title: HO-3867, a curcumin analog, sensitizes cisplatin-resistant ovarian carcinoma, leading to therapeutic synergy through STAT3 inhibition.
abstract: Cisplatin resistance is a major obstacle in the treatment of ovarian cancer. Drug combinations with synergistic or complementary functions are a promising strategy to overcome this issue. We studied the anticancer efficacy of a novel compound, HO-3867, used in combination with cisplatin against chemotherapy-resistant ovarian cancer. A2780R cells, a cisplatin-resistant human ovarian cancer cell line, were exposed to 1, 5, or 10 uM of HO-3867 alone or in combination with cisplatin (10 ug/ml) for 24 hours. Cell viability (MTT), proliferation (BrdU), cell-cycle analysis (FACS), and protein expression (western blot) were used for in vitro studies. STAT3 overexpression was performed using transfected STAT3 cDNA. In vivo studies used cisplatin-resistant xenograft tumors grown in nude mice and treated with 100-ppm HO-3867 and weekly injections of 4-mg/kg cisplatin. HO-3867/cisplatin combination treatment significantly inhibited cisplatin-resistant cell proliferation in a concentration-dependent manner. The inhibition was associated with increased expression of p53 and p21, and decreased expression of cdk5 and cyclin D1. Apoptosis was induced by activation of Bax, cytochrome c release, and stimulated cleavage of caspase-9, caspase-3, and PARP. Overexpression of STAT3 decreased the HO-3867-induced apoptosis. The combination treatment significantly inhibited the growth of cisplatin-resistant xenograft tumors with significant downregulation of pSTAT3, and without apparent toxicity to healthy tissues. The combination treatment exhibited synergistic anticancer efficacy, which appears largely due to HO-3867-induced downregulation of pSTAT3. The results, combined with the previously-reported safety features of HO-3867, suggest the potential use of this compound as a safe and effective adjuvant for the treatment of ovarian cancer.
authors: Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
authors: Karuppaiyah
authors: K
authors: Selvendiran
authors: Shabnam
authors: S
authors: Ahmed
authors: Alex
authors: A
authors: Dayton
authors: M Lakshmi
authors: ML
authors: Kuppusamy
authors: Brian K
authors: BK
authors: Rivera
authors: Tamás
authors: T
authors: Kálai
authors: Kálmán
authors: K
authors: Hideg
authors: Periannan
authors: P
authors: Kuppusamy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010881:Piperidones / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C541427:(3,5-bis((4-fluorophenyl)methylidene)-1-((1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)piperidin-4-one); D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D010881:Piperidones; D050796:STAT3 Transcription Factor; D003474:Curcumin; D002945:Cisplatin