title: Inhibition of cisplatin-resistance by RNA interference targeting metallothionein using reducible oligo-peptoplex.
abstract: Effective intracellular level of a platinum anti-cancer drug, cisplatin, following repeated injections can be decreased either by the active efflux via ATP pump or by interactions with glutathione and metallothionein. Cisplatin in cytoplasm preferably binds to cysteine-rich proteins such as glutathione and metallothionein (MT). Detoxification of cisplatin by intracellular thiol-containing proteins has been considered to be major hurdles to overcome. The short hairpin RNA targeting MT (shMT) was tested to down-regulate MT and recover cisplatin resistance. A reducible polymer, poly(oligo-d-arginine) (rPOA), formed stable complex with shMT and demonstrated superior transfection efficiency. Efficient transfection of shMT/rPOA oligo-peptoplexes was found to significantly inhibit MT over-expression, resulting in 45% decrease of cell viability compared to the cisplatin alone group. This decrease was mediated by the synergistic effect of shMT/rPOA oligo-peptoplex and cisplatin. Co-administration of shMT/rPOA oligo-peptoplex and cisplatin in in vivo tumor model showed noticeable tumor-suppressing effect by inducing reversal of cisplatin resistance following effective intracellular delivery of shMT by rPOA. Combination therapy through co-administration of shMT/rPOA oligo-peptoplex and cisplatin was found to effectively reverse cisplatin resistance by RNA interference and consequently improve anti-cancer activity of cisplatin.
authors.affiliation: Department of Bioengineering, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Jong-Hwan
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Chae
authors.affiliation: Department of Bioengineering, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Jang Kyoung
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Hyung Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Jee Young
authors.initials: JY
authors.lastname: Chung
authors.affiliation: Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-791, Republic of Korea. Electronic address: yongheekim@hanyang.ac.kr.
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005079:Excipients; D020868:Gene Silencing; D008546:Melanoma, Experimental / Q000188:drug therapy; D008668:Metallothionein / Q000096:biosynthesis*; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D005079:Excipients; D034741:RNA, Small Interfering; D008668:Metallothionein; D002945:Cisplatin
keywords: Cisplatin resistance; Combination therapy; Metallothionein; RNA interference