ArticleJournal of pineal research2016
Melatonin-induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy.
Article in Journal of pineal research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers, 2 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
74 citing papers in PubMed, 2 syntheses or guidelines pooled it, 148 citations in OpenAlex.
- Melatonin in cancer treatment.The Cochrane database of systematic reviews · 2025Pooled it
- 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
- Corynoline enhances sorafenib sensitivity in hepatocellular carcinoma via NOS3-mediated ROS production.Chinese medicine · 2025Article
- 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
- Mitochondrial autophagy-related lncRNAs as prognostic biomarkers and therapeutic targets in gastric adenocarcinoma.Discover oncology · 2025Article
- Mitochondrial alterations and signatures in hepatocellular carcinoma.Cancer metastasis reviews · 2025Review
- Mitophagy-related regulated cell death: molecular mechanisms and disease implications.Cell death & disease · 2024Review
- Unveiling the Protective Role of Melatonin in Osteosarcoma: Current Knowledge and Limitations.Biomolecules · 2024Review
- Circadian rhythms and inflammatory diseases of the liver and gut.Liver research (Beijing, China) · 2023Review
- Anti-proliferative effect of melatonin in human hepatoma HepG2 cells occurs mainly through cell cycle arrest and inflammation inhibition.Scientific reports · 2023Article
- Deciphering the Role of Melatonin-Related Signatures in Tumor Immunity and the Prognosis of Clear Cell Renal Cell Carcinoma.Oxidative medicine and cellular longevity · 2023Article
- Article
- piR-823 inhibits cell apoptosis via modulating mitophagy by binding to PINK1 in colorectal cancer.Cell death & disease · 2022Article
- Flubendazole induces mitochondrial dysfunction and DRP1-mediated mitophagy by targeting EVA1A in breast cancer.Cell death & disease · 2022Article
- Use of Melatonin in Cancer Treatment: Where Are We?International journal of molecular sciences · 2022Review
- Role of SLC39A6 in the development and progression of liver cancer.Oncology letters · 2022Article
- Review
- Melatonin and Phytomelatonin: Chemistry, Biosynthesis, Metabolism, Distribution and Bioactivity in Plants and Animals-An Overview.International journal of molecular sciences · 2021Review
14 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Effects of sorafenib in hepatocellular carcinoma (HCC) are frequently transient due to tumor-acquired resistance, a phenotype that could be targeted by other molecules to reduce this adaptive response. Because melatonin is known to exert antitumor effects in HCC cells, this study investigated whether and how melatonin reduces resistance to sorafenib. Susceptibility to sorafenib (10 nmol/L to 50 μmol/L) in the presence of melatonin (1 and 2 mmol/L) was assessed in HCC cell lines HepG2, HuH7, and Hep3B. Cell viability was reduced by sorafenib from 1 μmol/L in HepG2 or HuH7 cells, and 2.5 μmol/L in Hep3B cells. Co-administration of melatonin and sorafenib exhibited a synergistic cytotoxic effect on HepG2 and HuH7 cells, while Hep3B cells displayed susceptibility to doses of sorafenib that had no effect when administrated alone. Co-administration of 2.5 μmol/L sorafenib and 1 mmol/L melatonin induced apoptosis in Hep3B cells, increasing PARP hydrolysis and BAX expression. We also observed an early colocalization of mitochondria with lysosomes, correlating with the expression of mitophagy markers PINK1 and Parkin and a reduction of mitofusin-2 and mtDNA compared with sorafenib administration alone. Moreover, increased reactive oxygen species production and mitochondrial membrane depolarization were elicited by drug combination, suggesting their contribution to mitophagy induction. Interestingly, Parkin silencing by siRNA to impair mitophagy significantly reduced cell killing, PARP cleavage, and BAX expression. These results demonstrate that the pro-oxidant capacity of melatonin and its impact on mitochondria stability and turnover via mitophagy increase sensitivity to the cytotoxic effect of sorafenib.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.