Sensitization for anticancer drug-induced apoptosis by betulinic Acid.
We previously described that betulinic acid (BetA), a naturally occurring pentacyclic triterpenoid, induces apoptosis in tumor cells through the mitochondrial pathway. Here, for the first time, we provide evidence that BetA cooperated with anticancer drugs to induce apoptosis and to inhibit clonogenic survival of tumor cells. Combined treatment with BetA and anticancer drugs acted in concert to induce loss of mitochondrial membrane potential and the release of cytochrome c and Smac from mitochondria, resulting in activation of caspases and apoptosis. Overexpression of Bcl-2, which blocked mitochondrial perturbations, also inhibited the cooperative effect of BetA and anticancer drugs, indicating that cooperative interaction involved the mitochondrial pathway. Notably, cooperation of BetA and anticancer drugs was found for various cytotoxic compounds with different modes of action (e.g., doxorubicin, cisplatin, Taxol, VP16, or actino-mycin D). Importantly, BetA and anticancer drugs cooperated to induce apoptosis in different tumor cell lines, including p53 mutant cells, and also in primary tumor cells, but not in human fibroblasts indicating some tumor specificity. These findings indicate that using BetA as sensitizer in chemotherapy-based combination regimens may be a novel strategy to enhance the efficacy of anticancer therapy, which warrants further investigation.
Fulda
Simone
S
University Children's Hospital, Prittwitzstrasse 43, Ulm 89075, Germany. simone.fulda@medizin.uni-ulm.de
Debatin
Klaus-Michael
KM
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D002945:Cisplatin / Q000008:administration & dosage; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins; D045304:Cytochromes c / Q000378:metabolism; D003609:Dactinomycin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000008:administration & dosage; D005347:Fibroblasts / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D053978:Pentacyclic Triterpenes; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014315:Triterpenes / Q000008:administration & dosage; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000094062:Betulinic Acid
D015938:Complement Membrane Attack Complex; D006023:Glycoproteins; D053978:Pentacyclic Triterpenes; D019253:Proto-Oncogene Proteins c-bcl-2; C047610:SC5b-9 protein complex; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; D005047:Etoposide; D004317:Doxorubicin; D003165:Complement System Proteins; D045304:Cytochromes c; D020169:Caspases; D017239:Paclitaxel; D002945:Cisplatin; D000094062:Betulinic Acid