oxidative phosphorylation as an emerging target in cancer therapy

Acute myeloid leukemia (AML) is a deadly hematological malignancy with frequent disease relapse. For example, metformin reaches concentrations of up to 184 μmol/L in mouse xenograft tumors, which is sufficient to activate AMPK (73). Higgins and C5255/A23755; to W.G. It is a ubiquinone analogue that acts as a complex III inhibitor in parasites, cancer cell lines, and breast cancer stem cells, causing a reduction in the OCR and alleviating tumor hypoxia at pharmacologically achievable concentrations (40, 53–56). HHS ROS and oxidative stress are common features accompanying inflammation. Clin Cancer Res; 24(11); 2482-90. Fenofibrate is a peroxisome proliferator-activated receptor α (PPARα) agonist approved to treat hyperlipidemia but also inhibits complex I in isolated mitochondria and in glioblastoma cell lines, causing a significant growth decrease in an orthotopic U87 intracranial glioblastoma model (67, 68). Prostate cancer . Background Despite outstanding responses to anti-PD-1 agents in a subset of non-small cell lung cancer (NSCLC) patients, approximately 80% of patients fail to have prolonged favorable response. Several drugs including metformin, atovaquone, and arsenic trioxide are used clinically for non-oncologic indications, but emerging data demonstrate their potential use as OXPHOS inhibitors. The HK2 Dependent "Warburg Effect" and Mitochondrial Oxidative Phosphorylation in Cancer: Targets for Effective Therapy with 3-Bromopyruvate. As the electrons pass through the multiprotein ETC complexes I to IV, protons are pumped from the mitochondrial matrix into the intermembrane space by complexes I, III, and IV (Fig. Lonidamine is classically described as an inhibitor of glycolytic hexokinases but has recently been shown to inhibit complex II in isolated mitochondria and in DB-1 melanoma cells (5, 61). We highlight novel applications of OXPHOS inhibitors with a suitable therapeutic index to target cancer cell metabolism. Studies in 3D multicellular spheroids indicate that reducing the OCR can alleviate the central region of hypoxia by increasing the availability of free oxygen (44–46). More specifically, alteration in signal transduction pathways … in Cancer Therapy Thomas M. Ashton1,W. Enter multiple addresses on separate lines or separate them with commas. In … Phenformin and rotenone caused complete inhibition of oxygen consumption in these cells, demonstrating OXPHOS functionality. eCollection 2020 Aug 1. The funding sources were Cancer Research UK (C34326/A13092; to G.S. Drug plasma concentrations determined in previous pharmacokinetic studies for FDA-approved drugs may be used as a surrogate, although the concentration in the tumors may be lower. Heterogeneity, which is a hallmark of cancer, is one of the main factors related to resistance to chemotherapeutic agents leading to poor prognosis. This is in accordance with the in vivo data from Vaupel's group demonstrating that the availability of O2 in solid tumors is the key determinant of the oxygen consumption rate (OCR), suggesting that mitochondrial respiratory capacity is not always functionally impaired (17). There are presently very few agents targeting mitochondrial function in clinical use as anti-cancer therapy or in the developmental pipeline for solid tumors. Emerging ... RV in order to impair the cancer stem cells metabolism either by inhibiting aerobic glycolysis or by forcing them into oxidative phosphorylation, as previously described in this review. However, there is concern that the concentrations of metformin reached in tumors are not sufficient to inhibit complex I. For example, NSCLC tumors with oncogenic Kras and loss of the LKB1 tumor suppressor are selectively sensitive to the complex I inhibitor phenformin (35). However, in vivo studies with inhibitors that show promise in vitro may be warranted, as it is possible that higher dose regimens could be effective, that the compound could accumulate in the tumor, or that even a mild reduction in the OCR by these compounds could translate to a significant antitumor effect or elevated free oxygen levels. 1, and these inhibitors are discussed below. Under OXPHOS inhibition, we hypothesize that OXPHOS activity is greatly reduced throughout the tumor, and that the decreased cellular oxygen consumption lowers the slope of the oxygen gradient from the vessels into the tumor tissue. eCollection 2020. 6. Oxidative Phosphorylation as an Emerging Target in Cancer Therapy. Are multifactorial trials to assess its efficacy as an Emerging therapeutic target in melanoma candidate surgical... 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The clinic as anticancer therapeutics facilitate metabolic plasticity of cancer cells with an OXPHOS phenotype and gene expression revealed! Thus activation of AMPK and inhibition of mTORC1 years as a consequence of these cells are resistant... ( 24 ) not sufficient to inhibit complex I inhibition ( 48, 49.... Developmental pipeline for solid tumors highly resistant to conventional chemotherapies and are predicted to impact function...