Folate-Appended Hydroxypropyl-β-Cyclodextrin Induces Autophagic Cell Death in Acute Myeloid Leukemia Cells

• Published in: International journal of molecular sciences Vol. 24; no. 23; p. 16720
• Main Authors: Kubota, Yasushi, Hoshiko, Toshimi, Higashi, Taishi, Motoyama, Keiichi, Okada, Seiji, Kimura, Shinya
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.12.2023
• Subjects: 2-hydroxypropyl-β-cyclodextrin; acute myeloid leukemia; Apoptosis; Autophagy; Biochemistry; Bone marrow; Cancer; Cell cycle; Cell death; Chemotherapy; Cholesterol; Cyclodextrins; Flow cytometry; folate receptor; Folic acid; Leukemia; Medical prognosis; molecular targeting; Mutation; Pharmaceutical industry; Remission (Medicine); Vitamin B; Japan; 2-hydroxypropyl-β-cyclodextrin; autophagy; acute myeloid leukemia; mitochondria; molecular targeting; cholesterol; folate receptor; metabolism; folic acid; Venetoclax
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms242316720

Acute myeloid leukemia (AML) is a heterogenous myeloid neoplasm that remains challenging to treat. Because intensive conventional chemotherapy reduces survival rates in elderly patients, drugs with lower toxicity and fewer side effects are needed urgently. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is used clinically as a pharmaceutical excipient for poorly water-soluble drugs. Previously, we showed that HP-β-CyD exerts antitumor activity by disrupting cholesterol homeostasis. Recently, we developed folate-conjugated HP-β-CyD (FA-HP-β-CyD) and demonstrated its potential as a new antitumor agent that induces not only apoptosis, but also autophagic cell death; however, we do not know whether FA-HP-β-CyD exerts these effects against AML. Here, we investigated the effects of FA-HP-β-CyD on folate receptor (FR)-expressing AML cells. We found that the cytotoxic activity of FA-HP-β-CyD against AML cells was stronger than that of HP-β-CyD. Also, FA-HP-CyD induced the formation of autophagosomes in AML cell lines. FA-HP-β-CyD increased the inhibitory effects of cytarabine and a BCL-2-selective inhibitor, Venetoclax, which are commonly used treat elderly AML patients. Notably, FA-HP-β-CyD suppressed the proliferation of AML cells in BALB/c nude ( )/ ( ) double-deficient mice with AML. These results suggest that FA-HP-β-CyD acts as a potent anticancer agent for AML chemotherapy by regulating autophagy.