CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss

Teitz, Tal; Fang, Jie; Goktug, Asli N.; Bonga, Justine D.; Diao, Shiyong; Hazlitt, Robert A.; Iconaru, Luigi I.; Morfouace, Marie; Currier, Duane; Zhou, Yinmei; Umans, Robyn A.; Taylor, Michael R.; Cheng, Cheng; Min, Jaeki; Freeman, Burgess B.; Peng, Junmin; Roussel, Martine F.; Kriwacki, Richard W.; Guy, R. Kiplin; Chen, Taosheng; Zuo, Jian

doi:10.1084/jem.20172246

Cited by 85 publications

(143 citation statements)

References 64 publications

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“…In this study, we showed that DOX treatment induced cardiomyocyte apoptosis through CDK2 activation. Our data are in agreement with most recent findings that activation of CDK2 by the DNAdamaging anticancer drug cisplatin results in cochlear cell apoptosis and hearing loss in rodents (29). Taken together, these findings suggested that CDK2 inhibition may have broad therapeutic applications against cancer treatmentrelated normal tissue toxicity.…”

Section: Discussionsupporting

confidence: 93%

Inhibition of cyclin-dependent kinase 2 protects against doxorubicin-induced cardiomyocyte apoptosis and cardiomyopathy

Xia

Liu

Chen

et al. 2018

Journal of Biological Chemistry

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Edited by Xiao-Fan WangWith the rapid increase in cancer survival because of improved diagnosis and therapy in the past decades, cancer treatment-related cardiotoxicity is becoming an urgent healthcare concern. The anthracycline doxorubicin (DOX), one of the most effective chemotherapeutic agents to date, causes cardiomyopathy by inducing cardiomyocyte apoptosis. We demonstrated previously that overexpression of the cyclin-dependent kinase (CDK) inhibitor p21 promotes resistance against DOXinduced cardiomyocyte apoptosis. Here we show that DOX exposure provokes cardiac CDK2 activation and cardiomyocyte cell cycle S phase reentry, resulting in enhanced cellular sensitivity to DOX. Genetic or pharmacological inhibition of CDK2 markedly suppressed DOX-induced cardiomyocyte apoptosis. Conversely, CDK2 overexpression augmented DOX-induced apoptosis. We also found that DOX-induced CDK2 activation in the mouse heart is associated with up-regulation of the pro-apoptotic BCL2 family member BCL2-like 11 (Bim), a BH3-only protein essential for triggering Bax/Bak-dependent mitochondrial outer membrane permeabilization. Further experiments revealed that DOX induces cardiomyocyte apoptosis through CDK2-dependent expression of Bim. Inhibition of CDK2 with roscovitine robustly repressed DOX-induced mitochondrial depolarization. In a cardiotoxicity model of chronic DOX exposure (5 mg/kg weekly for 4 weeks), roscovitine administration significantly attenuated DOX-induced contractile dysfunction and ventricular remodeling. These findings identify CDK2 as a key determinant of DOX-induced cardiotoxicity. CDK2 activation is necessary for DOX-induced Bim expression and mitochondrial damage. Our results suggest that pharmacological inhibition of CDK2 may be a cardioprotective strategy for preventing anthracycline-induced heart damage.

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Section: Discussionsupporting

confidence: 93%

Inhibition of cyclin-dependent kinase 2 protects against doxorubicin-induced cardiomyocyte apoptosis and cardiomyopathy

Xia

Liu

Chen

et al. 2018

Journal of Biological Chemistry

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“…Kenpaullone promoted cell survival in the cochlea and prevented hearing loss by reducing cisplatin-induced mitochondrial production of ROS. 44…”

Section: Protective Agents-preclinical Studiesmentioning

confidence: 99%

Mechanisms of Cisplatin-Induced Ototoxicity and Prevention

2019

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Cisplatin is a highly effective antineoplastic agent used to treat solid tumors. Unfortunately, the administration of this drug leads to significant side effects, including ototoxicity, nephrotoxicity, and neurotoxicity. This review addresses the mechanisms of cisplatin-induced ototoxicity and various strategies tested to prevent this distressing adverse effect. The molecular pathways underlying cisplatin ototoxicity are still being investigated. Cisplatin enters targeted cells in the cochlea through the action of several transporters. Once it enters the cochlea, cisplatin is retained for months to years. It can cause DNA damage, inhibit protein synthesis, and generate reactive oxygen species that can lead to inflammation and apoptosis of outer hair cells, resulting in permanent hearing loss. Strategies to prevent cisplatin ototoxicity have utilized antioxidants, transport inhibitors, G-protein receptor agonists, and anti-inflammatory agents. There are no FDA-approved drugs to prevent cisplatin ototoxicity. It is critical that potential protective agents do not interfere with the antitumor efficacy of cisplatin.

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“…These results highlight the utility of strategies that harness the results from genomic analyses to uncover additional agents to prevent ototoxicity, the validity of which should be tested in model organisms. Already established model organisms that have been successfully used to investigate potential otoprotectants include mouse cochlear explants, as well as zebrafish and murine models . Optimization of these model organisms is ongoing and of importance to studies who aim to move toward the implementation of otoprotectants in the clinical setting, a recent publication has described the development of a CIO mouse model that is consistent with the hearing loss phenotype observed in humans experiencing CIO …”

Section: Future Avenues Of Researchmentioning

confidence: 99%

“…Already established model organisms that have been successfully used to investigate potential otoprotectants include mouse cochlear explants, as well as zebrafish and murine models. 63 Optimization of these model organisms is ongoing and of importance to studies who aim to move toward the implementation of otoprotectants in the clinical setting, a recent publication has described the development of a CIO mouse model that is consistent with the hearing loss phenotype observed in humans experiencing CIO. 64 Expanding research beyond a single trait A final avenue of interest would be to examine the relevance of genetic factors that are associated with CIO to other traits.…”

Section: Future Avenues Of Research Standardization Of Phenotypes Andmentioning

confidence: 99%

Pharmacogenomics of Cisplatin‐Induced Ototoxicity: Successes, Shortcomings, and Future Avenues of Research

Drögemöller

Wright

et al. 2019

Clin Pharma and Therapeutics

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Cisplatin is a highly effective chemotherapeutic. Unfortunately, its use is limited by cisplatin‐induced ototoxicity (CIO). Substantial research has been performed to uncover the genetic variants associated with CIO; however, there has been a lack of consistency in the results that have been reported. This paper aims to provide an overview of the current state of CIO genomics research, delving into the shortcomings of past research, and providing recommendations for future avenues of study.

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CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss

Cited by 85 publications

References 64 publications

Inhibition of cyclin-dependent kinase 2 protects against doxorubicin-induced cardiomyocyte apoptosis and cardiomyopathy

Inhibition of cyclin-dependent kinase 2 protects against doxorubicin-induced cardiomyocyte apoptosis and cardiomyopathy

Mechanisms of Cisplatin-Induced Ototoxicity and Prevention

Pharmacogenomics of Cisplatin‐Induced Ototoxicity: Successes, Shortcomings, and Future Avenues of Research

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