title: Combination effects of SC144 and cytotoxic anticancer agents.
abstract: Previously, we synthesized a series of hydrazide class of compounds and examined their cytotoxicity in a number of cancer cell lines. Among these analogues, SC144 exhibited potent cytotoxicity against a panel of drug-sensitive and drug-resistant cancer cell lines. To further explore its therapeutic potentials in the combination settings, we evaluated the synergy between SC144 and selected conventional chemotherapeutic agents in in-vitro cancer cell models. SC144 showed synergism with both 5-fluorouracil and oxaliplatin when cotreated in colorectal cancer HT29 cells. Pretreatment with SC144 in oxaliplatin-resistant HTOXAR3 cells was more effective than oxaliplatin pretreatment. In addition, the combination of SC144 and paclitaxel exhibited synergism in MDA-MB-435 cells with a schedule-dependent block in cell cycle. In an MDA-MB-435 mouse xenograft model, coadministration of SC144 and paclitaxel delayed tumor growth in an SC144 dose-dependent manner. Evaluation of the pharmacokinetics of SC144 revealed that intraperitoneal administration of SC144 showed a two-compartmental pharmacokinetics elimination profile that was not observed in the oral dosing. In summary, these studies further validate SC144 as a novel anticancer agent and provide insights for developing combination therapies for both drug-sensitive and drug-resistant cancers.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences , School of Pharmacy, University of Southern California, Los Angeles, California, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Oshima
authors.forename: Xuefei
authors.initials: X
authors.lastname: Cao
authors.forename: Fedora
authors.initials: F
authors.lastname: Grande
authors.forename: Roppei
authors.initials: R
authors.lastname: Yamada
authors.forename: Antonio
authors.initials: A
authors.lastname: Garofalo
authors.forename: Stan
authors.initials: S
authors.lastname: Louie
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati