title: Synergistic combination therapy with nanoliposomal C6-ceramide and vinblastine is associated with autophagy dysfunction in hepatocarcinoma and colorectal cancer models.
abstract: Autophagy, a catabolic survival pathway, is gaining attention as a potential target in cancer. In human liver and colon cancer cells, treatment with an autophagy inducer, nanoliposomal C6-ceramide, in combination with the autophagy maturation inhibitor, vinblastine, synergistically enhanced apoptotic cell death. Combination treatment resulted in a marked increase in autophagic vacuole accumulation and decreased autophagy maturation, without diminution of the autophagy flux protein P62. In a colon cancer xenograft model, a single intravenous injection of the drug combination significantly decreased tumor growth in comparison to the individual treatments. Most importantly, the combination treatment did not result in increased toxicity as assessed by body weight loss. The mechanism of combination treatment-induced cell death both in vitro and in vivo appeared to be apoptosis. Supportive of autophagy flux blockade as the underlying synergy mechanism, treatment with other autophagy maturation inhibitors, but not autophagy initiation inhibitors, were similarly synergistic with C6-ceramide. Additionally, knockout of the autophagy protein Beclin-1 suppressed combination treatment-induced apoptosis in vitro. In conclusion, in vitro and in vivo data support a synergistic antitumor activity of the nanoliposomal C6-ceramide and vinblastine combination, potentially mediated by an autophagy mechanism.
authors.affiliation: Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, United States.
authors.forename: Pavan P
authors.initials: PP
authors.lastname: Adiseshaiah
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Clogston
authors.forename: Christopher B
authors.initials: CB
authors.lastname: McLeland
authors.forename: Jamie
authors.initials: J
authors.lastname: Rodriguez
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Potter
authors.forename: Barry W
authors.initials: BW
authors.lastname: Neun
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Skoczen
authors.forename: Sriram S
authors.initials: SS
authors.lastname: Shanmugavelandy
authors.forename: Mark
authors.initials: M
authors.lastname: Kester
authors.forename: Stephan T
authors.initials: ST
authors.lastname: Stern
authors.forename: Scott E
authors.initials: SE
authors.lastname: McNeil
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D056945:Hep G2 Cells; D006801:Humans; D007275:Injections, Intravenous; D008081:Liposomes; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D034622:RNA Interference; D000071456:Sequestosome-1 Protein; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D014747:Vinblastine / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D002518:Ceramides; D008081:Liposomes; D008565:Membrane Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101954:N-caproylsphingosine; D014747:Vinblastine; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7
keywords: Autophagy; Ceramide; Combination therapy