Lee, Jinju Cho, Young Jae Lee, Jeong-Won Ahn, Hyung Jun 2024-01-19T17:32:39Z 2024-01-19T17:32:39Z 2021-09-05 2020-05-10 0168-3659 https://pubs.kist.re.kr/handle/201004/118627 Despite the promising anticancer effects of kinesin spindle protein (KSP) inhibition, functional plasticity of kinesins induced resistance against KSP inhibitors in a variety of cancers, leading to clinical failure. Additionally, paclitaxel is a widely used anticancer agent, but drug resistance has limited its use in the recurrent cancers. To overcome resistance against KSP inhibitors, we paired KSP inhibition with microtubule stabilization using KSP siRNA and paclitaxel. To enable temporal co-localization of both drugs in tumor cells in vivo, we exploited PEGylated cationic liposomes carrying both simultaneously. Drug synergism study shows that resistance against KSP inhibition can be suppressed by the action of microtubule-stabilizing paclitaxel, because microtubule stabilization prevents a different kinesin Kif15 from replacing all essential functions of KSP when KSP is inhibited. Our combination therapy showed more effective antiproliferative activity in vitro and in vivo than either paclitaxel or KSP siRNA alone. Ultimately, we could observe significantly improved therapeutic effects in the drug-resistant in vivo models, including cell line and patient-derived xenografts. Taken together, our combination therapy provides a potential anticancer strategy to overcome resistance against KSP inhibitors. Particularly, this strategy also provides an efficient approach to improve the therapeutic effects of paclitaxel in the drug-resistant cancers. English ELSEVIER COMBINATION THERAPY DELIVERY SIRNA CHEMOTHERAPY NANOPARTICLES EXPRESSION TOXICITY DYNAMICS PATIENT TARGETS KSP siRNA/paclitaxel-loaded PEGylated cationic liposomes for overcoming resistance to KSP inhibitors: Synergistic antitumor effects in drug-resistant ovarian cancer Article 10.1016/j.jconrel.2020.02.013 1 JOURNAL OF CONTROLLED RELEASE, v.321, pp.184 - 197 JOURNAL OF CONTROLLED RELEASE 321 184 197 scie scopus 000526179100014 2-s2.0-85079331637 Chemistry, Multidisciplinary Pharmacology & Pharmacy Chemistry Pharmacology & Pharmacy Article COMBINATION THERAPY DELIVERY SIRNA CHEMOTHERAPY NANOPARTICLES EXPRESSION TOXICITY DYNAMICS PATIENT TARGETS RNAi Paclitaxel Drug-resistance Resistance to KSP inhibition Antitumor effect Drug synergism