A coumarin derivative (RKS262) inhibits cell-cycle progression, causes pro-apoptotic signaling and cytotoxicity in ovarian cancer cells.
Coumarin derivative RKS262 belongs to a new class of potential anti-tumor agents. RKS262 was identified by structural optimization of Nifurtimox which is currently undergoing phase II clinical trials to treat high-risk neuroblastoma. In a NCI(60) cell-line assay RKS262 exhibited significant cytotoxicity in ovarian cancer cells and a variety of other cell lines exceeding effects of commercial drugs such as cisplatin, 5-FU, cyclophosphamide or sapacitabine. Various leukemia cell-lines were most sensitive (GI(50): ~ 10 nM) while several non-small cell lung cancer cell lines and few cell lines from other tissues were relatively resistant (GI(50) > 1 µM) to RKS262 treatment. The mechanism of cytotoxicity was examined using ovarian cancer cell-line OVCAR-3 as a model. RKS262 treatment resulted in a reduced mitochondria-transmembrane-depolarization potential. RKS262 effects included up-regulation of apoptotic markers and were not correlated with activation of pro-apoptotic MAP-Kinases (p38, SAP/JNK). RKS262 exerted strong inhibitory effects on oncogene ras, down-regulated DNA-pk KU-80 subunit expression and caused activation of Akt. A signature effect of RKS262 is the regulation of the mitochondrial Bcl2-family pathway. Pro-apoptotic factors Bid, Bad and Bok were up-regulated while expression of pro-survival factors Bcl-xl and Mcl-1 was inhibited. Moreover, at sub-cytotoxic doses RKS262 delayed OVCAR-3 cell-cycle progression through G2 phase and up-regulated p27 while cyclin-D1 and Cdk-6 were down-regulated, indicating that RKS262 is a specific cyclin/CDK inhibitor. In summary, RKS262 has been identified as a molecule belonging to a new class of potential chemotherapeutic agents affecting the viability of multiple cancer cell-lines and causing selective adverse effects on the viability of ovarian cancer cells.
Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital of RI, The Warren Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI 02905, USA.
Rakesh K
RK
Singh
Thilo S
TS
Lange
Kyu Kwang
KK
Kim
Laurent
L
Brard
D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000473:pathology*; D010984:Platinum / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D014408:Biomarkers, Tumor; D003374:Coumarins; D003499:Cyclic S-Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; C557291:RKS 262; D010984:Platinum; C030123:coumarin