title: Synthetic triterpenoid cyano enone of methyl boswellate activates intrinsic, extrinsic, and endoplasmic reticulum stress cell death pathways in tumor cell lines.
abstract: We explored the effect of a novel synthetic triterpenoid compound cyano enone of methyl boswellates (CEMB) on various prostate cancer and glioma cancer cell lines. CEMB displayed concentration-dependent cytotoxic activity with submicromolar lethal dose 50% (LD(50)) values in 10 of 10 tumor cell lines tested. CEMB-induced cytotoxicity is accompanied by activation of downstream effector caspases (caspases 3 and 7) and by upstream initiator caspases involved in both the extrinsic (caspase 8) and intrinsic (caspase 9) apoptotic pathways. By using short interfering RNAs (siRNA), we show evidence that knockdown of caspase 8, DR4, Apaf-1, and Bid impairs CEMB-induced cell death. Similar to other proapoptotic synthetic triterpenoid compounds, CEMB-induced apoptosis involved endoplasmic reticulum stress, as shown by partial rescue of tumor cells by siRNA-mediated knockdown of expression of genes involved in the unfolded protein response such as IRE1α, PERK, and ATF6. Altogether, our results suggest that CEMB stimulates several apoptotic pathways in cancer cells, suggesting that this compound should be evaluated further as a potential agent for cancer therapy.
authors: Sanford-Burnham Medical Research Institute, 10901 N Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Palaniyandi
authors: P
authors: Ravanan
authors: Renata
authors: R
authors: Sano
authors: Priti
authors: P
authors: Talwar
authors: Satoshi
authors: S
authors: Ogasawara
authors: Shu-ichi
authors: S
authors: Matsuzawa
authors: Michael
authors: M
authors: Cuddy
authors: Sanjay K
authors: SK
authors: Singh
authors: G S R Subba
authors: GS
authors: Rao
authors: Paturu
authors: P
authors: Kondaiah
authors: John C
authors: JC
authors: Reed
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000378:metabolism; D009828:Oleanolic Acid / Q000737:chemistry; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014315:Triterpenes / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D053477:Apoptotic Protease-Activating Factor 1; D051023:BH3 Interacting Domain Death Agonist Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014315:Triterpenes; D009828:Oleanolic Acid; D020169:Caspases