common in OSCC and is often mediated by the Bcl-2 family proteins. Among all anti-apoptotic Bcl-2 family members, Mcl-1 functions as a major survival factor, particularly in solid cancers. Despite the confirmed importance of Mcl-1 in several neoplasms, the role of Mcl-1 in OSCC survival has yet to be explored. In this study, we found that knocking down Mcl-1 sensitized OSCC cells to ABT-737, which binds to Bcl-2/Bcl-xL but not Mcl-1. We report for the first time that a BH3 mimetic, Sabutoclax, which functions as an inhibitor of all anti-apoptotic Bcl-2 proteins, induced cancer-specific cell death in an Mcl-1-dependent manner through both apoptosis and toxic mitophagy. In vivo studies demonstrated that Sabutoclax alone decreased tumor growth in a carcinogen-induced tongue OSCC mouse model. In a combination regimen, Sabutoclax and COX-2 inhibitor, Celecoxib, synergistically inhibited the growth of OSCC in vitro and also significantly reduced OSCC tumor growth in vivo. Overall, these results identify Mcl-1 as a therapeutic prospective target in OSCC.


Subject(s)
Biphenyl Compounds/pharmacology , Carcinoma, Squamous Cell/drug therapy , Celecoxib/pharmacology , Gossypol/analogs & derivatives , Mouth Neoplasms/drug therapy , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Nitrophenols/pharmacology , Sulfonamides/pharmacology , 4-Nitroquinoline-1-oxide/pharmacology , Animals , Apoptosis/drug effects , Apoptosis Regulatory Proteins/genetics , Autophagy-Related Protein 5 , Autophagy-Related Protein 7 , Beclin-1 , Cell Line, Tumor , Cyclooxygenase 2 Inhibitors/pharmacology , Female , Gossypol/pharmacology , Humans , Membrane Proteins/genetics , Mice , Mice, Inbred BALB C , Mice, Nude , Microtubule-Associated Proteins/genetics , Mitophagy/drug effects , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors , Piperazines/pharmacology , Proto-Oncogene Proteins/genetics , Quinolones/pharmacology , RNA Interference , RNA, Small Interfering , Random Allocation , Ubiquitin-Activating Enzymes/genetics , Xenograft Model Antitumor Assays , bcl-X Protein/antagonists & inhibitors
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