ArticleOncotarget2017
Melatonin enhances sorafenib actions in human hepatocarcinoma cells by inhibiting mTORC1/p70S6K/HIF-1α and hypoxia-mediated mitophagy.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 1 of them a synthesis that pooled it.
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Who cites it
46 citing papers in PubMed, 1 synthesis or guideline pooled it, 73 citations in OpenAlex.
- Antitumor Effects of Quercetin in Hepatocarcinoma In Vitro and In Vivo Models: A Systematic Review.Nutrients · 2019Pooled it
- Advances in mitophagy research in hepatocellular carcinoma: mechanisms and therapeutic implications.Journal of gastrointestinal oncology · 2026Review
- The multifaceted functions of selective autophagy in cancer: molecular basis, consequences, and clinical prospects.Molecular cancer · 2026Review
- Article
- Hepatocellular Carcinoma Around the Clock.Current oncology (Toronto, Ont.) · 2026Review
- GRB2 Promotes Sorafenib Resistance in Hepatocellular Carcinoma Cells Under Hypoxia by Activating the PI3K/AKT Signaling Pathway.Journal of hepatocellular carcinoma · 2026Article
- The advantages and challenges of sorafenib combination therapy: Drug resistance, toxicity and future directions (Review).Oncology letters · 2025Review
- Bibliometric and visualized analysis of mitophagy in liver cancer from 1998 to 2024.Discover oncology · 2025Article
- The contribution of circadian clock to the biological processes.Frontiers in molecular biosciences · 2024Review
- Unraveling the Janus-Faced Role of Autophagy in Hepatocellular Carcinoma: Implications for Therapeutic Interventions.International journal of molecular sciences · 2023Review
- Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance.Journal of experimental & clinical cancer research : CR · 2023Review
- Influence of Various Light Regimes on Morphofunctional Condition of Transplantable Melanoma B16.Biomedicines · 2023Article
- TargetingJournal of Zhejiang University. Science. B · 2023Article
- A comprehensive review of the relationship between autophagy and sorafenib-resistance in hepatocellular carcinoma: ferroptosis is noteworthy.Frontiers in cell and developmental biology · 2023Review
- Differences between water-soluble and water-insoluble melanin derived fromFood chemistry: X · 2022Article
- Interactions of melatonin with various signaling pathways: implications for cancer therapy.Cancer cell international · 2022Review
- Review
- Overcoming the therapeutic resistance of hepatomas by targeting the tumor microenvironment.Frontiers in oncology · 2022Review
- Link of sorafenib resistance with the tumor microenvironment in hepatocellular carcinoma: Mechanistic insights.Frontiers in pharmacology · 2022Review
- Removal of Environmental Nanoparticles Increases Protein Synthesis and Energy Production in Healthy Humans.Frontiers in bioengineering and biotechnology · 2022Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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