Combining PEGylated mito-atovaquone with MCT and Krebs cycle redox inhibitors as a potential strategy to abrogate tumor cell proliferation.
Combining PEGylated mito-atovaquone with MCT and Krebs cycle redox inhibitors as a potential strategy to abrogate tumor cell proliferation.
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DOI：
10.1038/s41598-022-08984-6
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发表时间：
2022-03-24
影响因子：
4.6
通讯作者：
Kalyanaraman B
中科院分区：
文献类型：
--
作者：
Cheng G;Hardy M;You M;Kalyanaraman B
Glycolytic and mitochondrial oxidative metabolism, which are two major energy sources in tumors, are potential targets in cancer treatment. Metabolic reprogramming from glycolysis to mitochondrial oxidative metabolism and vice versa is an adaptive strategy with which tumor cells obtain energy to survive and thrive under the compromised conditions of glycolysis and mitochondrial respiration. Developing highly potent, nontoxic, and tumor-selective oxidative phosphorylation (OXPHOS) inhibitors may help advance therapeutic targeting of mitochondrial drugs in cancer. The FDA-approved antimalarial drug atovaquone (ATO), a mitochondrial complex III inhibitor, was repurposed in cancer treatment. Here, we developed a new class of PEGylated mitochondria-targeted ATO (Mito-(PEG)n-ATO). Depending on the PEGylation chain length (n), Mito-PEG-ATO analogs inhibit both mitochondrial complex I- and complex III-induced oxygen consumption in human pancreatic (MiaPaCa-2) and brain (U87MG) cancer cells. Mito-PEG5-ATO is one of the most potent antiproliferative mitochondria-targeted compounds (IC50 = 38 nM) in MiaPaCa-2 cells, and is more effective than other inhibitors of OXPHOS in MiaPaCa-2 and U87MG cells. Furthermore, we show that the combined use of the most potent OXPHOS-targeted inhibitors (Mito-PEG5-ATO) and inhibitors of monocarboxylate transporters (MCT-1 and MCT-4), Krebs cycle redox metabolism, or glutaminolysis will synergistically abrogate tumor cell proliferation. Potential clinical benefits of these combinatorial therapies are discussed.
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影响因子：
11.2
作者：
Beloueche-Babari M;Wantuch S;Casals Galobart T;Koniordou M;Parkes HG;Arunan V;Chung YL;Eykyn TR;Smith PD;Leach MO
通讯作者：
Leach MO
影响因子：
14.8
作者：
Chen YJ;Mahieu NG;Huang X;Singh M;Crawford PA;Johnson SL;Gross RW;Schaefer J;Patti GJ
通讯作者：
Patti GJ
影响因子：
5.8
作者：
Cheng G;Hardy M;Topchyan P;Zander R;Volberding P;Cui W;Kalyanaraman B
通讯作者：
Kalyanaraman B
影响因子：
4.8
作者：
Boyle, Kathleen A.;Van Wickle, Jonathan;Dwinell, Michael B.
通讯作者：
Dwinell, Michael B.
影响因子：
8.8
作者：
Benjamin, Don;Robay, Dimitri;Hall, Michael N.
通讯作者：
Hall, Michael N.