Abstract
Therapy-Induced Senescence (TIS) is a form of senescence that is typically described in malignant cells in response to the exposure of cancer chemotherapy or radiation but can also be precipitated in non-malignant cells. TIS has been shown to contribute to the development of several cancer therapy–related adverse effects; however, evidence on its role in mediating chemotherapy-induced neurotoxicity, such as Chemotherapy-induced Peripheral Neuropathy (CIPN), is limited. We here show that cisplatin treatment over two cycles (cumulative dose of 23 mg/kg) provoked mechanical allodynia and thermal hyperalgesia in Sprague–Dawley rats. Isolation of dorsal root ganglia (DRG) from the cisplatin-treated rats demonstrated robust SA-β-gal upregulation at both day 8 (after the first cycle) and day 18 (after the second cycle), decreased lmnb1 expression, increased expression of cdkn1a and cdkn2a, and of several factors of the Senescence-associated Secretory Phenotype (SASP) (Il6, Il1b, and mmp9). Moreover, single-cell calcium imaging of cultured DRGs revealed a significant increase in terms of the magnitude of KCl-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats. No significant change was observed in terms of the magnitude of capsaicin-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats but with decreased area under the curve of the responses in cisplatin-treated rats. Further evidence to support the contribution of TIS to therapy adverse effects is required but should encourage the use of senescence-modulating agents (senotherapeutics) as novel palliative approaches to mitigate chemotherapy-induced neurotoxicity.
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The raw data supporting the findings of this study are available upon request from the corresponding authors.
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Acknowledgements
The authors would like to thank the Cell Therapy Center (University of Jordan) for granting access to the use of the microscopic imaging facility and are grateful for Prof. Mohammed El-Khateeb, Khadeejeh Alrashed and Raja’a Fathallah from National Center for Diabetes, Endocrinology and Genetics for their help in using the NanoDrop 1000 spectrophotometer. All authors are highly thankful to the Researchers Supporting Project number (RSPD-2024R786), King Saud University, Riyadh, Saudi Arabia.
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This work is supported by funding provided by the Deanships of Scientific Research at both The Hashemite University (grant no. 743/51/2022) and The University of Jordan (grant no. 2475).
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All authors contributed to the study conception, design, and manuscript writing. RNA extraction and real-time PCR were performed by Randa Naffa. Animal studies, DRGs extraction and calcium signaling assays were performed by Noor A. Barakat. SA-β-gal staining and microscopic imaging was performed by Mohammad A. Ismail. Moureq R. Alotaibi edited and revised the final manuscript. Tareq Saleh and Mohammad Alsalem contributed to experimental procedures, were responsible for funding acquisition, supervised the work, performed data analysis, and wrote the manuscript. All authors read and approved the final version of the manuscript.
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Saleh, T., Naffa, R., Barakat, N.A. et al. Cisplatin Provokes Peripheral Nociception and Neuronal Features of Therapy-Induced Senescence and Calcium Dysregulation in Rats. Neurotox Res 42, 10 (2024). https://doi.org/10.1007/s12640-024-00690-7
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DOI: https://doi.org/10.1007/s12640-024-00690-7