Year-end Sale % OFF 
Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the second most frequent cause of cancer-related death worldwide (Ferlay et al, 2015; Torre et al, 2015)
If endoplasmic reticulum (ER) stress is prolonged over time, unfolded protein response (UPR) might be overwhelmed because that organelle may be full of unfolded and useless proteins, and that situation would generate programmed cell death through CHOP (C/EBP homologous protein) mediator, which is a transcription factor involved in the increase of the expression of a lot of genes related with apoptosis pathway (Verfaillie et al, 2010; Malhi and Kaufman, 2011)
Sorafenib is one of the most promising drugs for palliative treatment in HCC, but the appearance of resistant cells, and the rise of diverse side effects alter the optimal efficiency of sorafenib therapy
Summary
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the second most frequent cause of cancer-related death worldwide (Ferlay et al, 2015; Torre et al, 2015). ↑Levels both in vivo and in vitro models, leading to induction of survival autophagy, survival pathways, and increasing sorafenib cell resistance (Zhai et al, 2014)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
