title: HSP32 (HO-1) inhibitor, copoly(styrene-maleic acid)-zinc protoporphyrin IX, a water-soluble micelle as anticancer agent: In vitro and in vivo anticancer effect.
abstract: We reported previously the antitumor effect of heme oxygenase-1 (HO-1) inhibition by zinc protoporphyrin IX (ZnPP). ZnPP per se is poorly water soluble and thus cannot be used as anticancer chemotherapeutic. Subsequently, we developed water-soluble micelles of ZnPP using styrene-maleic acid copolymer (SMA), which encapsulated ZnPP (SMA-ZnPP). In this report, the in vitro and in vivo therapeutic effects of SMA-ZnPP are described. In vitro experiments using 11 cultured tumor cell lines and six normal cell lines revealed a remarkable cytotoxicity of SMA-ZnPP against various tumor cells; average IC(50) is about 11.1 μM, whereas the IC(50) to various normal cells is significantly higher, that is, more than 50 μM. In the pharmacokinetic study, we found that SMA-ZnPP predominantly accumulated in the liver tissue after i.v. injection, suggesting its applicability for liver cancer. As expected, a remarkable antitumor effect was achieved in the VX-2 tumor model in the liver of rabbit that is known as one the most difficult tumor models to cure. Antitumor effect was also observed in murine tumor xenograft, that is, B16 melanoma and Meth A fibrosarcoma. Meanwhile, no apparent side effects were found even at the dose of ∼7 times higher concentration of therapeutics dose. These findings suggest a potential of SMA-ZnPP as a tool for anticancer therapy toward clinical development, whereas further investigations are warranted.
authors.affiliation: Laboratory of Microbiology and Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.forename: Khaled
authors.initials: K
authors.lastname: Greish
authors.forename: Haibo
authors.initials: H
authors.lastname: Qin
authors.forename: Long
authors.initials: L
authors.lastname: Liao
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maeda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D045744:Cell Line, Tumor; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D005260:Female; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D008665:Metalloporphyrins / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011137:Polystyrenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D011817:Rabbits; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D008298:Maleates; D008665:Metalloporphyrins; D008823:Micelles; D011137:Polystyrenes; C518727:copoly(styrene-maleic acid)-zinc protoporphyrin; D051547:Heme Oxygenase-1