| Author: | Wang, Lei |
| Title: | Mechanistic study of autophagy-targeting modulators as potent antiproliferation strategy for acute myeloid leukaemia |
| Advisors: | Zhao, Yanxiang (ABCT) |
| Degree: | Ph.D. |
| Year: | 2025 |
| Department: | Department of Applied Biology and Chemical Technology |
| Pages: | 191 pages : color illustrations |
| Language: | English |
| Abstract: | Acute myeloid leukemia (AML) is the most aggressive form of leukemia, with a five-year relative survival rate of only 31.9%. Despite significant advancements in therapeutics over the past two decades, the prognosis for AML patients remains poor. This is mainly due to high relapse rates and limited treatment options for older adults, who constitute the majority of AML cases and are often unable to tolerate intensive chemotherapy. Current first-line treatments primarily rely on traditional chemotherapy, administered either as monotherapy or in combination with autologous transplantation. However, both are associated with substantial toxicity and have stringent physiological requirements, which further restricts their applicability to elderly patients. Thus, there is a persistent and urgent need for novel, less toxic therapies to improve outcomes for AML patients. In this study, we identified Beclin-1-targeting stapled peptides (Tat-SPs) as potent inducers of autophagy-related autotic cell death in AML cell lines. Tat-SPs exhibited robust antiproliferative activity against AML cells as single agents and exhibited synergistic effects when combined with standard chemotherapies such as Cytarabine or Venetoclax in vitro. Tat-SPs also triggered notable mitochondrial dysfunction, including loss of mitochondrial membrane potential, elevated reactive oxygen species (ROS) levels, suppression of basal and maximal oxidative phosphorylation (OXPHOS) and activation of the mitochondrial permeability transition pore (MPTP). We carried out mechanistic studies to investigate the cell death processes induced in AML cells after treatment by Tat-SPs. Our results show that Tat-SPs only induced autosis, a form of autophagy-dependent cell death while other known programmed cell death processes such as apoptosis, ferroptosis, necroptosis, and pyroptosis were not involved. We also identified intracellular Ca²⁺ calcium as a key mediator of cell death induced by Tat-SPs. Supplementing Ca²⁺ to culture medium or co-treatment with calcium regulators alleviated Tat-SP-induced cytotoxicity. Furthermore, we also investigated the impact of Tat-SPs on immune cells as autophagy is known to be involved in both innate and adaptive immunity. Our data showed that Tat-SPs may activate T cells by promoting IL2 production and facilitating the nuclear translocation of NFAT1. Tat-SP4 also enhanced phagocytosis in macrophage cells. Lastly, we carried out animal studies to assess the anti-AML activity of Tat-SPs in vivo. In AML-bearing mice, lead Tat-SPs significantly reduced leukemia burden and improved overall survival. Our pharmacokinetic studies showed that the lead candidate Tat-SP4 was rapidly absorbed at systemic level and reached maximum serum concentration of ~3.9 μM 5 minutes after injection at 40 mg/kg dosage and with detectable levels of ~2 μM persisting at 2 hours post-administration. Overall, our study highlights autophagy-targeting Tat-SPs as promising therapeutic candidates for AML. By triggering autotic cell death in AML cells and modulating both innate and adaptive immune response, Tat-SPs may offer a novel strategy to target both AML and the tumor microenvironment. |
| Rights: | All rights reserved |
| Access: | open access |
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