Abstract
The antiangiogenic effects of sustained sorafenib treatment in hepatocellular carcinoma (HCC) lead to the occurrence of hypoxia-mediated drug resistance resulting in low therapy efficiency and negative outcomes. Combined treatments with coadjuvant compounds to target the hypoxia-inducible factor-1α (HIF-1α) represent a promising therapeutic approach through which sorafenib efficiency may be improved. Melatonin is a well-documented oncostatic agent against different cancer types. Here, we evaluated whether melatonin could enhance sorafenib cytotoxicity and overcome the hypoxia-mediated resistance mechanisms in HCC. The pharmacological melatonin concentration (2 mM) potentiated the oncostatic effects of sorafenib (5 μM) on Hep3B cells even under hypoxia. Melatonin downregulated the HIF-1α protein synthesis through the inhibition of the mammalian target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase beta-1 (p70S6K)/ribosomal protein S6 (RP-S6) pathway, although the indole enhanced Akt phosphorylation by the mTORC1/C2 negative feedback. Furthermore, melatonin and sorafenib coadministration reduced the HIF-1α-mitophagy targets expression, impaired autophagosome formation and subsequent mitochondria and lysosomes colocalization. Together, our results indicate that melatonin improves the Hep3B sensitivity to sorafenib, preventing HIF-1α synthesis to block the cytoprotective mitophagy induced by the hypoxic microenvironment, an important element of the multifactorial mechanisms responsible for the chemotherapy failure.
Highlights
Hepatocellular carcinoma (HCC) represents the sixth most diagnosed cancer with rising incidence worldwide [1]
Our results indicate that melatonin improves the Hep3B sensitivity to sorafenib, preventing hypoxia-inducible factor-1α (HIF-1α) synthesis to block the cytoprotective mitophagy induced by the hypoxic microenvironment, an important element of the multifactorial mechanisms responsible for the chemotherapy failure
Melatonin enhances sorafenib cytotoxicity under normoxic and hypoxic conditions Sustained sorafenib treatments for hepatocellular carcinoma (HCC) are ineffective since its antiangiogenic effects lead to a www.impactjournals.com/oncotarget selection of highly-resistant cells adapted to oxygen and nutrient deprivation [2]
Summary
Hepatocellular carcinoma (HCC) represents the sixth most diagnosed cancer with rising incidence worldwide [1]. While sorafenib moderates HCC progression in early stages, due to its antiangiogenic, antiproliferative and proapoptotic properties, continued sorafenib treatment decreases microvessel density and increases tumor hypoxia [2], leading to an imbalance between cell survival and death programs (autophagy, including mitophagy which is an autophagy form that controls mitochondrial homeostasis, and apoptosis) and contributing eventually in decreased drug sensitivity [4]. There is an urgent need to understand the mechanisms of acquired resistance to sorafenib which include, among others, changes in the tumor microenvironment and in survival and death processes, using hypoxia-related models to explore alternative compounds to improve the conventional therapy sensitivity
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