CHK1 inhibi tion also kinase inhibitor CHIR99021 inhibits RAD51 binding to DNA. HSP90 is also implicated in the FA pathway and HR, since FANCA, BRCA2, CHK1 and CDKs are clients of HSP90. CDK inhibition leads to perturbation of cell cycle, proliferation and checkpoints, and compromises CHK1, BRCA2 and RAD51 Inhibitors,Modulators,Libraries functions, which can lead to impaired FA pathway and HR. A possible role for PKC, cathepsin B, lysosome and casein kinase II in the regulation of the FA pathway and HR has not been reported yet, and is worth testing in the future. Whether these chemicals directly target some components of the FA pathway remains to be determined. Further studies of the pathways affected by these inhibitors may shed light on new regulatory mechanisms of the FA pathway and HR. A total of 14 out of the 26 chemicals that inhibit the FA pathway sensitized ovarian cancer cells to cisplatin.

The majority showed Inhibitors,Modulators,Libraries a stronger synergism with cisplatin in FA proficient than in FA deficient cells, suggesting that FA pathway inhibitory activity of these compounds contributes to the cisplatin sensitization. The chemicals that synergized with cisplatin in both FA pathway deficient and proficient cells probably did so through mechanisms independent of the FA path way, such as inhibition of RAD51 Inhibitors,Modulators,Libraries recruitment and HR, or other mechanisms. The inhibition of the FA pathway and these other mechanisms may independently or synergistically participate in the increased sensitization to cisplatin observed using these chemicals. Most synergistic interactions between FA pathway inhibitors and cisplatin were stronger at higher killing levels, suggesting that these combinations are relevant for cancer therapy.

Inhibitors,Modulators,Libraries Although the role of the FA pathway in cellular resistance to ICL inducing agents, such as cisplatin, has been established, some FA pathway inhibitors did not synergize with cisplatin. Their activity on targets other than the FA pathway may prevent chemosensitization. Alternatively, cisplatin treatment may alleviate their toxicity. It is also possible that the effects of combining cisplatin and the inhibitors vary in cell type and context specific manners. Whether the inhibitors synergize with cisplatin in different types of tumor cells remains to be systematically determined. CHK1 inhibitors have been used in preclinical and clinical trials to treat p53 deficient and, more recently, p53 proficient cancers.

A CHK1 inhibitor, G?6976, has been suggested to sensitize FA deficient cells to cisplatin. Our results showed that CHK1 inhibitors sensitized p53 wild type, FA proficient and deficient ovarian cancer Inhibitors,Modulators,Libraries cells to cisplatin. SB218078 and UCN 01 showed a significantly stronger synergism with cisplatin in the FA proficient cell line than in the FA deficient cell line, while no difference between the two cell lines Crizotinib supplier was detected with G?6976.