Unraveling the Biochemical Markers of Chemotherapy-Induced Peripheral Neuropathy
Author
Ennabe, MichelleIssue Date
2023Keywords
BortezomibCell Signaling
Chemotherapy Induced Peripheral Neuropathy
iPSCs
Paclitaxel
Vincristine
Advisor
Lybarger, Lonnie
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The University of Arizona.Rights
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.Abstract
Introduction: Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a significant side effect of neurotoxic chemotherapy, characterized by sensory and motor disturbances that impact patients' quality of life. This study delves into how chemotherapy alters cellular components, leading to CIPN development, and identifies certain drugs, like bortezomib, paclitaxel, and vincristine, as key contributors to this condition. The research underscores the necessity of understanding these mechanisms for better management of chemotherapy treatments and improved patient outcomes. Aim: This study aims to understand the cellular mechanisms of chemotherapy-induced nerve pain and damage, using induced sensory neurons (iSNs) from human induced pluripotent stem cells (iPSCs) to investigate the effects of different chemotherapy drugs over time. Methods: The study employed iPSCs derived from healthy individuals' skin biopsies. These iPSCs were cultivated and then differentiated into post-mitotic iSNs using a well-established methodology. The iSNs were exposed to chemotherapy drugs for a time course evaluation of protein levels indicative of cellular stress. Samples were collected at 12h intervals up to 72h. Immunoassays were completed using the WesTM system by ProteinSimple. Proteins selected for study included ATF3, p-EIF2a, JNK1, JNK2, p-MKK4, p-MAPK14, and NMNAT2. Results: Four experiments were completed for both bortezomib and paclitaxel. The effects of bortezomib on iSNs showed a significant rise in ATF3, and a significant decline in the other stress markers. Paclitaxel exposure led to a significant increase in p-EIF2a and a significant decrease in JNK1 and JNK2; however the ratio of p-JNK/JNK was not significant. One experiment was completed for vincristine exposure. The levels of ATF3, p-EIF2a, NMNAT2, and p-MKK4 increased throughout the 72h exposure, and a temporal rise was observed for p-JNK1/JNK1, p-JNK2/JNK2, and p-MAPK14. Conclusion: The chemotherapy drugs appear to trigger the Integrated Stress Response (ISR), evident from alterations in the levels of ATF3 and p-EIF2a. Furthermore, only vincristine demonstrates potential activation of the SAPK/JNK and p38 MAPK signaling cascades, though additional data are necessary to confirm these observations.Type
Electronic Thesistext
Degree Name
M.S.Degree Level
mastersDegree Program
Graduate CollegeCellular and Molecular Medicine