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Article

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

1
Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan
2
Saitama Medical Center, Department of Transfusion Medicine and Cell Therapy, Saitama Medical University, Kawagoe 350-8550, Japan
3
Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
4
Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto 862-0973, Japan
5
Saga Medical Center Koseikan, Department of Hematology, Saga 849-8571, Japan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Masahiro Kizaki
Cancers 2021, 13(21), 5413; https://doi.org/10.3390/cancers13215413
Received: 25 September 2021 / Revised: 17 October 2021 / Accepted: 25 October 2021 / Published: 28 October 2021
(This article belongs to the Special Issue Molecular Genetics and Treatment of Chronic Myeloid Leukemia)
2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is a cyclic oligosaccharide widely used as an excipient in pharmaceutical preparations, in addition to also being used as a cholesterol regulator. HP-β-CyD was used in clinical trials for patients with Niemann-Pick Type C disease to remove accumulated intracellular lipid. HP-β-CyD has anti-leukemia activity by inducing apoptosis and cell-cycle arrest; however, the antitumor activity of HP-β-CyD lacks tumor cell-selectivity. Taking advantage of the fact that folate receptors are highly expressed in many cancer cells, we synthesized folate-appended HP-β-CyD (FA-HP-β-CyD) to confer tumor cell-selectivity to HP-β-CyD. FA-HP-β-CyD inhibited the proliferation of chronic myeloid leukemia (CML) cells and the mechanism underlying the effect of FA-HP-β-CyD in inducing cell death may involve autophagy. The combination of FA-HP-β-CyD and ABL tyrosine kinase inhibitors (imatinib and ponatinib) had a synergistic inhibitory effect on CML cells. In a mouse model of BCR-ABL-induced leukemia, FA-HP-β-CyD had a stronger inhibitory effect on leukemia progression than HP-β-CyD or imatinib.
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. View Full-Text
Keywords: HP-β-CyD; folic acid; folate receptor; BCR-ABL; cholesterol; mitophagy; autophagy; autophagic cell death; tumor targeting HP-β-CyD; folic acid; folate receptor; BCR-ABL; cholesterol; mitophagy; autophagy; autophagic cell death; tumor targeting
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MDPI and ACS Style

Hoshiko, T.; Kubota, Y.; Onodera, R.; Higashi, T.; Yokoo, M.; Motoyama, K.; Kimura, S. Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death. Cancers 2021, 13, 5413. https://doi.org/10.3390/cancers13215413

AMA Style

Hoshiko T, Kubota Y, Onodera R, Higashi T, Yokoo M, Motoyama K, Kimura S. Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death. Cancers. 2021; 13(21):5413. https://doi.org/10.3390/cancers13215413

Chicago/Turabian Style

Hoshiko, Toshimi, Yasushi Kubota, Risako Onodera, Taishi Higashi, Masako Yokoo, Keiichi Motoyama, and Shinya Kimura. 2021. "Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death" Cancers 13, no. 21: 5413. https://doi.org/10.3390/cancers13215413

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