التفاصيل البيبلوغرافية
| العنوان: |
Identification and In Vivo Validation of Unique Anti-Oncogenic Mechanisms Involving Protein Kinase Signaling and Autophagy Mediated by the Investigational Agent PV-10. |
| المؤلفون: |
Tran, Son1 (AUTHOR), Sipila, Patrick1 (AUTHOR), Thakur, Satbir1 (AUTHOR), Zhang, Chunfen1 (AUTHOR), Narendran, Aru1 (AUTHOR) a.narendran@ucalgary.ca |
| المصدر: |
Cancers. Apr2024, Vol. 16 Issue 8, p1520. 11p. |
| مصطلحات موضوعية: |
*PROTEINS, *CELL migration inhibition, *PROTEIN kinases, *AUTOPHAGY, *RESEARCH funding, *INVESTIGATIONAL drugs, *ANTINEOPLASTIC agents, *BREAST tumors, *HEAD & neck cancer, *CHALONES, *CELLULAR signal transduction, *IN vivo studies, *COLORECTAL cancer, *IMMUNODIAGNOSIS, *TUMOR markers, *CELL lines, *TUMOR suppressor genes, *MICE, *METASTASIS, *RESEARCH methodology, *ANIMAL experimentation, *DRUG development, *TESTIS tumors, *CELL surface antigens, *PHARMACODYNAMICS |
| مستخلص: |
Simple Summary: Novel therapeutics are urgently needed for high-risk and refractory solid tumors. Clinical studies have demonstrated the safety and efficacy of PV-10 (10% rose bengal sodium) by intralesional injection in skin cancer. However, this agent has not yet been evaluated for the treatment of various adult solid tumors. The aim of our study was to test PV-10 in breast, colorectal, head and neck, and testicular cancers. Using a combination of in vitro and in vivo experiments, we found that PV-10 exhibits anti-cancer activity against a panel of human cell lines derived from these tumors. Our results support further clinical development of PV-10 for the treatment of solid tumors in adults. PV-10 is a 10% formulation of rose bengal sodium that has potent immunotherapeutic and anti-cancer activity against various tumors, including metastatic melanoma and refractory neuroblastoma. Currently, PV-10 is undergoing clinical testing for refractory metastatic neuroendocrine cancer and melanomas. However, preclinical investigation of PV-10 activity and its mechanisms against phenotypically and molecularly diverse adult solid tumors had not been conducted. In a panel of human cell lines derived from breast, colorectal, head and neck, and testicular cancers, we demonstrated that PV-10 induces cytotoxicity by apoptotic and autophagic pathways involving caspase-mediated PARP cleavage, downregulation of SQSTM1/p62, and upregulation of beclin-1. Treatment with PV-10 also consistently reduced phosphorylation of WNK1, which has been implicated in cancer cell migration and autophagy inhibition. By wound healing assay, PV-10 treatment inhibited the migration of cancer cells. Finally, significant inhibition of tumor growth was also noted in tumor-bearing mice treated with PV-10 by intralesional or systemic administration. In addition to known PV-10-mediated tumor-specific cytotoxic effects, we identified the mechanisms of PV-10 and provide new insights into its effect on autophagy and metastasis. Our data provide essential mechanism-based evidence and biomarkers of activity to formulate clinical studies of PV-10 in the future. [ABSTRACT FROM AUTHOR] |
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