The identification of dual protective agents against cisplatin-induced oto- and nephrotoxicity using the zebrafish model

Wertman, Jaime; Melong, Nicole; Stoyek, Matthew R.; Piccolo, Olivia; Langley, Stewart; Orr, Benno; Steele, Shelby L.; Razaghi, Babak; Berman, Jason N.

doi:10.7554/elife.56235

Cited by 17 publications

(11 citation statements)

References 109 publications

(156 reference statements)

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“…23 Uncontrolled hypertension leads to high intra-glomerular pressure, which damages the blood vessels in the kidney, thus damaging glomeruli and resulting in reduced GFR. 34 Our study revealed that adult cancer patients who received platinum agents were two times likely to develop nephrotoxicity than those who received other treatment regimens, a finding similar to other studies done in Switzerland, 31 Canada, 35 Brazil, 36 and Ethiopia. 37 The high prevalence of nephrotoxicity among adult cancer patients who received platinum agents may be due to the preventive strategies used where hydration with normal saline and administration of magnesium sulphate were the preventive measures for nephrotoxicity.…”

supporting

confidence: 89%

Prevalence and Risk Factors of Nephrotoxicity Among Adult Cancer Patients at Mbarara Regional Referral Hospital

Isiiko¹,

Atwiine²,

Oloro³

2021

CMAR

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Background: Nephrotoxicity is common among cancer patients, yet some anti-cancer drugs, for example, platinum derivatives, are nephrotoxic and have narrow therapeutic indices. If nephrotoxicity is not managed, it can progress to kidney injury, which results in unregulated blood pressure, hormonal imbalance, electrolyte imbalance, body fluid imbalance and death. However, the burden of nephrotoxicity among adult cancer patients in Uganda is not documented in the literature. Objective: This study assessed the prevalence and risk factors of nephrotoxicity among cancer patients receiving chemotherapy at Mbarara Regional Referral Hospital Cancer Unit (MRRHCU). Methods: The study was a cross-sectional study carried out at the MRRHCU, Uganda. All the 206 adult cancer patients who received at least three cycles of chemotherapy and fulfilled the inclusion criteria were included. A data collection form was used to collect data, which was recorded into Microsoft Excel version 2013. Data were analyzed using Stata version 12.1. Results: Of the 206 participants, 74 (35.9%) developed nephrotoxicity with majority in stage 1 (n = 83, 40.3%) and stage 2 (n = 55, 26.7%). In the multivariate logistic regression of risk factors for nephrotoxicity, age >50 years old (aOR: 1.80, 95% CI: 1.06, 1.91; p > 0.001), hypertension (aOR: 1.71, 95% CI: 1.74, 1.94; p = 0.011) and use of platinum agents (aOR: 2.04, 95% CI: 1.82, 3.34; p = 0.002) were significant independent risk factors of nephrotoxicity. Conclusion: About one-third (1/3) of the adult cancer patients at MRRHCU develop nephrotoxicity, which indicates a high burden of nephrotoxicity. The prevention of progression of nephrotoxicity from grades 0, 1 or 2 to grade 3 or 4 is therefore necessary, especially among the patients with risk factors, such as hypertension and age >50 years old and use of platinum agents.

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supporting

confidence: 89%

Prevalence and Risk Factors of Nephrotoxicity Among Adult Cancer Patients at Mbarara Regional Referral Hospital

Isiiko¹,

Atwiine²,

Oloro³

2021

CMAR

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“…Interestingly, we found that exogenous DA also protects from cisplatin-induced neuronal damage. Similar findings have been reported in Zebrafish model, in which high DA levels (or alternatively L-miosine) not only protect from ototoxicity but also from nephrotoxicity induced by cisplatin but without affecting the toxicity in tumoral cells (Wertman et al, 2020). Although further experiments are needed to unravel the mechanisms beyond such protectiveness, there are two hypotheses to explain why increased DA levels mediate oto- and nephroprotection.…”

Section: Discussionsupporting

confidence: 86%

Insights into cisplatin-induced neurotoxicity and mitochondrial dysfunction in Caenorhabditis elegans

Martínez-Fernández

Bergamino

Brena

et al. 2021

Preprint

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Cisplatin is the most common drug in first-line chemotherapy against solid tumors. We and others have previously used the nematode Caenorhabditis elegans to identify genetic factors influencing the sensitivity and resistance to cisplatin. In this study, we take advantage of C. elegans to explore cisplatin effects on mitochondrial functions and investigate cisplatin-induced neurotoxicity through a high-resolution semi-automated system for evaluating locomotion. Firstly, we report that a high-glucose diet sensitizes C. elegans to cisplatin at the physiological level and that mitochondrial CED-13 protects the cell from cisplatin-induced oxidative stress. Additionally, by assessing mitochondrial function with a Seahorse Analyzer, we observed a detrimental additive effect of cisplatin and glucose in mitochondrial respiration. Secondly, since we previously found that catechol-O-methyltransferases (involved in dopamine degradation) were upregulated upon cisplatin exposure, we studied the protective role of the FDA-approved drug dopamine against cisplatin-induced neurotoxicity. To implement the use of the Tierpsy Tracker system for measuring neurotoxicity in C. elegans, we showed that abnormal displacements and body postures in cat-2 mutants, which have the dopamine synthesis pathway disrupted, can be rescued by adding dopamine. Then, we used such a system to demonstrate that dopamine treatment protects from the dose-dependent neurotoxicity caused by cisplatin.

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“…Interestingly, we found that exogenous DA also protects against cisplatin-induced animal locomotion and posture alterations, presumably caused by DA signaling perturbations because dopaminergic neuron integrity is not affected. Similar findings have been reported in a zebrafish model, in which high DA levels (or alternatively L-mimosine) not only protect against ototoxicity but also nephrotoxicity induced by cisplatin, without affecting the toxicity in tumoral cells ( Wertman et al, 2020 ). Although further experiments are needed to unravel the mechanisms beyond such protectiveness, there are two hypotheses to explain why increased DA levels mediate oto- and nephroprotection.…”

Section: Discussionsupporting

confidence: 86%

Insights into cisplatin-induced neurotoxicity and mitochondrial dysfunction in Caenorhabditis elegans

Martínez-Fernández

Bergamino

Schiavi

et al. 2022

Disease Models &Amp; Mechanisms

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Cisplatin is the most common drug in first-line chemotherapy against solid tumors. We and others have previously used the nematode Caenorhabditis elegans to identify genetic factors influencing the sensitivity and resistance to cisplatin. In this study, we use C. elegans to explore cisplatin effects on mitochondrial functions and investigate cisplatin-induced neurotoxicity through a high-resolution system for evaluating locomotion. Firstly, we report that a high-glucose diet sensitizes C. elegans to cisplatin at the physiological level and that mitochondrial CED-13 protects the cell from cisplatin-induced oxidative stress. Additionally, by assessing mitochondrial function with a Seahorse Analyzer, we observed a detrimental effect of cisplatin and glucose in mitochondrial respiration. Secondly, since catechol-O-methyltransferases (involved in dopamine degradation) are upregulated upon cisplatin exposure, we studied the protective role of dopamine against cisplatin-induced neurotoxicity. To implement the use of the Tierpsy Tracker system for measuring neurotoxicity, we showed that abnormal displacements and body postures in cat-2 mutants, which have the dopamine synthesis disrupted, can be rescued by adding dopamine. Then, we demonstrated that dopamine treatment protects from the dose-dependent neurotoxicity caused by cisplatin.

show abstract

The identification of dual protective agents against cisplatin-induced oto- and nephrotoxicity using the zebrafish model

Cited by 17 publications

References 109 publications

Prevalence and Risk Factors of Nephrotoxicity Among Adult Cancer Patients at Mbarara Regional Referral Hospital

Prevalence and Risk Factors of Nephrotoxicity Among Adult Cancer Patients at Mbarara Regional Referral Hospital

Insights into cisplatin-induced neurotoxicity and mitochondrial dysfunction in Caenorhabditis elegans

Insights into cisplatin-induced neurotoxicity and mitochondrial dysfunction in Caenorhabditis elegans

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