Modulation of Autophagy by Sorafenib: Effects on Treatment Response
| Autor: | Raquel Ordóñez, Jordi Muntané, José L. Mauriz, Javier González-Gallego, Néstor Prieto-Domínguez, Andrés García-Palomo, Anna Fernández |
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| Přispěvatelé: | Instituto de Salud Carlos III, Ministerio de Educación, Cultura y Deporte (España) |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Sorafenib autophagy cancer therapeutic Hepatocellular carcinoma Cell Dug resistance Review Biology 03 medical and health sciences dug resistance 0302 clinical medicine microRNA medicine Autophagy Pharmacology (medical) Protein kinase A neoplasms PI3K/AKT/mTOR pathway Pharmacology AMPK hepatocellular carcinoma digestive system diseases Cancer therapeutic Cell biology 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis sorafenib Intracellular medicine.drug |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Frontiers in Pharmacology |
| Popis: | The multikinase inhibitor sorafenib is, at present, the only drug approved for the treatment of hepatocellular carcinoma (HCC), one of the most lethal types of cancer worldwide. However, the increase in the number of sorafenib tumor resistant cells reduces efficiency. A better knowledge of the intracellular mechanism of the drug leading to reduced cell survival could help to improve the benefits of sorafenib therapy. Autophagy is a bulk cellular degradation process activated in a broad range of stress situations, which allows cells to degrade misfolded proteins or dysfunctional organelles. This cellular route can induce survival or death, depending on cell status and media signals. Sorafenib, alone or in combination with other drugs is able to induce autophagy, but cell response to the drug depends on the complex integrative crosstalk of different intracellular signals. In cancerous cells, autophagy can be regulated by different cellular pathways (Akt-related mammalian target of rapamycin (mTOR) inhibition, 5′ AMP-activated protein kinase (AMPK) induction, dissociation of B-cell lymphoma 2 (Bcl-2) family proteins from Beclin-1), or effects of some miRNAs. Inhibition of mTOR signaling by sorafenib and diminished interaction between Beclin-1 and myeloid cell leukemia 1 (Mcl-1) have been related to induction of autophagy in HCC. Furthermore, changes in some miRNAs, such as miR-30α, are able to modulate autophagy and modify sensitivity in sorafenib-resistant cells. However, although AMPK phosphorylation by sorafenib seems to play a role in the antiproliferative action of the drug, it does not relate with modulation of autophagy. In this review, we present an updated overview of the effects of sorafenib on autophagy and its related activation pathways, analyzing in detail the involvement of autophagy on sorafenib sensitivity and resistance. CIBERehd is funded by Instituto de la Salud Carlos III, Spain. NP and RO are granted by the Program “Formación del Profesorado Universitario” (Becas FPU, references FPU13/04173 and FPU12/01433, respectively) from Ministerio de Educación, Cultura y Deporte (Spain). |
| Databáze: | OpenAIRE |
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