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

Area of Science:

• Oncology
• Pharmacology

Background:

• Acute myeloid leukemia (AML) presents treatment challenges, particularly for elderly patients, necessitating drugs with reduced toxicity.
• 2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is a pharmaceutical excipient with previously demonstrated antitumor properties via cholesterol homeostasis disruption.
• Folate-conjugated HP-β-CyD (FA-HP-β-CyD) was developed as a novel antitumor agent inducing apoptosis and autophagic cell death.

Purpose of the Study:

• To investigate the efficacy of FA-HP-β-CyD against folate receptor (FR)-expressing acute myeloid leukemia (AML) cells.
• To determine if FA-HP-β-CyD enhances the effects of standard AML chemotherapies.

Main Methods:

• Assessed the cytotoxic activity of FA-HP-β-CyD and HP-β-CyD on AML cell lines.
• Investigated FA-HP-β-CyD's effect on autophagosome formation in AML cells.
• Evaluated the combined effects of FA-HP-β-CyD with cytarabine and Venetoclax in AML cell lines and in a mouse model.

Main Results:

• FA-HP-β-CyD exhibited stronger cytotoxic activity against AML cells compared to HP-β-CyD.
• FA-HP-β-CyD induced autophagosome formation in AML cell lines, indicating autophagy regulation.
• FA-HP-β-CyD potentiated the inhibitory effects of cytarabine and Venetoclax on AML cells.
• FA-HP-β-CyD suppressed AML cell proliferation in a relevant preclinical mouse model.

Conclusions:

• FA-HP-β-CyD demonstrates significant anticancer potential for AML treatment.
• FA-HP-β-CyD acts as a potent agent by regulating autophagy and enhancing conventional chemotherapy.
• This compound represents a promising therapeutic strategy for AML, especially for elderly patients seeking reduced toxicity.