Metformin protects from oxaliplatin induced peripheral neuropathy in rats

Martinez, Nicolas W.; Sánchez, Antonia Reyes; Diaz, Paula; Broekhuizen, Richard; Godoy, Juan A.; Mondaca, Sebastián; Catenaccio, Alejandra; Macanas, P.; Nervi, Bruno; Calvo, Margarita; Court, Felipe A.

doi:10.1016/j.ynpai.2020.100048

Cited by 21 publications

(20 citation statements)

References 79 publications

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“…Others have reported that oxaliplatin upregulates FOS in neurons in vitro , but whether this effect is unique to oxaliplatin remains to be investigated. Interestingly, another group reported that oxaliplatin-treated mice exhibited neuronal damage (demonstrated by an upregulation of FOS and ATF3) that was reversible by treatment with metformin, which they suggest as a possible combination therapy to prevent/treat this side effect [ 42 , 43 ]. Accordingly, ATF3 appeared in a list of transcripts which were regulated differentially by cisplatin vs. oxaliplatin ( Figure 6A ).…”

Section: Resultsmentioning

confidence: 99%

Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells

et al. 2021

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Colorectal cancer (CRC) caused over 900,000 deaths worldwide in 2020. A majority of late-stage CRC patients are treated with 5-fluorouracil (5-FU) combined with either irinotecan (CPT-11), oxaliplatin, or both. Despite their widespread use, the mechanisms of efficacy and toxicity of these drugs remain incompletely understood. While previous work has investigated cellular responses to these agents individually, we directly compare the transcriptomic and cytokine profiles of HCT116 wild-type and p53−/− colorectal cancer cells treated with these drugs and report pan-drug, drug-specific, drug class-specific, p53-independent, and p53-dependent signatures. We observed downregulation of histone genes by 5-FU (that significantly correlates with improved survival in CRC patients) and upregulation of FOS and ATF3 by oxaliplatin (which may contribute to peripheral neuropathy). BTG2 was identified as a top gene upregulated by all four drugs, suggesting its critical role in the cellular response to chemotherapy in CRC. Soluble TRAILR2 (death receptor 5; DR5) is a decoy receptor for TRAIL, an apoptosis-inducing cytokine. TRAILR2 was down-regulated by oxaliplatin and 5-FU, was not affected by CPT-11, and was increased by cisplatin. There was an increase in IL-8 by oxaliplatin and increase in ferritin by cisplatin which may contribute to cancer cell survival. Novel drug-specific mechanisms of efficacy or toxicity identified in these signatures may be targeted with combination therapies or development of new targeted therapies. Together, the findings here contribute to our understanding of the molecular bases of efficacy and toxicity of chemotherapeutic agents often used for treatment of GI cancer such as CRC.

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Section: Resultsmentioning

confidence: 99%

Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells

et al. 2021

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“…Genetic deletion of PKR or the expression of a dominant-negative form of PKR inhibits RAN translation. Moreover, metformin, a drug widely used for treating type 2 diabetes and recently tested in neurodegenerative disorders ( Gantois et al, 2019 ; Martinez et al, 2020 ), showed an inhibiting effect on RAN translation and PKR activation ( Zu et al, 2020 ). It remains to be elucidated how metformin inhibits PKR and its possible effects in neurodegenerative diseases.…”

Section: Pkr Role In Age-related Neurodegenerative Diseasesmentioning

confidence: 99%

The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration

Martinez

Gómez

Matus

2021

Front. Aging Neurosci.

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There is a growing evidence describing a decline in adaptive homeostasis in aging-related diseases affecting the central nervous system (CNS), many of which are characterized by the appearance of non-native protein aggregates. One signaling pathway that allows cell adaptation is the integrated stress response (ISR), which senses stress stimuli through four kinases. ISR activation promotes translational arrest through the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α) and the induction of a gene expression program to restore cellular homeostasis. However, depending on the stimulus, ISR can also induce cell death. One of the ISR sensors is the double-stranded RNA-dependent protein kinase [protein kinase R (PKR)], initially described as a viral infection sensor, and now a growing evidence supports a role for PKR on CNS physiology. PKR has been largely involved in the Alzheimer’s disease (AD) pathological process. Here, we reviewed the antecedents supporting the role of PKR on the efficiency of synaptic transmission and cognition. Then, we review PKR’s contribution to AD and discuss the possible participation of PKR as a player in the neurodegenerative process involved in aging-related pathologies affecting the CNS.

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“…Metformin, an anti-diabetic drug, showed neuroprotective effects against other chemotherapy-induced neuropathies, and therefore it has recently been tested in vivo for alleviating the oxaliplatin-induced neuropathy in rats. It was able to decrease levels of ROS and markers of oxidative stress and to ameliorate intraepidermal fibers degeneration, gliosis, and sensitivity [ 77 ]. The new drug in the treatment of multiple sclerosis - dimethyl fumarate (DMF) was tested because of its neuroprotective properties on cisplatin and oxaliplatin-induced neurodegeneration in the in vitro study [ 78 ].…”

Section: Antioxidants In the Treatment Of Platinum-based Chemothermentioning

confidence: 99%

Antioxidant Supplementation in the Treatment of Neurotoxicity Induced by Platinum-Based Chemotherapeutics—A Review

Stanković

Selaković

Mihailović

et al. 2020

IJMS

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Cancer represents one of the most pernicious public health problems with a high mortality rate among patients worldwide. Chemotherapy is one of the major therapeutic approaches for the treatment of various malignancies. Platinum-based drugs (cisplatin, oxaliplatin, carboplatin, etc.) are highly effective chemotherapeutic drugs used for the treatment of several types of malignancies, but their application and dosage are limited by their toxic effects on various systems, including neurotoxicity. Simultaneously, researchers have tried to improve the survival rate and quality of life of cancer patients and decrease the toxicity of platinum-containing drugs by combining them with non-chemotherapy-based drugs, dietary supplements and/or antioxidants. Additionally, recent studies have shown that the root cause for the many side effects of platinum chemotherapeutics involves the production of reactive oxygen species (ROS) in naive cells. Therefore, suppression of ROS generation and their inactivation with antioxidants represents an appropriate approach for platinum drug-induced toxicities. The aim of this paper is to present an updated review of the protective effects of different antioxidant agents (vitamins, dietary antioxidants and supplements, medicaments, medicinal plants and their bioactive compounds) against the neurotoxicity induced by platinum-based chemotherapeutics. This review highlights the high potential of plant antioxidants as adjuvant strategies in chemotherapy with platinum drugs.

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Metformin protects from oxaliplatin induced peripheral neuropathy in rats

Cited by 21 publications

References 79 publications

Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells

Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells

The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration

Antioxidant Supplementation in the Treatment of Neurotoxicity Induced by Platinum-Based Chemotherapeutics—A Review

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