Drug-Induced Mitochondrial Toxicity in the Geriatric Population: Challenges and Future Directions

Will, Yvonne; Shields, Jefry E.; Wallace, Kendall B.

doi:10.3390/biology8020032

Cited by 50 publications

(63 citation statements)

References 119 publications

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“…Most of drug-induced mitochondrial toxicities were not detected in preclinical animal studies. Most of these effects have been proven through studies in isolated cells and mitochondria [33]. Our results showed that Ara-C, and IFOS significantly induce mitochondrial membrane potential collapse in isolated rat neurons, which is consistent with previously published data examining anticancer drugs-induced mitochondrial toxicity in other tissues.…”

Section: Discussionsupporting

confidence: 92%

“…Mitochondrial toxicity has been identified to cause organ toxicity to the central nervous system, kidney, skeletal muscle, heart and liver [32]. Drug classes identified to cause mitochondrial toxicity are anti-diabetic, cholesterol lowering, anti-depressants, pain medications, certain antibiotics, and anti-cancer drugs [33]. Most of drug-induced mitochondrial toxicities were not detected in preclinical animal studies.…”

Section: Discussionmentioning

confidence: 99%

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Trifluoperazine an Antipsychotic Drug and Inhibitor of Mitochondrial Permeability Transition Protects Cytarabine and Ifosfamide-Induced Neurotoxicity

et al. 2020

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The link between Ca2+ dysregulation, mitochondria damages, oxidative stress and cellular derangement is particularly evident in neurotoxicity induced by chemotherapeutic agents. In the current study, we investigated effects of trifluoperazine (TFP) as an inhibitor of calmodulin against the cytotoxicity induced by cytarabine (Ara-C) and Ifosfamide (IFOS) on isolated rat neurons and also the mechanisms involved in this toxicity. Isolated rat neurons were pretreated with TFP (100 µM) for 5 min at 37°C, then Ara-C (226 µM) and IFOS (290 µM) were added in separate experiments. After 3 h, the cytotoxicity, reactive oxygen species (ROS), lysosomal membrane destabilization, mitochondrial membrane potential (MMP), lipid peroxidation (LP), glutathione (GSH) and glutathione disulfide (GSSG) levels were measured. Ara-C and IFOS treatments caused a significant decrease in cellular viability, which was accompanied by ROS generation, GSSG/GSH ratio, lipid peroxidation and lysosomal and mitochondrial damages. On the other hand, TFP (100 µM) pre-treatment attenuated Ara-C and IFOS -induced decrease in cell viability. In addition, TFP (100 µM) pre-treatment significantly protected against Ara-C and IFOS -induced increase in ROS generation, lysosomal and mitochondrial damages, lipid peroxidation levels and decrease in GSH/GSSG ratio. Our data provided insights into the mechanism of protection by TFP against Ara-C and IFOS neurotoxicity, which is related, to neuronal ROS formation and mitochondrial damages.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Trifluoperazine an Antipsychotic Drug and Inhibitor of Mitochondrial Permeability Transition Protects Cytarabine and Ifosfamide-Induced Neurotoxicity

et al. 2020

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“…Given the central role of mitochondria in energy metabolism, tissue health and ageing, there is increasing concern regarding the long-term effect that xenobiotics may have on mitochondrial function. Mitochondrial perturbations are likely to increase sensitivity to xenobiotics, decrease cellular repair mechanisms and contribute to both chronic disease states and accelerated ageing (Will et al 2019 ). The most direct method to assess mitochondrial activity is by measuring oxygen consumption rates (OCR).…”

Section: Discussionmentioning

confidence: 99%

“…There is accumulating evidence that chemical-induced organ toxicity involves disruption of mitochondrial function more frequently than previously considered (Dykens and Will 2007 ; Will et al 2019 ; Dreier et al 2019 ). Mitochondrial perturbations can have major effects on tissues and organs due to their key role in fatty acid metabolism, energy production and generation of reactive oxygen species (ROS).…”

Section: Introductionmentioning

confidence: 99%

Multiparametric assessment of mitochondrial respiratory inhibition in HepG2 and RPTEC/TERT1 cells using a panel of mitochondrial targeting agrochemicals

et al. 2020

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Evidence is mounting for the central role of mitochondrial dysfunction in several pathologies including metabolic diseases, accelerated ageing, neurodegenerative diseases and in certain xenobiotic-induced organ toxicity. Assessing mitochondrial perturbations is not trivial and the outcomes of such investigations are dependent on the cell types used and assays employed. Here we systematically investigated the effect of electron transport chain (ETC) inhibitors on multiple mitochondrial-related parameters in two human cell types, HepG2 and RPTEC/TERT1. Cells were exposed to a broad range of concentrations of 20 ETC-inhibiting agrochemicals and capsaicin, consisting of inhibitors of NADH dehydrogenase (Complex I, CI), succinate dehydrogenase (Complex II, CII) and cytochrome bc1 complex (Complex III, CIII). A battery of tests was utilised, including viability assays, lactate production, mitochondrial membrane potential (MMP) and the Seahorse bioanalyser, which simultaneously measures extracellular acidification rate [ECAR] and oxygen consumption rate [OCR]. CI inhibitors caused a potent decrease in OCR, decreased mitochondrial membrane potential, increased ECAR and increased lactate production in both cell types. Twenty-fourhour exposure to CI inhibitors decreased viability of RPTEC/TERT1 cells and 3D spheroid-cultured HepG2 cells in the presence of glucose. CI inhibitors decreased 2D HepG2 viability only in the absence of glucose. CII inhibitors had no notable effects in intact cells up to 10 µM. CIII inhibitors had similar effects to the CI inhibitors. Antimycin A was the most potent CIII inhibitor, with activity in the nanomolar range. The proposed CIII inhibitor cyazofamid demonstrated a mitochondrial uncoupling signal in both cell types. The study presents a comprehensive example of a mitochondrial assessment workflow and establishes measurable key events of ETC inhibition.

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“…However, a gradually increasing intraperitoneal PP dose reduced breast cancer growth without causing death in mice [ 83 ]. Drug-induced mitochondrial toxicity can further lead to liver, muscle, kidney and central nervous system failure [ 84 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting Mitochondria in Melanoma

et al. 2020

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Drastically elevated glycolytic activity is a prominent metabolic feature of cancer cells. Until recently it was thought that tumor cells shift their entire energy production from oxidative phosphorylation (OXPHOS) to glycolysis. However, new evidence indicates that many cancer cells still have functional OXPHOS, despite their increased reliance on glycolysis. Growing pre-clinical and clinical evidence suggests that targeting mitochondrial metabolism has anti-cancer effects. Here, we analyzed mitochondrial respiration and the amount and activity of OXPHOS complexes in four melanoma cell lines and normal human dermal fibroblasts (HDFs) by Seahorse real-time cell metabolic analysis, immunoblotting, and spectrophotometry. We also tested three clinically approved antibiotics, one anti-parasitic drug (pyrvinium pamoate), and a novel anti-cancer agent (ONC212) for effects on mitochondrial respiration and proliferation of melanoma cells and HDFs. We found that three of the four melanoma cell lines have elevated glycolysis as well as OXPHOS, but contain dysfunctional mitochondria. The antibiotics produced different effects on the melanoma cells and HDFs. The anti-parasitic drug strongly inhibited respiration and proliferation of both the melanoma cells and HDFs. ONC212 reduced respiration in melanoma cells and HDFs, and inhibited the proliferation of melanoma cells. Our findings highlight ONC212 as a promising drug for targeting mitochondrial respiration in cancer.

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Drug-Induced Mitochondrial Toxicity in the Geriatric Population: Challenges and Future Directions

Cited by 50 publications

References 119 publications

Trifluoperazine an Antipsychotic Drug and Inhibitor of Mitochondrial Permeability Transition Protects Cytarabine and Ifosfamide-Induced Neurotoxicity

Trifluoperazine an Antipsychotic Drug and Inhibitor of Mitochondrial Permeability Transition Protects Cytarabine and Ifosfamide-Induced Neurotoxicity

Multiparametric assessment of mitochondrial respiratory inhibition in HepG2 and RPTEC/TERT1 cells using a panel of mitochondrial targeting agrochemicals

Targeting Mitochondria in Melanoma

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