title: A potent tumoricidal co-drug 'Bet-CA'--an ester derivative of betulinic acid and dichloroacetate selectively and synergistically kills cancer cells.
abstract: Selective targeting of cancer cells employing multiple combinations as co-drug holds promise for new generation therapeutics. Betulinic acid (BA), a plant secondary metabolite kills cancer cells and Dichloroacetate (DCA) is capable of reversing the Warburg phenotype by inhibiting pyruvate dehydrogenase kinase (PDK). Here, we report synthesis, characterization and tumoricidal potential of a co-drug Bet-CA, where a DCA molecule has been appended on C-3 hydroxyl group of BA to generate an ester derivative for increased solubility and subsequent cleavage by internal esterase(s) to release one unit each of BA and DCA. In vitro studies revealed pronounced synergistic cytotoxicity of Bet-CA against a broad spectrum of cancer cells and it selectively killed them when co-cultured with human fibroblasts. Bet-CA treatment increased reactive oxygen species (ROS) production, significantly altered mitochondrial membrane potential gradient (ΔΨm); followed by the release of cytochrome c (Cyt c) which prompted cells to undergo mitochondria mediated apoptosis. In vivo experimentation expectedly exhibited tumor inhibitory potential of Bet-CA and clinically achievable doses did not produce any apparent toxicity. Taken together, results suggestively raise an important corollary hypothesis stating that Bet-CA selectively and synergistically combats cancer without producing toxic manifestations and emerges to be the prospect for the new generation therapeutics.
authors.affiliation: Drug Development Diagnostics and Biotechnology Division, CSIR- Indian Institute of Chemical Biology (CSIR-IICB), 4, Raja S.C. Mullick Road, Kolkata-700032, West Bengal, India.
authors.forename: Suchandrima
authors.initials: S
authors.lastname: Saha
authors.affiliation: Drug Development Diagnostics and Biotechnology Division, CSIR- Indian Institute of Chemical Biology (CSIR-IICB), 4, Raja S.C. Mullick Road, Kolkata-700032, West Bengal, India.
authors.forename: Monisankar
authors.initials: M
authors.lastname: Ghosh
authors.affiliation: Drug Development Diagnostics and Biotechnology Division, CSIR- Indian Institute of Chemical Biology (CSIR-IICB), 4, Raja S.C. Mullick Road, Kolkata-700032, West Bengal, India.
authors.forename: Samir Kumar
authors.initials: SK
authors.lastname: Dutta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004357:Drug Synergism; D004952:Esters / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D041681:NIH 3T3 Cells; D018384:Oxidative Stress / Q000187:drug effects; D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species / Q000378:metabolism; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000094062:Betulinic Acid
chemical_list: D000970:Antineoplastic Agents; C000601985:Bet-CA compound; D004952:Esters; D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species; D014315:Triterpenes; D003999:Dichloroacetic Acid; D020169:Caspases; D000094062:Betulinic Acid