Synchronous effects of targeted mitochondrial complex I inhibitors on tumor and immune cells abrogate melanoma progression

AbuEid, Mahmoud; McAllister, Donna; McOlash, Laura; Harwig, Megan Cleland; Cheng, Gang; Drouillard, Donovan; Boyle, Kathleen A.; Hardy, Micaël; Zielonka, Jacek; Johnson, Bryon D.; Hill, Rolla B.; Kalyanaraman, Balaraman; Dwinell, Michael B.

doi:10.1016/j.isci.2021.102653

Cited by 21 publications

(28 citation statements)

References 61 publications

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“…Mito-ATO and other mitochondria-targeted compounds (Mito-hydroxyurea and Mito-magnolol) activate T cells and inhibit regulatory T cells (T regs ) and myeloid-derived suppressor cells 29 , 61 , 62 . In addition to increasing intracellular lactate levels, AZD-3965 has pronounced effects on cancer cell metabolism (enhanced mitochondrial oxidative metabolism and improved bioenergetics).…”

Section: Discussionmentioning

confidence: 99%

“…Although the present data were obtained from in vitro cell culture experiments, the proposed strategy should be translatable to in vivo mouse xenografts. A related non-PEGylated analog, Mito-ATO, inhibited immunosuppressive T regs and myeloid-derived suppressor cells in bone marrow cells and another mitochondria-compound-inhibited tumor growth in immune competent mice xenografts 29 , 61 , 62 . PEGylated biopharmaceuticals, micelles, nanoparticles, and liposomes were shown to induce immunogenicity 64 .…”

Section: Discussionmentioning

confidence: 99%

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Combining PEGylated mito-atovaquone with MCT and Krebs cycle redox inhibitors as a potential strategy to abrogate tumor cell proliferation

Cheng

Hardy

You

et al. 2022

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Combining PEGylated mito-atovaquone with MCT and Krebs cycle redox inhibitors as a potential strategy to abrogate tumor cell proliferation

Cheng

Hardy

You

et al. 2022

Sci Rep

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“…Mito‐magnolol inhibited tumor progression in an immune‐competent mouse xenograft model 22 . Also, Mito‐magnolol remodeled the TIME in a mouse melanoma model.…”

Section: Antiproliferative Effects Of Mito‐magnolol In Drug‐resistant...mentioning

confidence: 93%

“…33 Mito-magnolol inhibited tumor progression in an immune-competent mouse xenograft model. 22 Also, Mitomagnolol remodeled the TIME in a mouse melanoma model. Mito-magnolol induced infiltration of T cells, decreased MDSCs, and decreased tumor-associated macrophages in melanoma tumors.…”

Section: Effects Of Mito -Magnolol In Drug-resistant Melanoma Cellsmentioning

confidence: 98%

“…Increased mitochondrial biogenesis and upregulated OXPHOS genes are associated with enhanced mitochondrial respiration in drug‐resistant melanoma cells. A mitochondria‐targeted analog of magnolol (Mito‐magnolol) was shown to potently inhibit melanoma cell proliferation and tumor growth in murine melanoma xenografts 22,33 33 …”

Section: Antiproliferative Effects Of Mito‐magnolol In Drug‐resistant...mentioning

confidence: 99%

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Exploiting the tumor immune microenvironment and immunometabolism using mitochondria‐targeted drugs: Challenges and opportunities in racial disparity and cancer outcome research

Kalyanaraman

2022

The FASEB Journal

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Black and Hispanic cancer patients have a higher incidence of cancer mortality. Many factors (e.g., socioeconomic differences, insufficient access to healthcare) contribute to racial disparity. Emerging research implicates biological disparity in cancer outcomes. Studies show distinct differences in the tumor immune microenvironment (TIME) in Black cancer patients. Studies also have linked altered mitochondrial metabolism to changes in immune cell activation in TIME. Recent publications revealed a novel immunomodulatory role for triphenylphosphonium‐based mitochondrial‐targeted drugs (MTDs). These are synthetically modified, naturally occurring molecules (e.g., honokiol, magnolol, metformin) or FDA‐approved small molecule drugs (e.g., atovaquone, hydroxyurea). Modifications involve conjugating the parent molecule via an alkyl linker chain to a triphenylphosphonium moiety. These modified molecules (e.g., Mito‐honokiol, Mito‐magnolol, Mito‐metformin, Mito‐atovaquone, Mito‐hydroxyurea) accumulate in tumor cell mitochondria more effectively than in normal cells and inhibit mitochondrial respiration, induce reactive oxygen species, activate AMPK and redox transcription factors, and inhibit cancer cell proliferation. Besides these intrinsic effects of MTDs in redox signaling and proliferation in tumors, MTDs induced extrinsic effects in the TIME of mouse xenografts. MTD treatment inhibited tumor‐suppressive immune cells, myeloid‐derived suppressor cells, and regulatory T cells, and activated T cells and antitumor immune effects. One key biological disparity in Black cancer patients was related to altered mitochondrial oxidative metabolism; MTDs targeting vulnerabilities in tumor cells and the TIME may help us understand this biological disparity. Clinical trials should include an appropriate number of Black and Hispanic cancer patients and should validate the intratumoral, antihypoxic effects of MTDs with imaging.

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Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria‐Targeted Atovaquone

et al. 2022

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Atovaquone, an FDA‐approved drug for malaria, is known to inhibit mitochondrial electron transport. A recently synthesized mitochondria‐targeted atovaquone increased mitochondrial accumulation and antitumor activity in vitro. Using an in situ vaccination approach, local injection of mitochondria‐targeted atovaquone into primary tumors triggered potent T cell immune responses locally and in distant tumor sites. Mitochondria‐targeted atovaquone treatment led to significant reductions of both granulocytic myeloid‐derived suppressor cells and regulatory T cells in the tumor microenvironment. Mitochondria‐targeted atovaquone treatment blocks the expression of genes involved in oxidative phosphorylation and glycolysis in granulocytic‐myeloid‐derived suppressor cells and regulatory T cells, which may lead to death of granulocytic‐myeloid‐derived suppressor cells and regulatory T cells. Mitochondria‐targeted atovaquone inhibits expression of genes for mitochondrial complex components, oxidative phosphorylation, and glycolysis in both granulocytic‐myeloid‐derived suppressor cells and regulatory T cells. The resulting decreases in intratumoral granulocytic‐myeloid‐derived suppressor cells and regulatory T cells could facilitate the observed increase in tumor‐infiltrating CD4 + T cells. Mitochondria‐targeted atovaquone also improves the anti‐tumor activity of PD‐1 blockade immunotherapy. The results implicate granulocytic‐myeloid‐derived suppressor cells and regulatory T cells as novel targets of mitochondria‐targeted atovaquone that facilitate its antitumor efficacy.

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Synchronous effects of targeted mitochondrial complex I inhibitors on tumor and immune cells abrogate melanoma progression

Cited by 21 publications

References 61 publications

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

Exploiting the tumor immune microenvironment and immunometabolism using mitochondria‐targeted drugs: Challenges and opportunities in racial disparity and cancer outcome research

Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria‐Targeted Atovaquone

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