Induction of mitophagy-mediated antitumor activity with folate-appended methyl-β-cyclodextrin

• Published in: International journal of nanomedicine 2017-01, Vol.12, p.3433-3446
• Main Authors: Kameyama, Kazuhisa, Motoyama, Keiichi, Tanaka, Nao, Yamashita, Yuki, Higashi, Taishi, Arima, Hidetoshi
• Format: Article
• Language: English
• Subjects: Adenosine triphosphate; Angiogenesis; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Autophagy; Autophagy - drug effects; beta-Cyclodextrins - chemistry; beta-Cyclodextrins - pharmacology; Cancer; Cell Survival - drug effects; Cervical cancer; Clinical trials; folate receptor; Folate Receptor 1 - metabolism; Folic Acid - chemistry; Folic Acid - pharmacology; Graduate studies; Humans; KB Cells - drug effects; Kinases; Life sciences; Male; methyl--cyclodextrin; Mice; Mice, Inbred BALB C; Mitochondria; Mitochondrial Degradation - drug effects; mitophagy; Molecular Targeted Therapy - methods; Original Research; Protein Kinases - metabolism; Reactive oxygen species; tumor targeting; Tumors; Vitamin B; Xenograft Model Antitumor Assays
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S133482

Mitophagy is the specific autophagic elimination system of mitochondria, which regulates cellular survival via the removal of damaged mitochondria. Recently, we revealed that folate-appended methyl-β-cyclodextrin (FA-M-β-CyD) provides selective antitumor activity in folate receptor-α (FR-α)-expressing cells by the induction of autophagy. In this study, to gain insight into the detailed mechanism of this antitumor activity, we focused on the induction of mitophagy by the treatment of FR-α-expressing tumor cells with FA-M-β-CyD. In contrast to methyl-β-cyclodextrin, FA-M-β-CyD entered KB cells, human epithelial cells from a fatal cervical carcinoma (FR-α (+)) through FR-α-mediated endocytosis. The transmembrane potential of isolated mitochondria after treatment with FA-M-β-CyD was significantly elevated. In addition, FA-M-β-CyD lowered adenosine triphosphate (ATP) production and promoted reactive oxygen species production in KB cells (FR-α (+)). Importantly, FA-M-β-CyD enhanced light chain 3 (LC3) conversion (LC3-I to LC3-II) in KB cells (FR-α (+)) and induced PTEN-induced putative kinase 1 (PINK1) protein expression, which is involved in the induction of mitophagy. Furthermore, FA-M-β-CyD had potent antitumor activity in BALB/c mice xenografted with KB cells (FR-α (+)) without any significant side effects. Taken together, these findings demonstrate that the autophagic cell death elicited by FA-M-β-CyD could be associated with mitophagy induced by an impaired mitochondrial function.