Martins Waleska Kerllen, Silva Maryana do Nascimento da, Pandey Kiran, Maejima Ikuko, Ramalho Ercília, Olivon Vania Claudia, Diniz Susana Nogueira, Grasso Daniel
Laboratory of Cell and Membrane (LCM), Anhanguera University of São Paulo (UNIAN), Rua Raimundo Pereira de Magalhães, 3,305. Pirituba, São Paulo, 05145-200, Brazil.
Center for Neural Science, New York University, Meyer Building, Room 823, 4 Washington Place, New York, NY, 10003, USA.
Curr Res Pharmacol Drug Discov. 2021 Jun 1;2:100033. doi: 10.1016/j.crphar.2021.100033. eCollection 2021.
Autophagy is a critical metabolic process that supports homeostasis at a basal level and is dynamically regulated in response to various physiological and pathological processes. Autophagy has some etiologic implications that support certain pathological processes due to alterations in the lysosomal-degradative pathway. Some of the conditions related to autophagy play key roles in highly relevant human diseases, e.g., cardiovascular diseases (15.5%), malignant and other neoplasms (9.4%), and neurodegenerative conditions (3.7%). Despite advances in the discovery of new strategies to treat these age-related diseases, autophagy has emerged as a therapeutic option after preclinical and clinical studies. Here, we discuss the pitfalls and success in regulating autophagy initiation and its lysosome-dependent pathway to restore its homeostatic role and mediate therapeutic effects for cancer, neurodegenerative, and cardiac diseases. The main challenge for the development of autophagy regulators for clinical application is the lack of specificity of the repurposed drugs, due to the low pharmacological uniqueness of their target, including those that target the PI3K/AKT/mTOR and AMPK pathway. Then, future efforts must be conducted to deal with this scenery, including the disclosure of key components in the autophagy machinery that may intervene in its therapeutic regulation. Among all efforts, those focusing on the development of novel allosteric inhibitors against autophagy inducers, as well as those targeting autolysosomal function, and their integration into therapeutic regimens should remain a priority for the field.
自噬是一种关键的代谢过程，在基础水平上维持体内平衡，并在应对各种生理和病理过程时受到动态调节。由于溶酶体降解途径的改变，自噬具有一些病因学意义，支持某些病理过程。一些与自噬相关的病症在高度相关的人类疾病中起关键作用，例如心血管疾病（15.5%）、恶性肿瘤和其他肿瘤（9.4%）以及神经退行性疾病（3.7%）。尽管在发现治疗这些与年龄相关疾病的新策略方面取得了进展，但自噬在临床前和临床研究后已成为一种治疗选择。在此，我们讨论在调节自噬起始及其溶酶体依赖性途径以恢复其体内平衡作用并介导对癌症、神经退行性疾病和心脏病的治疗效果方面的陷阱与成功之处。开发用于临床应用的自噬调节剂的主要挑战在于重新利用的药物缺乏特异性，这是由于其靶点（包括那些靶向PI3K/AKT/mTOR和AMPK途径的靶点）的药理学独特性较低。因此，未来必须努力应对这种情况，包括揭示自噬机制中可能干预其治疗调节的关键成分。在所有努力中，专注于开发针对自噬诱导剂的新型变构抑制剂以及靶向自溶酶体功能的抑制剂，并将它们整合到治疗方案中，仍应是该领域的优先事项。
