Motoyama Keiichi, Onodera Risako, Tanaka Nao, Kameyama Kazuhisa, Higashi Taishi, Kariya Ryusho, Okada Seiji, Arima Hidetoshi
Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University.
Biol Pharm Bull. 2015;38(3):374-9. 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.
黑色素瘤是一种危及生命的疾病，其发病率正在逐渐上升。尽管有众多的治疗方法，但传统的全身化疗并未降低黑色素瘤患者的死亡率，这可能是由于其对正常组织产生毒性所致。最近，我们开发了叶酸偶联的甲基-β-环糊精（FA-M-β-CyD），并阐明了其作为一种参与自噬性细胞死亡的新型抗肿瘤药物的潜力。然而，FA-M-β-CyD是否对黑色素瘤具有抗癌作用仍不确定。因此，在本研究中，我们研究了FA-M-β-CyD对表达叶酸受体-α（FR-α）的黑色素瘤细胞的选择性细胞毒性作用。FA-M-β-CyD对Ihara细胞（一种表达FR-α的人黑色素瘤细胞系）显示出细胞毒性作用。与甲基-β-环糊精形成鲜明对比的是，FA-M-β-CyD通过FR-α介导的内吞作用进入Ihara细胞[FR-α(+)]。此外，FA-M-β-CyD在Ihara细胞中引发了自噬体的形成。值得注意的是，FA-M-β-CyD抑制了携带Ihara细胞的BALB/c裸重组激活基因-2（Rag-2）/ Janus激酶3（Jak3）双缺陷小鼠体内的黑色素瘤生长。因此，这些结果表明，FA-M-β-CyD可通过调节自噬作用，作为一种有效的黑色素瘤化疗抗癌药物。
