Combination effects of SC144 and cytotoxic anticancer agents

Previously, we synthesized a series of hydrazide class ofcompounds and examined their cytotoxicity in a number ofcancer cell lines. Among these analogues, SC144 exhibitedpotent cytotoxicity against a panel of drug-sensitive anddrug-resistant cancer cell lines. To further explore itstherapeutic potentials in the combination settings, weevaluated the synergy between SC144 and selectedconventional chemotherapeutic agents in in-vitro cancercell models. SC144 showed synergism with both5-fluorouracil and oxaliplatin when cotreated in colorectalcancer HT29 cells. Pretreatment with SC144 inoxaliplatin-resistant HTOXAR3 cells was more effectivethan oxaliplatin pretreatment. In addition, thecombination of SC144 and paclitaxel exhibited synergismin MDA-MB-435 cells with a schedule-dependent block incell cycle. In an MDA-MB-435 mouse xenograft model,coadministration of SC144 and paclitaxel delayed tumorgrowth in an SC144 dose-dependent manner. Evaluationof the pharmacokinetics of SC144 revealed thatintraperitoneal administration of SC144 showed atwo-compartmental pharmacokinetics elimination profilethat was not observed in the oral dosing. In summary,these studies further validate SC144 as a novel anticanceragent and provide insights for developing combinationtherapies for both drug-sensitive and drug-resistantcancers.