Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Current Research in Pharmacology and Drug Discovery |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590257121000201 |
| _version_ | 1819098064885907456 |
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| author | Waleska Kerllen Martins Maryana do Nascimento da Silva Kiran Pandey Ikuko Maejima Ercília Ramalho Vania Claudia Olivon Susana Nogueira Diniz Daniel Grasso |
| author_facet | Waleska Kerllen Martins Maryana do Nascimento da Silva Kiran Pandey Ikuko Maejima Ercília Ramalho Vania Claudia Olivon Susana Nogueira Diniz Daniel Grasso |
| author_sort | Waleska Kerllen Martins |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T00:25:03Z |
| format | Article |
| id | doaj.art-16a96c5e91654a9ab78c2a8b5837733a |
| institution | Directory Open Access Journal |
| issn | 2590-2571 |
| language | English |
| last_indexed | 2024-12-22T00:25:03Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Research in Pharmacology and Drug Discovery |
| spelling | doaj.art-16a96c5e91654a9ab78c2a8b5837733a2022-12-21T18:45:05ZengElsevierCurrent Research in Pharmacology and Drug Discovery2590-25712021-01-012100033Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directionsWaleska Kerllen Martins0Maryana do Nascimento da Silva1Kiran Pandey2Ikuko Maejima3Ercília Ramalho4Vania Claudia Olivon5Susana Nogueira Diniz6Daniel Grasso7Laboratory of Cell and Membrane (LCM), Anhanguera University of São Paulo (UNIAN), Rua Raimundo Pereira de Magalhães, 3,305. Pirituba, São Paulo, 05145-200, Brazil; Corresponding author.Laboratory of Cell and Membrane (LCM), Anhanguera University of São Paulo (UNIAN), Rua Raimundo Pereira de Magalhães, 3,305. Pirituba, São Paulo, 05145-200, BrazilCenter for Neural Science, New York University, Meyer Building, Room 823, 4 Washington Place, New York, NY, 10003, USALaboratory of Molecular Traffic, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa Machi, Maebashi, Gunma, 3718512, JapanLaboratory of Cell and Membrane (LCM), Anhanguera University of São Paulo (UNIAN), Rua Raimundo Pereira de Magalhães, 3,305. Pirituba, São Paulo, 05145-200, BrazilLaboratory of Pharmacology and Physiology, UNIDERP, Av. Ceará, 333. Vila Miguel Couto, Campo Grande, MS, 79003-010, BrazilLaboratory of Molecular Biology and Functional Genomics, Anhanguera University of São Paulo (UNIAN), Rua Raimundo Pereira de Magalhães, 3,305. Pirituba, São Paulo, 05145-200, BrazilInstituto de Estudios de la Inmunidad Humoral (IDEHU), Universidad de Buenos Aires, CONICET, Junín 954 p4, Buenos Aires, C1113AAD, Argentina; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2590257121000201Autophagy-targeted therapyActivation/inhibition of autophagyCancerCardiac or cardiovascular diseasesNeurodegenerative disorders |
| spellingShingle | Waleska Kerllen Martins Maryana do Nascimento da Silva Kiran Pandey Ikuko Maejima Ercília Ramalho Vania Claudia Olivon Susana Nogueira Diniz Daniel Grasso Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions Current Research in Pharmacology and Drug Discovery Autophagy-targeted therapy Activation/inhibition of autophagy Cancer Cardiac or cardiovascular diseases Neurodegenerative disorders |
| title | Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions |
| title_full | Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions |
| title_fullStr | Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions |
| title_full_unstemmed | Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions |
| title_short | Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions |
| title_sort | autophagy targeted therapy to modulate age related diseases success pitfalls and new directions |
| topic | Autophagy-targeted therapy Activation/inhibition of autophagy Cancer Cardiac or cardiovascular diseases Neurodegenerative disorders |
| url | http://www.sciencedirect.com/science/article/pii/S2590257121000201 |
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