Metformin modulate immune fitness in hepatocellular carcinoma: Molecular and cellular approach

El-Fattah, Eslam E. Abd; Zakaria, Amr Y.

doi:10.1016/j.intimp.2022.108889

Cited by 15 publications

(6 citation statements)

References 107 publications

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“…Collectively, some, but not all, preliminary findings imply that metformin may be beneficial as adjuvant to ICIs in the treatment of NAFLD-associated HCC, even though it is a medication that failed to histologically improve NAFLD. This old and cheap antidiabetic medication may improve some metabolic aberrations in NAFLD, but also may modulate the immune microenvironment of HCC [101]; however, this remains to be proven in the future, using specifically designed clinical trials in patients with exclusive NAFLD-associated HCC. On the other hand, limited data do not support the combination of metformin with TKIs; although these data do not warrant the setting of clinical trials towards this aim, the use of metformin in patients with T2DM and concomitant HCC may be reconsidered in clinical practice, at least until more observational data are published on this topic.…”

Section: Treatment Considerations For Nafld-associated Hccmentioning

confidence: 99%

Tumor Necrosis Factor-Alpha and Adiponectin in Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma

Vachliotis,

Valsamidis,

Polyzos

2023

Cancers

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Nonalcoholic fatty liver disease (NAFLD) is emerging as an important risk factor for hepatocellular carcinoma (HCC), whose prevalence is rising. Although the mechanisms of progression from NAFLD to HCC are not fully elucidated, tumor necrosis factor-α (TNF-α) and adiponectin, as well as their interplay, which seems to be antagonistic, may contribute to the pathophysiology of NAFLD-associated HCC. TNF-α initially aims to protect against hepatocarcinogenesis, but during the progression of NAFLD, TNF-α is increased, thus probably inducing hepatocarcinogenesis in the long-term, when NAFLD is not resolved. On the other hand, adiponectin, which is expected to exert anti-tumorigenic effects, is decreased during the progression of the disease, a trend that may favor hepatocarcinogenesis, but is paradoxically increased at end stage disease, i.e., cirrhosis and HCC. These observations render TNF-α and adiponectin as potentially diagnostic biomarkers and appealing therapeutic targets in the setting of NAFLD-associated HCC, possibly in combination with systematic therapy. In this regard, combination strategy, including immune checkpoint inhibitors (ICIs) with anti-TNF biologics and/or adiponectin analogs or medications that increase endogenous adiponectin, may warrant investigation against NAFLD-associated HCC. This review aims to summarize evidence on the association between TNF-α and adiponectin with NAFLD-associated HCC, based on experimental and clinical studies, and to discuss relevant potential therapeutic considerations.

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Section: Treatment Considerations For Nafld-associated Hccmentioning

confidence: 99%

Tumor Necrosis Factor-Alpha and Adiponectin in Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma

Vachliotis,

Valsamidis,

Polyzos

2023

Cancers

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“…The mechanisms by which metformin exerts its effects are diverse, including modulation of classical 5′-adenosine monophosphate-activated protein kinase (AMPK) signaling, anti-tumor angiogenesis, targeting of tumor stem cells, and regulation of insulin-like growth factor. Recent studies have demonstrated that the intestinal flora is critical for tumor immunotherapy, and that metformin also participates in regulation of the microbiota and affects the progression and treatment of tumors [48][49][50] . Metformin may serve as an adjuvant for ICIs and promote immune-mediated tumor clearance by overcoming or alleviating tumor-induced immunosuppression.…”

Section: Metforminmentioning

confidence: 99%

Repurposing drugs for solid tumor treatment: focus on immune checkpoint inhibitors

Liu,

Li,

Qin

et al. 2023

Cancer Biol Med

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Cancer remains a significant global health challenge with limited treatment options beyond systemic therapies, such as chemotherapy, radiotherapy, and molecular targeted therapy. Immunotherapy has emerged as a promising therapeutic modality but the efficacy has plateaued, which therefore provides limited benefits to patients with cancer. Identification of more effective approaches to improve patient outcomes and extend survival are urgently needed. Drug repurposing has emerged as an attractive strategy for drug development and has recently garnered considerable interest. This review comprehensively analyses the efficacy of various repurposed drugs, such as transforming growth factor-beta (TGF-β) inhibitors, metformin, receptor activator of nuclear factor-κB ligand (RANKL) inhibitors, granulocyte macrophage colony-stimulating factor (GM-CSF), thymosin α1 (Tα1), aspirin, and bisphosphonate, in tumorigenesis with a specific focus on their impact on tumor immunology and immunotherapy. Additionally, we present a concise overview of the current preclinical and clinical studies investigating the potential therapeutic synergies achieved by combining these agents with immune checkpoint inhibitors.

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“…Patients with insulin resistance were accompanied by elevated Kyn metabolites before hyperglycemia signs appeared [ 68 ]. It was found that patients on the metformin regimen had normal Trp metabolism and Kyn metabolites [ 69 ].…”

Section: Introductionmentioning

confidence: 99%

IDO/kynurenine pathway in cancer: possible therapeutic approaches

El-Fattah

2022

J Transl Med

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Cancer is one of the leading causes of death in both men and women worldwide. One of the main changes associated with cancer progression, metastasis, recurrence, and chemoresistance is the change in the tumor immune microenvironment, especially immunosuppression. Cancer immunosuppression appears in multiple forms, such as inhibition of immuno-stimulant cells with downregulation of immuno-stimulant mediators or through stimulation of immuno-suppressive cells with upregulation of immunosuppressive mediators. One of the most immunosuppressive mediators that approved potency in lung cancer progression is indoleamine 2,3-dioxygenase (IDO) and its metabolite kynurenine (Kyn). The current review tries to elucidate the role of IDO/Kyn on cancer proliferation, apoptosis, angiogenesis, oxidative stress, and cancer stemness. Besides, our review investigates the new therapeutic modalities that target IDO/Kyn pathway and thus as drug candidates for targeting lung cancer and drugs that potentiate IDO/Kyn pathway and thus can be cancer-promoting agents.

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Metformin modulate immune fitness in hepatocellular carcinoma: Molecular and cellular approach

Cited by 15 publications

References 107 publications

Tumor Necrosis Factor-Alpha and Adiponectin in Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma

Tumor Necrosis Factor-Alpha and Adiponectin in Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma

Repurposing drugs for solid tumor treatment: focus on immune checkpoint inhibitors

IDO/kynurenine pathway in cancer: possible therapeutic approaches

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