The role of Bcl-xL in synergistic induction of apoptosis by mapatumumab and oxaliplatin in combination with hyperthermia on human colon cancer.
Colorectal cancer is the third leading cause of cancer-related mortality in the world. The main cause of death because of colorectal cancer is hepatic metastases, which can be treated using isolated hepatic perfusion (IHP), allowing treatment of colorectal metastasis with various methods. In this study, we present a novel potent multimodality strategy comprising humanized death receptor 4 (DR4) antibody mapatumumab in combination with oxaliplatin and hyperthermia to treat human colon cancer cells. Oxaliplatin and hyperthermia sensitized colon cancer cells to mapatumumab in the mitochondrial-dependent apoptotic pathway and increased reactive oxygen species (ROS) production, leading to Bcl-xL phosphorylation at serine 62 in a c-jun-NH2-kinase (JNK)-dependent manner. Overexpression of Bcl-xL reduced the efficacy of the multimodality treatment, whereas phosphorylation of Bcl-xL decreased its antiapoptotic activity. The multimodality treatment dissociated Bcl-xL from Bax, allowing Bax oligomerization to induce cytochrome c release from mitochondria. In addition, the multimodality treatment significantly inhibited colorectal cancer xenografts' tumor growth. The successful outcome of this study will support the application of multimodality strategy to colorectal hepatic metastases.
Department of Surgery, University of Pittsburgh, Hillman Cancer Center, Pittsburgh, PA 15213, USA.
Xinxin
X
Song
Seog-Young
SY
Kim
Yong J
YJ
Lee
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D003131:Combined Modality Therapy; D045304:Cytochromes c / Q000378:metabolism; D004357:Drug Synergism; D045325:HCT116 Cells; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C494811:BCL2L1 protein, human; D009944:Organoplatinum Compounds; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000077150:Oxaliplatin; D045304:Cytochromes c; D048670:MAP Kinase Kinase 4; C507357:mapatumumab