Evaluation of Antitumor Effects of Folate-Conjugated Methyl-β-cyclodextrin in Melanoma

• Published in: Biological & pharmaceutical bulletin 2015/03/01, Vol.38(3), pp.374-379
• Main Authors: Motoyama, Keiichi, Onodera, Risako, Tanaka, Nao, Kameyama, Kazuhisa, Higashi, Taishi, Kariya, Ryusho, Okada, Seiji, Arima, Hidetoshi
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; autophagy; Autophagy - drug effects; beta-Cyclodextrins - pharmacology; beta-Cyclodextrins - therapeutic use; Cyclodextrins - pharmacology; Cyclodextrins - therapeutic use; Drug Combinations; Endocytosis; folate receptor; Folic Acid - metabolism; Folic Acid - pharmacology; Folic Acid - therapeutic use; Folic Acid Transporters - metabolism; Humans; melanoma; Melanoma - drug therapy; Melanoma - metabolism; methyl-β-cyclodextrin; Mice, Inbred BALB C; Mice, Nude; Phagosomes - metabolism
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b14-00531

Melanoma is a life-threatening disorder and its incidence is increasing gradually. Despite the numerous treatment approaches, conventional systemic chemotherapy has not reduced the mortality rate among melanoma patients, probably due to the induction of toxicity to normal tissues. Recently, we have developed folate-conjugated methyl-β-cyclodextrin (FA-M-β-CyD) and clarified its potential as a new antitumor agent involved in autophagic cell death. However, it remains uncertain whether FA-M-β-CyD exerts anticancer effects against melanomas. Therefore, in this study, we investigated the effects of FA-M-β-CyD on the folate receptor-α (FR-α)-expressing melanoma cell-selective cytotoxic effect. FA-M-β-CyD showed cytotoxic effects in Ihara cells, a human melanoma cell line expressing FR-α. In sharp contrast to methyl-β-cyclodextrin, FA-M-β-CyD entered Ihara cells [FR-α(+)] through FR-α-mediated endocytosis. Additionally, FA-M-β-CyD elicited the formation of autophagosomes in Ihara cells. Notably, FA-M-β-CyD suppressed melanoma growth in BALB/c nude recombinase-activating gene-2 (Rag-2)/Janus kinase 3 (Jak3) double deficient mice bearing Ihara cells. Therefore, these results suggest that FA-M-β-CyD could be utilized as a potent anticancer agent for melanoma chemotherapy by regulating autophagy.