1. Fluvastatin sensitizes pancreatic cancer cells toward radiation therapy and suppresses radiation- and/or TGF-β-induced tumor-associated fibrosis
- Author
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Shantibhusan Senapati, Amlan Priyadarshee Mohapatra, Voddu Suresh, Biswajit Das, Deepti Parida, Aliva Prity Minz, Debasish Mohapatra, Rajeeb K. Swain, and Usharani Nayak
- Subjects
Embryo, Nonmammalian ,Cell Survival ,medicine.medical_treatment ,Apoptosis ,Radiation Tolerance ,Pathology and Forensic Medicine ,Mice ,Transforming Growth Factor beta ,In vivo ,Cell Line, Tumor ,Radioresistance ,Pancreatic cancer ,Autophagy ,medicine ,Animals ,Humans ,Fluvastatin ,Molecular Biology ,Cells, Cultured ,Zebrafish ,Chemistry ,Neoplasms, Experimental ,Cell Biology ,medicine.disease ,Fibrosis ,In vitro ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,Radiation therapy ,Cell culture ,NIH 3T3 Cells ,Hepatic stellate cell ,Cancer research ,medicine.drug - Abstract
Pancreatic cancer (PC) is highly resistant to chemo and radiotherapy. Radiation-induced fibrosis (RIF) is a major cause of clinical concern for various malignancies, including PC. In this study, we aimed to evaluate the radiosensitizing and anti-RIF potential of fluvastatin in PC. Short-term viability and clonogenic survival assays were used to evaluate the radiosensitizing potential of fluvastatin in multiple human and murine PC cell lines. The expression of different proteins was analyzed to understand the mechanisms of fluvastatin-mediated radiosensitization of PC cells and its anti-RIF effects in both mouse and human pancreatic stellate cells (PSCs). Finally, these effects of fluvastatin and/or radiation were assessed in an immune-competent syngeneic murine model of PC. Fluvastatin radiosensitized multiple PC cell lines, as well as radioresistant cell lines in vitro, by inhibiting radiation-induced DNA damage repair response. Nonmalignant cells, such as PSCs and NIH3T3 cells, were less sensitive to fluvastatin-mediated radiosensitization than PC cells. Interestingly, fluvastatin suppressed radiation and/or TGF-β-induced activation of PSCs, as well as the fibrogenic properties of these cells in vitro. Fluvastatin considerably augmented the antitumor effect of external radiation therapy and also suppressed intra-tumor RIF in vivo. These findings suggested that along with radiation, fluvastatin co-treatment may be a potential therapeutic approach against PC.
- Published
- 2022
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