MitoTracker Deep Red (MTDR) Is a Metabolic Inhibitor for Targeting Mitochondria and Eradicating Cancer Stem Cells (CSCs), With Anti-Tumor and Anti-Metastatic Activity In Vivo

Sargiacomo, Camillo; Stonehouse, Sophie; Moftakhar, Zahra; Sotgia, Federica; Lisanti, Michael P.

doi:10.3389/fonc.2021.678343

Cited by 16 publications

(7 citation statements)

References 42 publications

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“…Recently, we also demonstrated that treatment with a panel of mitochondrially-targeted therapeutics, which potently inhibit mitochondrial protein translation or OXPHOS, could block tumor cell metastasis, using an in vivo pre-clinical model (54)(55)(56). These results indicated that ATP levels are functionally critical for the processes fueling aggressive tumor cell behaviors and spontaneous metastasis.…”

Section: Using Atp As a Biomarker To Metabolically Fractionate The Cancer Cell Population: Implications For Atp-depletion Therapymentioning

confidence: 83%

High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy

et al. 2021

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Recently, we presented evidence that high mitochondrial ATP production is a new therapeutic target for cancer treatment. Using ATP as a biomarker, we isolated the “metabolically fittest” cancer cells from the total cell population. Importantly, ATP-high cancer cells were phenotypically the most aggressive, with enhanced stem-like properties, showing multi-drug resistance and an increased capacity for cell migration, invasion and spontaneous metastasis. In support of these observations, ATP-high cells demonstrated the up-regulation of both mitochondrial proteins and other protein biomarkers, specifically associated with stemness and metastasis. Therefore, we propose that the “energetically fittest” cancer cells would be better able to resist the selection pressure provided by i) a hostile micro-environment and/or ii) conventional chemotherapy, allowing them to be naturally-selected for survival, based on their high ATP content, ultimately driving tumor recurrence and distant metastasis. In accordance with this energetic hypothesis, ATP-high MDA-MB-231 breast cancer cells showed a dramatic increase in their ability to metastasize in a pre-clinical model in vivo. Conversely, metastasis was largely prevented by treatment with an FDA-approved drug (Bedaquiline), which binds to and inhibits the mitochondrial ATP-synthase, leading to ATP depletion. Clinically, these new therapeutic approaches could have important implications for preventing treatment failure and avoiding cancer cell dormancy, by employing ATP-depletion therapy, to target even the fittest cancer cells.

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Section: Using Atp As a Biomarker To Metabolically Fractionate The Cancer Cell Population: Implications For Atp-depletion Therapymentioning

confidence: 83%

High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy

et al. 2021

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“…Magmas, a highly conserved and essential protein overexpressed in aggressive prostate cancer, is an attractive novel target. Mitochondrial targets such as Magmas have been shown to have an increasing role in the development of cancer stem cells and therapeutic resistance [ 7 , 8 ]. Traditional chemotherapy is dependent on cell growth to be effective and the dormancy of CSCs is one of the reasons for their treatment resistance.…”

Section: Introductionmentioning

confidence: 99%

Magmas Inhibition in Prostate Cancer: A Novel Target for Treatment-Resistant Disease

Yang

Das

Aljitawi

et al. 2022

Cancers

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The purpose of our study was to evaluate Magmas as a potential target in prostate cancer. In addition, we evaluated our synthetic Magmas inhibitor (BT#9) effects on prostate cancer and examined the molecular mechanism of BT#9. A cell viability assay showed that treatment with BT#9 caused a significant decrease in the viability of DU145 and PC3 prostate cancer cells with little effect on the viability of WPMY-1 normal prostate cells. Western blot proved that BT#9 downregulated the Magmas protein and caspase-3 activation. Flow cytometry studies demonstrated increased apoptosis and disturbed mitochondrial membrane potential. However, the main mode of cell death was caspase-independent necrosis, which was correlated with the accumulation of mitochondrial and intra-cellular Reactive Oxygen Species (ROS). Taken together, our data suggest Magmas is a potential molecular target for the treatment of prostate cancer and that Magmas inhibition results in ROS-dependent and caspase-independent necrotic cell death.

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“…However, genetic approaches yield longer-lasting labeling and are relatively non-toxic compared to fluorescent dyes. Studies in breast cancer cell lines found that Mitotracker deep red inhibits basal respiration and blocks ATP synthesis at concentrations at or above 500 nM ( Sargiacomo et al, 2021 ). Although the toxicity of mitochondria dyes is likely cell-type dependent, care must be taken to avoid artifacts by using the lowest-possible concentration for labeling.…”

Section: Resultsmentioning

confidence: 99%

Analysis of mitochondrial dynamics and function in the retinal pigment epithelium by high-speed high-resolution live imaging

Tan

Li²,

Germer³

et al. 2022

Front. Cell Dev. Biol.

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Mitochondrial dysfunction is strongly implicated in neurodegenerative diseases including age-related macular degeneration (AMD), which causes irreversible blindness in over 50 million older adults worldwide. A key site of insult in AMD is the retinal pigment epithelium (RPE), a monolayer of postmitotic polarized cells that performs essential functions for photoreceptor health and vision. Recent studies from our group and others have identified several features of mitochondrial dysfunction in AMD including mitochondrial fragmentation and bioenergetic defects. While these studies provide valuable insight at fixed points in time, high-resolution, high-speed live imaging is essential for following mitochondrial injury in real time and identifying disease mechanisms. Here, we demonstrate the advantages of live imaging to investigate RPE mitochondrial dynamics in cell-based and mouse models. We show that mitochondria in the RPE form extensive networks that are destroyed by fixation and discuss important live imaging considerations that can interfere with accurate evaluation of mitochondrial integrity such as RPE differentiation status and acquisition parameters. Our data demonstrate that RPE mitochondria show localized heterogeneities in membrane potential and ATP production that could reflect focal changes in metabolism and oxidative stress. Contacts between the mitochondria and organelles such as the ER and lysosomes mediate calcium flux and mitochondrial fission. Live imaging of mouse RPE flatmounts revealed a striking loss of mitochondrial integrity in albino mouse RPE compared to pigmented mice that could have significant functional consequences for cellular metabolism. Our studies lay a framework to guide experimental design and selection of model systems for evaluating mitochondrial health and function in the RPE.

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MitoTracker Deep Red (MTDR) Is a Metabolic Inhibitor for Targeting Mitochondria and Eradicating Cancer Stem Cells (CSCs), With Anti-Tumor and Anti-Metastatic Activity In Vivo

Cited by 16 publications

References 42 publications

High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy

High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy

Magmas Inhibition in Prostate Cancer: A Novel Target for Treatment-Resistant Disease

Analysis of mitochondrial dynamics and function in the retinal pigment epithelium by high-speed high-resolution live imaging

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