Manivannan Madhumita S, Peters Anthea, Gibson Spencer B
Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Front Oncol. 2025 Feb 24;15:1549792. doi: 10.3389/fonc.2025.1549792. eCollection 2025.
Lysosomes are dynamic organelles integral to cellular homeostasis, secretory pathways, immune responses, and cell death regulation. In cancers, lysosomes become dysregulated to sustain proliferative signaling, metabolism, and invasion. In hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL), leukemia cells demonstrate lysosome dysregulation with increased lysosomal activity, mTORC1 signaling, catabolic reactions, and autophagy. This supports the survival, metabolism, and proliferation of the leukemia cells. Lysosomes also play a critical role in treatment resistance by promoting cell survival and sequestration of drugs. This has led to the development of lysosome-targeted therapies such as cationic amphiphilic drugs (CAD), ATPase inhibitors or autophagy inhibitors to treat hematological malignancies. Lysosome-targeted treatments have shown effectiveness at inducing cell death by inhibiting cell survival mechanisms and inducing apoptosis. In addition, the combination of lysosome-targeted therapies with standard treatments gives synergistic apoptotic responses in leukemia cells. In this review, we will describe the lysosomal functions, their dysregulation in hematological malignancies and the development of lysosomal targeted therapies for leukemia treatment. By understanding lysosome dysregulation and developing lysosome-targeted agents, innovative treatment strategies could be effective in overcoming drug resistance in hematological malignancies.
溶酶体是对细胞内稳态、分泌途径、免疫反应和细胞死亡调节至关重要的动态细胞器。在癌症中，溶酶体功能失调以维持增殖信号传导、代谢和侵袭。在急性髓系白血病（AML）、急性淋巴细胞白血病（ALL）、慢性髓系白血病（CML）和慢性淋巴细胞白血病（CLL）等血液系统恶性肿瘤中，白血病细胞表现出溶酶体功能失调，溶酶体活性、mTORC1信号传导、分解代谢反应和自噬增加。这支持了白血病细胞的存活、代谢和增殖。溶酶体在促进细胞存活和药物隔离从而导致治疗耐药方面也起着关键作用。这促使了针对溶酶体的疗法的发展，如阳离子两亲性药物（CAD）、ATP酶抑制剂或自噬抑制剂来治疗血液系统恶性肿瘤。针对溶酶体的治疗已显示出通过抑制细胞存活机制和诱导凋亡来诱导细胞死亡的有效性。此外，针对溶酶体的疗法与标准治疗相结合在白血病细胞中产生协同凋亡反应。在这篇综述中，我们将描述溶酶体的功能、它们在血液系统恶性肿瘤中的失调以及针对白血病治疗的溶酶体靶向疗法的发展。通过了解溶酶体失调并开发针对溶酶体的药物，创新的治疗策略可能有效克服血液系统恶性肿瘤中的耐药性。
