Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan.
Department of Transfusion Medicine and Cell Therapy, Saitama Medical Center, Saitama Medical University, Kawagoe 350-8550, Japan.
Int J Mol Sci. 2023 Nov 24;24(23):16720. 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.
急性髓细胞白血病 (AML) 是一种异质性髓系肿瘤，仍然难以治疗。由于强化常规化疗降低了老年患者的生存率，因此急需毒性更低、副作用更少的药物。2-羟丙基-β-环糊精 (HP-β-CyD) 临床上用作难溶性药物的药用赋形剂。以前，我们发现 HP-β-CyD 通过破坏胆固醇稳态发挥抗肿瘤活性。最近，我们开发了叶酸偶联的 HP-β-CyD（FA-HP-β-CyD），并证明其作为一种新的抗肿瘤药物具有潜力，不仅可以诱导细胞凋亡，还可以诱导自噬性细胞死亡；然而，我们不知道 FA-HP-β-CyD 是否对 AML 发挥这些作用。在这里，我们研究了 FA-HP-β-CyD 对表达叶酸受体 (FR) 的 AML 细胞的影响。我们发现 FA-HP-β-CyD 对 AML 细胞的细胞毒性活性强于 HP-β-CyD。此外，FA-HP-CyD 在 AML 细胞系中诱导自噬体的形成。FA-HP-β-CyD 增加了阿糖胞苷和 BCL-2 选择性抑制剂 Venetoclax 的抑制作用，这些药物常用于治疗老年 AML 患者。值得注意的是，FA-HP-β-CyD 抑制了 AML 细胞在 BALB/c 裸鼠 ()/ () 双缺陷小鼠中 AML 的增殖。这些结果表明，FA-HP-β-CyD 通过调节自噬作用，作为 AML 化疗的一种有效的抗癌药物。
