Induction of mitophagy-mediated antitumor activity with folate-appended methyl-[beta]-cyclodextrin

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-[beta]-cyclodextrin (FA-M-[beta]-CyD) provides selective antitumor activity in folate receptor-[alpha]...

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Published in:International journal of nanomedicine 2017-01, Vol.12, p.3433
Main Authors: Kameyama, Kazuhisa, Motoyama, Keiichi, Tanaka, Nao, Yamashita, Yuki, Higashi, Taishi, Arima, Hidetoshi
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Language:English
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Cancer treatment
Cyclodextrins
Folic acid
Physiological aspects
Properties
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container_title International journal of nanomedicine
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creator Kameyama, Kazuhisa
Motoyama, Keiichi
Tanaka, Nao
Yamashita, Yuki
Higashi, Taishi
Arima, Hidetoshi
description 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-[beta]-cyclodextrin (FA-M-[beta]-CyD) provides selective antitumor activity in folate receptor-[alpha] (FR-[alpha])-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-[alpha]-expressing tumor cells with FA-M-[beta]-CyD. In contrast to methyl-[beta]-cyclodextrin, FA-M-[beta]-CyD entered KB cells, human epithelial cells from a fatal cervical carcinoma (FR-[alpha] (+)) through FR-[alpha]-mediated endocytosis. The transmembrane potential of isolated mitochondria after treatment with FA-M-[beta]-CyD was significantly elevated. In addition, FA-M-[beta]-CyD lowered adenosine triphosphate (ATP) production and promoted reactive oxygen species production in KB cells (FR-[alpha] (+)). Importantly, FA-M-[beta]-CyD enhanced light chain 3 (LC3) conversion (LC3-I to LC3-II) in KB cells (FR-[alpha] (+)) and induced PTEN-induced putative kinase 1 (PINK1) protein expression, which is involved in the induction of mitophagy. Furthermore, FA-M-[beta]-CyD had potent antitumor activity in BALB/c nu/nu mice xenografted with KB cells (FR-[alpha] (+)) without any significant side effects. Taken together, these findings demonstrate that the autophagic cell death elicited by FA-M-[beta]-CyD could be associated with mitophagy induced by an impaired mitochondrial function. Keywords: mitophagy, autophagy, folate receptor, methyl-[beta]-cyclodextrin, tumor targeting
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Importantly, FA-M-[beta]-CyD enhanced light chain 3 (LC3) conversion (LC3-I to LC3-II) in KB cells (FR-[alpha] (+)) and induced PTEN-induced putative kinase 1 (PINK1) protein expression, which is involved in the induction of mitophagy. Furthermore, FA-M-[beta]-CyD had potent antitumor activity in BALB/c nu/nu mice xenografted with KB cells (FR-[alpha] (+)) without any significant side effects. Taken together, these findings demonstrate that the autophagic cell death elicited by FA-M-[beta]-CyD could be associated with mitophagy induced by an impaired mitochondrial function. 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source Taylor & Francis_OA刊; Publicly Available Content Database; PubMed Central
subjects Cancer treatment
Cyclodextrins
Folic acid
Physiological aspects
Properties
title Induction of mitophagy-mediated antitumor activity with folate-appended methyl-[beta]-cyclodextrin
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