Targeting Mitochondria and Oxidative Stress in Cancer- and Chemotherapy-Induced Muscle Wasting

Huot, Joshua R.; Baumfalk, Dryden R.; Resendiz, Aridai; Bonetto, Andrea; Smuder, Ashley J.; Penna, Fabio

doi:10.1089/ars.2022.0149

Cited by 6 publications

(4 citation statements)

References 201 publications

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“…Mitochondria are the main source of oxidative stress in skeletal muscle, and studies have shown oxidative stress plays an important role in the regulation of muscle mass during cachexia (Huot et al., 2023 ). For this reason, we used the mitochondria‐targeted superoxide‐sensitive fluorophore Mitosox and mitochondria labeling fluorophore MitoTracker to measure superoxide in cachectic conditions.…”

Section: Resultsmentioning

confidence: 99%

“…There is evidence in a rodent model of cancer cachexia that mitochondrial dysfunction precedes loss of muscle mass, making mitochondria an attractive target to combat cancer cachexia (Brown et al., 2017 ). Oxidative stress in the form of increased reactive oxygen species (ROS) contributes to cancer cachexia (Huot et al., 2023 ). Paradoxically, clinical trials using antioxidant treatments have been largely ineffective (Assi & Rebillard, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia

Hain,

Kimball,

Waning

2024

Physiological Reports

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Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients. Mice inoculated with Lewis lung carcinoma (LLC) cells lose weight, muscle mass, and have lower muscle sirtuin‐1 (sirt1) expression. Nicotinic acid (NA) is a precursor to nicotinamide dinucleotide (NAD+) which is exhausted in cachectic muscle and is a direct activator of sirt1. Mice lost body and muscle weight and exhibited reduced skeletal muscle sirt1 expression after inoculation with LLC cells. C2C12 myotubes treated with LLC‐conditioned media (LCM) had lower myotube diameter. We treated C2C12 myotubes with LCM for 24 h with or without NA for 24 h. C2C12 myotubes treated with NA maintained myotube diameter, sirt1 expression, and had lower mitochondrial superoxide. We then used a sirt1‐specific small molecule activator SRT1720 to increase sirt1 activity. C2C12 myotubes treated with SRT1720 maintained myotube diameter, prevented loss of sirt1 expression, and attenuated mitochondrial superoxide production. Our data provides evidence that NA may be beneficial in combating cancer cachexia by maintaining sirt1 expression and decreasing mitochondrial superoxide production.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia

Hain,

Kimball,

Waning

2024

Physiological Reports

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“… 3 , 9 , 17 Indeed, abnormal mitochondrial homeostasis and quality control have been directly related to the multifactorial nature of cachexia, and strategies aimed at preserving the muscle mitochondrial pool have been investigated as potential therapies against cancer- and chemotherapy-induced muscle wasting. 3 , 38 , 65 , 66 As already mentioned above, these mitochondrial dysfunctions are known to drive skeletal muscle atrophy through oxidative and metabolic stress. 3 , 21 Our observations here are consistent with our published work on mitochondrial stress induced by chemotherapy.…”

Section: Discussionmentioning

confidence: 96%

Long-term Musculoskeletal Consequences of Chemotherapy in Pediatric Mice

Huot,

Livingston,

et al. 2024

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Thanks to recent progress in cancer research, most children treated for cancer survive into adulthood. Nevertheless, the long-term consequences of anticancer agents are understudied, especially in the pediatric population. We and others have shown that routinely administered chemotherapeutics drive musculoskeletal alterations, which contribute to increased treatment-related toxicity and long-term morbidity. Yet, the nature and scope of these enduring musculoskeletal defects following anticancer treatments and whether they can potentially impact growth and quality of life in young individuals remain to be elucidated. Here, we aimed at investigating the persistent musculoskeletal consequences of chemotherapy in young (pediatric) mice. Four-week-old male mice were administered a combination of 5-FU, leucovorin, irinotecan (a.k.a., Folfiri) or the vehicle for up to 5 weeks. At time of sacrifice, skeletal muscle, bones, and other tissues were collected, processed, and stored for further analyses. In another set of experiments, chemotherapy-treated mice were monitored for up to 4 weeks after cessation of treatment. Overall, the growth rate was significantly slower in the chemotherapy-treated animals, resulting in diminished lean and fat mass, as well as significantly smaller skeletal muscles. Interestingly, 4 weeks after cessation of the treatment, the animals exposed to chemotherapy showed persistent musculoskeletal defects, including muscle innervation deficits and abnormal mitochondrial homeostasis. Altogether, our data supports that anticancer treatments may lead to long-lasting musculoskeletal complications in actively growing pediatric mice and support the need for further studies to determine the mechanisms responsible for these complications, so that new therapies to prevent or diminish chemotherapy-related toxicities can be identified.

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“…Antioxidant compounds can be useful to alleviate the oxidative stress and also to reduce the oxidative damages associated with chemotherapy. Fortifying the antioxidant defense is a strategy considered to reduce side effects of chemotherapy [40]. The antioxidant properties of the phenylpyrazolones can contribute to the anticancer activity of the molecules and facilitate drug combination.…”

Section: Discussionmentioning

confidence: 99%

Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties

et al. 2023

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Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism is known for the drug edaravone (1) which is also an aldehyde-reactive molecule. The present study reports the synthesis and functional characterization of new molecules (2–5) with an improved anti-PD-L1 activity. The leading fluorinated molecule 5 emerges as a potent checkpoint inhibitor, avidly binding to PD-L1, inducing its dimerization, blocking PD-1/PD-L1 signaling mediated by phosphatase SHP-2 and reactivating the proliferation of CTLL-2 cells in the presence of PD-L1. In parallel, the compound maintains a significant antioxidant activity, characterized using electron paramagnetic resonance (EPR)-based free radical scavenging assays with the probes DPPH and DMPO. The aldehyde reactivity of the molecules was investigated using 4-hydroxynonenal (4-HNE), which is a major lipid peroxidation product. The formation of drug-HNE adducts, monitored by high resolution mass spectrometry (HRMS), was clearly identified and compared for each compound. The study leads to the selection of compound 5 and the dichlorophenyl-pyrazolone unit as a scaffold for the design of small molecule PD-L1 inhibitors endowed with antioxidant properties.

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Targeting Mitochondria and Oxidative Stress in Cancer- and Chemotherapy-Induced Muscle Wasting

Cited by 6 publications

References 201 publications

Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia

Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia

Long-term Musculoskeletal Consequences of Chemotherapy in Pediatric Mice

Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties

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