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

Simple Summary 2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) is a cyclic oligosaccharide widely used as an excipient in pharmaceutical preparations, in addition to also being used as a cholesterol regulator. HP-beta-CyD was used in clinical trials for patients with Niemann-Pick Type C disease to remove accumulated intracellular lipid. HP-beta-CyD has anti-leukemia activity by inducing apoptosis and cell-cycle arrest; however, the antitumor activity of HP-beta-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-beta-CyD (FA-HP-beta-CyD) to confer tumor cell-selectivity to HP-beta-CyD. FA-HP-beta-CyD inhibited the proliferation of chronic myeloid leukemia (CML) cells and the mechanism underlying the effect of FA-HP-beta-CyD in inducing cell death may involve autophagy. The combination of FA-HP-beta-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-beta-CyD had a stronger inhibitory effect on leukemia progression than HP-beta-CyD or imatinib. 2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) is widely used as an enabling excipient in pharmaceutical formulations. We previously demonstrated that HP-beta-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-beta-CyD, we synthesized folate-appended HP-beta-CyD (FA-HP-beta-CyD) and evaluated the potential of FA-HP-beta-CyD as an anticancer agent using chronic myeloid leukemia (CML) cells in vitro and in vivo. FA-HP-beta-CyD inhibited the growth of FR-expressing cells but not that of FR-negative cells. FA-HP-beta-CyD had stronger anti-leukemia and cell-binding activities than HP-beta-CyD in CML cells. Unlike HP-beta-CyD, FA-HP-beta-CyD entered CML cells through endocytosis and induced both apoptosis and autophagy via mitophagy. FA-HP-beta-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-beta-CyD was more effective than HP-beta-CyD at a ten-fold lower dose. These results indicate that FA-HP-beta-CyD may be a novel tumor-targeting agent for the treatment of leukemia.

Automated summary

2-Hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) is commonly used in pharmaceutical formulations and has shown anti-leukemia activity, but lacks tumor cell-selectivity. Folate-appended HP-beta-CyD (FA-HP-beta-CyD) has been synthesized to target cancer cells more effectively, showing stronger inhibitory effects on leukemia cells. FA-HP-beta-CyD may be a promising agent for targeted therapy against leukemia.