Laboratory investigation, 2022-03, Vol.102 (3), p.298-311
2022
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- Autor(en) / Beteiligte
- Titel
- Fluvastatin sensitizes pancreatic cancer cells toward radiation therapy and suppresses radiation- and/or TGF-β-induced tumor-associated fibrosis
- Ist Teil von
- Laboratory investigation, 2022-03, Vol.102 (3), p.298-311
- Ort / Verlag
- New York: Elsevier Inc
- Erscheinungsjahr
- 2022
- Quelle
- EZB-FREE-00999 freely available EZB journals
- Beschreibungen/Notizen
- 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. Fluvastatin, a cholesterol-lowering drug, radiosensitizes pancreatic cancer (PC) cells partly by inhibiting DNA damage response and/or autophagic flux. Fluvastatin also significantly suppresses intra-tumor radiation-induced fibrosis, as it inhibits radiation/TGF-β-induced activation of pancreatic stellate cells. Together, fluvastatin and radiation co-treatment may be a potential therapeutic approach against PC and warrants further clinical evaluation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0023-6837eISSN: 1530-0307DOI: 10.1038/s41374-021-00690-7Titel-ID: cdi_proquest_miscellaneous_2597501094
- Format
- –
- Schlagworte
- 13, 13/1, 13/2, 13/31, 13/51, 14/19, 14/34, 14/63, 631/337/1427/2122, 631/67/1059/485, 64/116, 64/60, 82/29, 82/51, 96/95, Animal models, Animals, Anticancer properties, Antitumor activity, Apoptosis - drug effects, Apoptosis - radiation effects, Autophagy - drug effects, Autophagy - radiation effects, Cancer, Cancer therapies, Cell activation, Cell Line, Tumor, Cell Survival - drug effects, Cell Survival - radiation effects, Cells, Cultured, Cholesterol, Deoxyribonucleic acid, DNA, DNA damage, DNA repair, Embryo, Nonmammalian - drug effects, Embryo, Nonmammalian - embryology, Embryo, Nonmammalian - radiation effects, Evaluation, Fibrosis, Fibrosis - prevention & control, Fluvastatin, Fluvastatin - pharmacology, Humans, Laboratory Medicine, Medicine, Medicine & Public Health, Mice, Mice, Inbred C57BL, Neoplasms, Experimental - drug therapy, Neoplasms, Experimental - pathology, Neoplasms, Experimental - radiotherapy, NIH 3T3 Cells, Pancreatic cancer, Pancreatic Neoplasms - drug therapy, Pancreatic Neoplasms - pathology, Pancreatic Neoplasms - radiotherapy, Pathology, Pheochromocytoma cells, Radiation, Radiation damage, Radiation effects, Radiation therapy, Radiation Tolerance - drug effects, Radiosensitization, Stellate cells, Transforming Growth Factor beta - pharmacology, Transforming growth factor-b, Tumors, Zebrafish - embryology