Therapeutic Effect of Y-27632 on Tumorigenesis and Cisplatin-Induced Peripheral Sensory Loss through RhoA-NF-κB.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of cancer therapy that frequently requires a reduction or cessation of treatments and negatively impacts the patient's quality of life. There is currently no effective means to prevent or treat CIPN. In this study, we developed and applied CIPN in an immunocompetent, syngeneic murine Lewis Lung Carcinoma (LLCab) model that enabled the elucidation of both tumor and host responses to cisplatin and treatments of Y-27632, a selective inhibitor of Rho kinase/p160ROCK. Y-27632 not only preserved cisplatin's efficacy toward tumor suppression but also the combination treatment inhibited tumor cell proliferation and increased cellular apoptosis. By alleviating the cisplatin-induced loss of epidermal nerve fibers (ENFs), Y-27632 protected tumor-bearing mice from cisplatin-induced reduction of touch sensation. Furthermore, quantitative proteomic analysis revealed the striking cisplatin-induced dysregulation in cellular stress (inflammation, mitochondrial deficiency, DNA repair, etc.)-associated proteins. Y-27632 was able to reverse the changes of these proteins that are associated with Rho GTPase and NF-κB signaling network, and also decreased cisplatin-induced NF-κB hyperactivation in both footpad tissues and tumor. Therefore, Y-27632 is an effective adjuvant in tumor suppression and peripheral neuroprotection. These studies highlight the potential of targeting the RhoA-NF-κB axis as a combination therapy to treat CIPN. IMPLICATIONS: This study, for the first time, demonstrated the dual antineoplastic and neuroprotective effects of Rho kinase/p160ROCK inhibition in a syngeneic immunocompetent tumor-bearing mouse model, opening the door for further clinical adjuvant development of RhoA-NF-κB axis to improve chemotherapeutic outcomes.

• Authors: Yi Zhu, George A Howard, Keith Pittman, Christi Boykin, Laura E Herring, Emily M Wilkerson, Kathryn Verbanac, Qun Lu
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 17 Issue 9 Pg. 1910-1919 (09 2019) ISSN: 1557-3125 [Electronic] United States
• PMID: 31189689 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Amides
• NF-kappa B
• Pyridines
• RHOA protein, human
• Y 27632
• rhoA GTP-Binding Protein
• Cisplatin

Topics

• Amides (administration & dosage, pharmacology)
• Animals
• Carcinoma, Lewis Lung (complications, drug therapy, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cisplatin (adverse effects, therapeutic use)
• Disease Models, Animal
• Gene Expression Regulation (drug effects)
• Humans
• Mice
• NF-kappa B (metabolism)
• Peripheral Nervous System Diseases (chemically induced, metabolism, prevention & control)
• Proteomics (methods)
• Pyridines (administration & dosage, pharmacology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays
• rhoA GTP-Binding Protein (metabolism)