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

Int J Nanomedicine. 2017 Apr 28;12:3433-3446. doi: 10.2147/IJN.S133482. eCollection 2017.

Abstract

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 nu/nu 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.

Keywords: autophagy; folate receptor; methyl-β-cyclodextrin; mitophagy; tumor targeting.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Autophagy / drug effects
  • Cell Survival / drug effects
  • Folate Receptor 1 / metabolism
  • Folic Acid / chemistry
  • Folic Acid / pharmacology*
  • Humans
  • KB Cells / drug effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mitophagy / drug effects
  • Molecular Targeted Therapy / methods
  • Protein Kinases / metabolism
  • Xenograft Model Antitumor Assays
  • beta-Cyclodextrins / chemistry
  • beta-Cyclodextrins / pharmacology*

Substances

  • Antineoplastic Agents
  • Folate Receptor 1
  • beta-Cyclodextrins
  • methyl-beta-cyclodextrin
  • Folic Acid
  • Protein Kinases
  • PTEN-induced putative kinase