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

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.

Supramolecular Complex of Methyl-β-cyclodextrin with Adamantane-Grafted Hyaluronic Acid as a Novel Antitumor Agent

“…13) Interestingly, we also demonstrated that FA-M-β-CyD induces the cell death via mitophagy, one of the autophagy, in KB cells. 17) In the latter case, FA-M-β-CyD enters the cells and impairs the mitochondrial function. Thus, M-β-CyDs could induce the different cell death mechanisms by acting outside or inside the cells.…”

“…16) Importantly, FA-M-β-CyD was selectively recognized by folate receptor-α overexpressing cancer cells, and induced mitophagy-mediated cell death, not apoptosis. 17) Thus, FA-M-β-CyD has the great potentials as novel antitumor agents. However, few reports are available on tumor targeting ligand-appended M-β-CyD except for FA-M-β-CyD.…”

IL-33 Is Essential for Adjuvant Effect of Hydroxypropyl-β-Cyclodexrin on the Protective Intranasal Influenza Vaccination

“…Previous studies have reported that DNA release due to cell death indirectly stimulated immune responses through IL-33 (38). It was found that cyclodextrins, particularly β-CDs, extract cholesterol and phospholipids from biological membranes by tapping them into their hydrophobic cores, resulting in the induction of cell death via several pathways (39)(40)(41)(42). Thus, further experiments are necessary to determine the mechanisms of IL-33 release after HP-β-CD intranasal administration.…”

Supramolecular Pharmaceutical Sciences: A Novel Concept Combining Pharmaceutical Sciences and Supramolecular Chemistry with a Focus on Cyclodextrin-Based Supermolecules

“…Recently, various bioactivities of CyDs have been demonstrated, and CyDs have been used as active pharmaceutical ingredients (APIs) against Niemann-Pick disease type C (NPC), [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] leukemia, 77) hyperlipidemia, 78) Alzheimer's disease, [79][80][81][82][83][84] cerebral ischemic injury, 85) atherosclerosis, 86) diabetic kidney disease, 87) chronic renal failure, 88) AIDS, 89,90) influenza, 91) peripheral artery disease, 92) sterility, [93][94][95] solid cancers, [96][97][98][99][100][101] bacterial growth, 102) α-synucleinopathy, 103) GM1-gangliosidosis, 104) septic shock, [105][106][107] hypervitaminosis, 108) and transthyretin-related familial amyloidotic polyneuropathy (FAP) …”