Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death

2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is widely used as an enabling excipient in pharmaceutical formulations. We previously demonstrated that HP-β-CyD disrupted cholesterol homeostasis, and inhibited the proliferation of leukemia cells by inducing apoptosis and cell-cycle arrest. Recently develo...

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Autores principales:	Toshimi Hoshiko, Yasushi Kubota, Risako Onodera, Taishi Higashi, Masako Yokoo, Keiichi Motoyama, Shinya Kimura
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	HP-β-CyD folic acid folate receptor BCR-ABL cholesterol mitophagy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/2008983a7b83468b8fed3c8cde418210
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spelling	oai:doaj.org-article:2008983a7b83468b8fed3c8cde4182102021-11-11T15:30:41ZFolic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death10.3390/cancers132154132072-6694https://doaj.org/article/2008983a7b83468b8fed3c8cde4182102021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5413https://doaj.org/toc/2072-66942-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is widely used as an enabling excipient in pharmaceutical formulations. We previously demonstrated that HP-β-CyD disrupted cholesterol homeostasis, and inhibited the proliferation of leukemia cells by inducing apoptosis and cell-cycle arrest. Recently developed drug delivery systems using folic acid (FA) and folic acid receptors (FR) are currently being used in cancer treatment. To confer tumor cell-selectivity to HP-β-CyD, we synthesized folate-appended HP-β-CyD (FA-HP-β-CyD) and evaluated the potential of FA-HP-β-CyD as an anticancer agent using chronic myeloid leukemia (CML) cells in vitro and in vivo. FA-HP-β-CyD inhibited the growth of FR-expressing cells but not that of FR-negative cells. FA-HP-β-CyD had stronger anti-leukemia and cell-binding activities than HP-β-CyD in CML cells. Unlike HP-β-CyD, FA-HP-β-CyD entered CML cells through endocytosis and induced both apoptosis and autophagy via mitophagy. FA-HP-β-CyD increased the inhibitory effects of the ABL tyrosine kinase inhibitors imatinib mesylate and ponatinib, which are commonly used in CML. In vivo experiments in a BCR-ABL leukemia mouse model showed that FA-HP-β-CyD was more effective than HP-β-CyD at a ten-fold lower dose. These results indicate that FA-HP-β-CyD may be a novel tumor-targeting agent for the treatment of leukemia.Toshimi HoshikoYasushi KubotaRisako OnoderaTaishi HigashiMasako YokooKeiichi MotoyamaShinya KimuraMDPI AGarticleHP-β-CyDfolic acidfolate receptorBCR-ABLcholesterolmitophagyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5413, p 5413 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	HP-β-CyD folic acid folate receptor BCR-ABL cholesterol mitophagy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	HP-β-CyD folic acid folate receptor BCR-ABL cholesterol mitophagy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Toshimi Hoshiko Yasushi Kubota Risako Onodera Taishi Higashi Masako Yokoo Keiichi Motoyama Shinya Kimura Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death
description	2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is widely used as an enabling excipient in pharmaceutical formulations. We previously demonstrated that HP-β-CyD disrupted cholesterol homeostasis, and inhibited the proliferation of leukemia cells by inducing apoptosis and cell-cycle arrest. Recently developed drug delivery systems using folic acid (FA) and folic acid receptors (FR) are currently being used in cancer treatment. To confer tumor cell-selectivity to HP-β-CyD, we synthesized folate-appended HP-β-CyD (FA-HP-β-CyD) and evaluated the potential of FA-HP-β-CyD as an anticancer agent using chronic myeloid leukemia (CML) cells in vitro and in vivo. FA-HP-β-CyD inhibited the growth of FR-expressing cells but not that of FR-negative cells. FA-HP-β-CyD had stronger anti-leukemia and cell-binding activities than HP-β-CyD in CML cells. Unlike HP-β-CyD, FA-HP-β-CyD entered CML cells through endocytosis and induced both apoptosis and autophagy via mitophagy. FA-HP-β-CyD increased the inhibitory effects of the ABL tyrosine kinase inhibitors imatinib mesylate and ponatinib, which are commonly used in CML. In vivo experiments in a BCR-ABL leukemia mouse model showed that FA-HP-β-CyD was more effective than HP-β-CyD at a ten-fold lower dose. These results indicate that FA-HP-β-CyD may be a novel tumor-targeting agent for the treatment of leukemia.
format	article
author	Toshimi Hoshiko Yasushi Kubota Risako Onodera Taishi Higashi Masako Yokoo Keiichi Motoyama Shinya Kimura
author_facet	Toshimi Hoshiko Yasushi Kubota Risako Onodera Taishi Higashi Masako Yokoo Keiichi Motoyama Shinya Kimura
author_sort	Toshimi Hoshiko
title	Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death
title_short	Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death
title_full	Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death
title_fullStr	Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death
title_full_unstemmed	Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death
title_sort	folic acid-appended hydroxypropyl-β-cyclodextrin exhibits potent antitumor activity in chronic myeloid leukemia cells via autophagic cell death
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2008983a7b83468b8fed3c8cde418210
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Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death

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