Metformin's Modulation of Immune Response and PD-L1 Regulation
Metformin has shown efficacy in enhancing the therapeutic effects of anti-PD-L1 antibodies through its impact on the gut microbiota. Studies in mouse models have demonstrated that metformin's regulation of gut microbiota boosts anti-tumor immunity, increasing CD8+ T-cell infiltration and IFN-γ expression, crucial components of the immune response against tumors. Additionally, a metformin-liposome combination reduced PD-L1 expression. It reversed hypoxia in tumor tissues, which amplified the immune reaction by alleviating T-cell exhaustion in photodynamic therapy (PDT) contexts.
Inhibition of Nrf2 Signaling and Reduction of Chemoresistance
Metformin's effect on Nrf2 signaling has gained attention for its role in reducing cancer chemoresistance. It downregulates Nrf2 transcriptional activity, often associated with resistance in cancers like hepatocellular carcinoma (HCC), and may be linked to improved sensitivity to chemotherapeutic drugs, such as cisplatin. This mechanism is vital in overcoming drug resistance that characterizes aggressive cancers.
Induction of Ferroptosis via Inhibition of UFMylation of SLC7A11
Metformin induces ferroptosis, a form of regulated cell death, in breast cancer cells by inhibiting the UFMylation process of SLC7A11. This pathway facilitates the accumulation of iron-dependent lipid peroxidation, lethal to cancer cells. Metformin and other ferroptosis-inducing agents have synergistic effects in enhancing cell death in specific breast cancer models, highlighting ferroptosis as a novel anti-cancer pathway mediated by metformin.
Inhibition of the Epithelial-Mesenchymal Transition (EMT) and Metastasis
Metformin has been observed to inhibit the EMT, a critical process in cancer metastasis, particularly in pancreatic cancer cells. By downregulating TGF-β1-induced EMT signaling, metformin reduces cancer cells' migration potential, limiting their ability to metastasize to distant organs. This pathway, involving the inhibition of Smad and Akt/mTOR pathways, demonstrates metformin's potential in reducing metastasis, a significant factor in cancer progression and patient prognosis.
Targeting Hypoxic Tumor Microenvironments by Modulating PDH and HIF-1α
Under hypoxic conditions commonly present in solid tumors, metformin increases pyruvate dehydrogenase (PDH) levels. It suppresses HIF-1α, a critical factor promoting survival in low-oxygen conditions. This reduces cancer cell proliferation and migration and enhances apoptosis, particularly in oral squamous cell carcinoma models. Metformin disrupts cancer cells’ metabolic adaptations that support growth and survival in oxygen-poor environments by targeting hypoxia-driven pathways.
Metformin’s Effect on Glutamine Metabolism and Autophagy
In various cancer cell types, metformin reduces glutaminase activity, leading to lower levels of glutamate and ammonia. This reduction limits autophagy, a survival mechanism in tumors under metabolic stress. By impairing glutamine metabolism, metformin disrupts cellular homeostasis, causing cell death, particularly in cancer cells reliant on high glutaminase activity for growth.
Influence on Cancer Stem Cells
Metformin reduces cancer stem cell (CSC) populations in colorectal cancer by altering glutamine metabolism, which CSCs rely on. This mechanism weakens CSCs' self-renewal capabilities, rendering them more susceptible to conventional therapies and reducing the likelihood of relapse.
Targeting Hypoxia-Driven HIF-1 Pathway in Multiple Myeloma
Hypoxia-inducible factor-1α (HIF-1α) significantly promotes tumor survival in low-oxygen conditions by enhancing glycolysis and angiogenesis. Metformin inhibits HIF-1α, suppressing these adaptive responses and leading to apoptosis in hypoxic cells in multiple myeloma and other cancers. This makes metformin a promising adjuvant to therapies targeting hypoxia-adapted cancer cells.
Inhibition of TGF-β-Induced EMT and Fibrosis
Metformin’s inhibition of TGF-β-induced EMT extends beyond pancreatic cancer, affecting other cancers and even fibrotic diseases. EMT is essential for metastasis, and metformin’s suppression of this process, notably through the downregulation of TGF-β/Smad signaling, limits the ability of cancer cells to invade new tissues.
Enhanced PDH Activity and Reduced HIF-1α in Hypoxic Conditions
Under hypoxia, metformin promotes pyruvate dehydrogenase (PDH) activity and reduces HIF-1α levels, impairing the Warburg effect and promoting apoptosis in cancers like oral squamous cell carcinoma. This dual action on energy metabolism and hypoxia adaptation is vital in metformin’s anti-tumor arsenal.
Metformin's Main Anti-Cancer Mechanisms
Please refer to the spreadsheet for more details on Metformin's synergistic combinations and effects against over 30 anticancer variables.
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