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.

No abstract

The standard treatment for elderly patients with acute myeloid leukemia (AML) is venetoclax (Ven), a BCL-2 selective inhibitor, combined with hypomethylating agents (HMAs) such as azacitidine (AZA) or decitabine (DAC). This regimen results in low toxicity, high response rates, and potentially durable remission; however, because of low oral bioavailability, these conventional HMAs must be administered intravenously or subcutaneously. A combination of oral HMAs and Ven would provide a therapeutic advantage over parenteral administration of drugs and improve quality of life by reducing the number of hospital visits. Previously, we showed the promising oral bioavailability and anti-leukemia effects of a new HMA, OR2100 (OR21). Here, we investigated the efficacy and underlying mechanism of OR21 when used in combination with Ven to treat AML. OR21/Ven showed synergistic anti-leukemia effects in vitro, and significantly prolonged survival without increasing toxicity in a human leukemia xenograft mice model. RNA sequencing following combination therapy revealed downregulation of VAMP7, which is involved in autophagic maintenance of mitochondrial homeostasis. Combination therapy led to accumulation of reactive oxygen species, leading to increased apoptosis. The data suggest that the combination of OR21 plus Ven is a promising candidate oral therapy for AML.

<p>IC50 in acute myeloid leukemia cell lines (µM)</p>

<p>Figure S5. The combination effect of venetoclax (Ven) and S63845 (S6) in acute myeloid leukemia.</p>