Nguyen Thao M, Joyce Paul, Ross David M, Bremmell Kristen, Jambhrunkar Manasi, Wong Sook S, Prestidge Clive A
Centre for Pharmaceutical Innovation, UniSA: Clinical and Health Sciences, University of South Australia, Adelaide, SA 5001, Australia.
Adelaide Medical School, University of Adelaide, Adelaide, SA 5001, Australia.
Pharmaceutics. 2024 Jan 31;16(2):209. doi: 10.3390/pharmaceutics16020209.
MP-A08 is a novel sphingosine kinase 1 (SPHK1) inhibitor with activity against acute myeloid leukemia (AML). A rationally designed liposome-based encapsulation and delivery system has been shown to overcome the physicochemical challenges of MP-A08 and enable its effective delivery for improved efficacy and survival of mice engrafted with human AML in preclinical models. To establish therapies that overcome AML's heterogeneous nature, here we explored the combination of MP-A08-loaded liposomes with both the standard chemotherapy, cytarabine, and the targeted therapy, venetoclax, against human AML cell lines. Cytarabine (over the dose range of 0.1-0.5 µM) in combination with MP-A08 liposomes showed significant synergistic effects (as confirmed by the Chou-Talalay Combination Index) against the chemosensitised human AML cell lines MV4-11 and OCI-AML3. Venetoclax (over the dose range of 0.5-250 nM) in combination with MP-A08 liposomes showed significant synergistic effects against the chemosensitised human AML cell lines, particularly in venetoclax-resistant human AML cells. This strong synergistic effect is due to multiple mechanisms of action, i.e., inhibiting MCL-1 through SPHK1 inhibition, leading to ceramide accumulation, activation of protein kinase R, ATF4 upregulation, and NOXA activation, ultimately resulting in MCL-1 degradation. These combination therapies warrant further consideration and investigation in the search for a more comprehensive treatment strategy for AML.
MP-A08是一种新型的鞘氨醇激酶1（SPHK1）抑制剂，对急性髓系白血病（AML）具有活性。一种经过合理设计的基于脂质体的包封和递送系统已被证明能够克服MP-A08的物理化学挑战，并使其能够有效递送，从而在临床前模型中提高移植了人类AML的小鼠的疗效和生存率。为了建立能够克服AML异质性的治疗方法，我们在此探索了负载MP-A08的脂质体与标准化疗药物阿糖胞苷以及靶向治疗药物维奈托克联合用于人类AML细胞系的情况。阿糖胞苷（在0.1 - 0.5 μM的剂量范围内）与MP-A08脂质体联合使用时，对化疗增敏的人类AML细胞系MV4-11和OCI-AML3显示出显著的协同作用（通过Chou-Talalay联合指数证实）。维奈托克（在0.5 - 250 nM的剂量范围内）与MP-A08脂质体联合使用时，对化疗增敏的人类AML细胞系显示出显著的协同作用，尤其是在对维奈托克耐药的人类AML细胞中。这种强大的协同作用归因于多种作用机制，即通过抑制SPHK1来抑制MCL-1，导致神经酰胺积累，激活蛋白激酶R，上调ATF4以及激活NOXA，最终导致MCL-1降解。这些联合治疗方法在寻找更全面的AML治疗策略方面值得进一步考虑和研究。
