Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells

Harati, Rania; Vandamme, Marc; Blanchet, Benoı̂t; Bardin, Christophe; Praz, Françoise; Hamoudi, Rifat; Desbois-Mouthon, Christèle

doi:10.1124/molpharm.120.000223

Cited by 13 publications

(8 citation statements)

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“…Among several bioinformatics approaches, we applied the absolute GSEA which is a useful tool for deducing biologically relevant information from large transcriptomics data, and is most robust as it targets a group of genes that share a category of functions or biological pathways, rather than individual genes. Particularly, the absolute GSEA has been widely applied in different types of cancers to identify potential tumor biomarkers involved in tumorigenesis, diagnosis and therapeutic (28,35,36). In this study, systematic bioinformatics analyses were used to compare and integrate transcriptomics data between HPV + and HPV --HNSCC.…”

Section: Discussionmentioning

confidence: 99%

Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis

et al. 2023

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IntroductionHead and neck cancer (HNC) is a highly prevalent and heterogeneous malignancy. Although extensive efforts have been made to advance its treatment, the prognosis remained poor with increased mortality. Human papillomaviruses (HPV) have been associated with high risk in HNC. TP53, a tumor suppressor, is the most frequently altered gene in HNC, therefore, investigating its target genes for the identification of novel biomarkers or therapeutic targets in HPV-related HNC progression is highly recommended.MethodsTranscriptomic profiles from three independent gene expression omnibus (GEO) datasets, including 44 HPV+ and 70 HPV- HNC patients, were subjected to integrative statistical and Bioinformatics analyses. For the top-selected marker, further in-silico validation in TCGA and GTEx databases and experimental validation in 65 (51 HPV- and 14 HPV+) subjects with histologically confirmed head and neck squamous cell carcinoma (HNSCC) have been performed.ResultsA total of 498 differentially expressed genes (DEGs) were identified including 291 up-regulated genes and 207 down-regulated genes in HPV+ compared to HPV- HNSCC patients. Functional annotations and gene set enrichment analysis (GSEA) showed that the up-regulated genes were significantly involved in p53-related pathways. The integrative analysis between the Hub-genes identified in the complex protein-protein network and the top frequent genes resulting from GSEA showed an intriguing correlation with five biomarkers which are EZH2, MDM2, PCNA, STAT5A and TYMS. Importantly, the MDM2 gene showed the highest gene expression difference between HPV+ and HPV- HNSCC (Average log2FC = 1.89). Further in-silico validation in a large HNSCC cohort from TCGA and GTEx databases confirmed the over-expression of MDM2 in HPV+ compared to HPV- HNSCC patients (p = 2.39E-05). IHC scoring showed that MDM2 protein expression was significantly higher in HPV+ compared to HPV- HNSCC patients (p = 0.031).DiscussionOur findings showed evidence that over-expression of MDM2, proto-oncogene, may affect the occurrence and proliferation of HPV-associated HNSCC by disturbing the p53-target genes and consequently the p53-related pathways.

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Section: Discussionmentioning

confidence: 99%

Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis

et al. 2023

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“…The establishment of sorafenib as a standard drug for advanced HCC is considered a turning point despite only a few months increase in median survival of patients [ 23 , 24 , 25 , 26 ]. Multiple side effects are also associated with sorafenib that may lead to early abatement of therapy [ 18 ]. In addition, the development of sorafenib resistance poses another clinically relevant problem.…”

Section: Discussionmentioning

confidence: 99%

“…Harati and colleagues examined the effect of a clinically relevant dose of metformin (50 mg/kg/d) on the antitumoral effects of sorafenib (15 mg/kg/d) using different modes of administration (concomitant versus sequential). They observed significantly reduced tumor volumes when metformin was administered concomitantly in comparison to the sorafenib-alone group with no antitumoral effects in the sequential group [ 18 ]. A recent study showed that although sorafenib treatment reduced tumor volume and prolonged median survival but increased lung metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…Additional risk factors that favor the development of HCC include Hispanic ethnicity, obesity, male gender, and diabetes [ 13 , 14 ]. Notably, a retrospective cohort study [ 15 ] identified diabetes as a major risk factor that is directly related to the pathogenesis of HCC [ 16 , 17 , 18 ]. Further, meta-analyses reported that the increased HCC risk in patients with type 2 diabetes is unrelated to alcohol consumption or viral hepatitis [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…Meanwhile, sorafenib is the mainstay drug for advanced HCC [ 23 , 24 , 25 , 26 ]. However, treatment outcomes are generally discouraging [ 18 ]. Among patients with advanced HCC, the median overall survival with sorafenib treatment is approximately 8 to 11 months [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma

Siddharth

Panjamurthy

et al. 2022

IJMS

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Hepatocellular carcinoma (HCC) incidence, as well as related mortality, has been steadily increasing in the USA and across the globe, partly due to the lack of effective therapeutic options for advanced HCC. Though sorafenib is considered standard-of-care for advanced HCC, it only improves median survival by a few months when compared to placebo. Sorafenib is also associated with several unpleasant side effects that often lead to early abatement of therapy. Here, we investigate whether a combination regimen including low-dose sorafenib and a non-toxic dose of anti-diabetic drug metformin can achieve effective inhibition of HCC. Indeed, combining metformin with low-dose sorafenib inhibited growth, proliferation, migration, and invasion potential of HCC cells. We observed a 5.3- and 1.9-fold increase in sub-G1 population in the combination treatment compared to sorafenib alone. We found that the combination of metformin enhanced the efficacy of sorafenib and inhibited the MAPK/ERK/Stat3 axis. Our in vivo studies corroborated the in vitro findings, and mice harboring HepG2-derived tumors showed effective tumor reduction upon treatment with low-dose sorafenib and metformin combination. This work sheds light on a therapeutic strategy aiming to augment sorafenib efficacy or dose-de-escalation that may prove beneficial in circumventing sorafenib resistance as well as minimizing related side effects.

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Fasting in combination with the cocktail Sorafenib:Metformin blunts cellular plasticity and promotes liver cancer cell death via poly-metabolic exhaustion

López-Cánovas,

Naranjo-Martínez,

Diaz-Ruiz

2024

Cell Oncol.

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Purpose Dual-Interventions targeting glucose and oxidative metabolism are receiving increasing attention in cancer therapy. Sorafenib (S) and Metformin (M), two gold-standards in liver cancer, are known for their mitochondrial inhibitory capacity. Fasting, a glucose-limiting strategy, is also emerging as chemotherapy adjuvant. Herein, we explore the anti-carcinogenic response of nutrient restriction in combination with sorafenib:metformin (NR-S:M). Results Our data demonstrates that, independently of liver cancer aggressiveness, fasting synergistically boosts the anti-proliferative effects of S:M co-treatment. Metabolic and Cellular plasticity was determined by the examination of mitochondrial and glycolytic activity, cell cycle modulation, activation of cellular apoptosis, and regulation of key signaling and metabolic enzymes. Under NR-S:M conditions, early apoptotic events and the pro-apoptotic Bcl-xS/Bcl-xL ratio were found increased. NR-S:M induced the highest retention in cellular SubG1 phase, consistent with the presence of DNA fragments from cellular apoptosis. Mitochondrial functionality, Mitochondrial ATP-linked respiration, Maximal respiration and Spare respiratory capacity, were all found blunted under NR-S:M conditions. Basal Glycolysis, Glycolytic reserve, and glycolytic capacity, together with the expression of glycogenic (PKM), gluconeogenic (PCK1 and G6PC3), and glycogenolytic enzymes (PYGL, PGM1, and G6PC3), were also negatively impacted by NR-S:M. Lastly, a TMT-proteomic approach corroborated the synchronization of liver cancer metabolic reprogramming with the activation of molecular pathways to drive a quiescent-like status of energetic-collapse and cellular death. Conclusion Altogether, we show that the energy-based polytherapy NR-S:M blunts cellular, metabolic and molecular plasticity of liver cancer. Notwithstanding the in vitro design of this study, it holds a promising therapeutic tool worthy of exploration for this tumor pathology.

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Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells

Cited by 13 publications

References 65 publications

Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis

Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis

Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma

Fasting in combination with the cocktail Sorafenib:Metformin blunts cellular plasticity and promotes liver cancer cell death via poly-metabolic exhaustion

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