Pravastatin reduces radiation-induced damage in normal tissues

Doi,Hiroshi; Matsumoto,Seiji; Odawara,Soichi; Shikata,Toshiyuki; Kitajima,Kazuhiro; Tanooka,Masao; Takada,Yasuhiro; Tsujimura,Tohru; Kamikonya,Norihiko; Hirota,Shozo

doi:10.3892/etm.2017.4192

Pravastatin reduces radiation-induced damage in normal tissues

Authors:
- Hiroshi Doi
- Seiji Matsumoto
- Soichi Odawara
- Toshiyuki Shikata
- Kazuhiro Kitajima
- Masao Tanooka
- Yasuhiro Takada
- Tohru Tsujimura
- Norihiko Kamikonya
- Shozo Hirota
View Affiliations

Affiliations: Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan, Department of Thoracic Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan, Department of Pharmacy, Hyogo College of Medicine Sasayama Medical Center, Sasayama, Hyogo 669‑2321, Japan, Department of Radiological Technology, Hyogo College of Medicine College Hospital, Nishinomiya, Hyogo 663‑8501, Japan, Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo 663‑8501, Japan
Published online on: March 8, 2017 https://doi.org/10.3892/etm.2017.4192
Pages: 1765-1772
Copyright: © Doi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Pravastatin is an inhibitor of 3-hydroxy-3‑methyl- glutaryl-coenzyme A reductase that has been reported to have therapeutic applications in a range of inflammatory conditions. The aim of the present study was to assess the radioprotective effects of pravastatin in an experimental animal model. Mice were divided into two groups: The control group received ionizing radiation with no prior medication, while the pravastatin group received pravastatin prior to ionizing radiation. Pravastatin was administered orally at 30 mg/kg body weight in drinking water at 24 and 4 h before irradiation. Intestinal crypt epithelial cell survival and the incidence of apoptosis in the intestine and lung were measured post‑irradiation. The effect of pravastatin on intestinal DNA damage was determined by immunohistochemistry. Finally, the effect of pravastatin on tumor response to radiotherapy was examined in a mouse mesothelioma xenograft model. Pravastatin increased the number of viable intestinal crypts and this effect was statistically significant in the ileum (P<0.0001). The pravastatin group showed significantly lower apoptotic indices in all examined parts of the intestine (P<0.0001) and tended to show reduced apoptosis in the lung. Pravastatin reduced the intestinal expression of ataxia-telangiectasia mutated and gamma‑H2AX after irradiation. No apparent pravastatin‑related differences were observed in the response of xenograft tumors to irradiation. In conclusion, pravastatin had radioprotective effects on the intestine and lung and reduced radiation‑induced DNA double‑strand breaks. Pravastatin may increase the therapeutic index of radiotherapy.

View Figures

View References

1	Kavanagh BD, Pan CC, Dawson LA, Das SK, Li XA, Ten Haken RK and Miften M: Radiation dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys. 76:(3 Suppl). S101–S107. 2010. View Article : Google Scholar : PubMed/NCBI
2	Lalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe DM, McGuire DM, Migliorati C, Nicolatou-Galitis O, Peterson DE, et al: MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 120:1453–1461. 2014. View Article : Google Scholar : PubMed/NCBI
3	Brizel DM, Wasserman TH, Henke M, Strnad V, Rudat V, Monnier A, Eschwege F, Zhang J, Russell L, Oster W and Sauer R: Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol. 18:3339–3345. 2000. View Article : Google Scholar : PubMed/NCBI
4	Jellema AP, Slotman BJ, Muller MJ, Leemans CR, Smeele LE, Hoekman K, Aaronson NK and Langendijk JA: Radiotherapy alone, versus radiotherapy with amifostine 3 times weekly, versus radiotherapy with amifostine 5 times weekly: A prospective randomized study in squamous cell head and neck cancer. Cancer. 107:544–553. 2006. View Article : Google Scholar : PubMed/NCBI
5	Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, Nakaya N, Nishimoto S, Muranaka M, Yamamoto A, et al: Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): A prospective andomized controlled trial. Lancet. 368:1155–1163. 2006. View Article : Google Scholar : PubMed/NCBI
6	Rosenson RS, Tangney CC and Casey LC: Inhibition of proinflammatory cytokine production by pravastatin. Lancet. 353:983–984. 1999. View Article : Google Scholar : PubMed/NCBI
7	Holler V, Buard V, Gaugler MH, Guipaud O, Baudelin C, Sache A, Mdel Perez R, Squiban C, Tamarat R, Milliat F and Benderitter M: Pravastatin limits radiation-induced vascular dysfunction in the skin. J Invest Dermatol. 129:1280–1291. 2009. View Article : Google Scholar : PubMed/NCBI
8	Haydont V, Bourgier C, Pocard M, Lusinchi A, Aigueperse J, Mathé D, Bourhis J and Vozenin-Brotons MC: Pravastatin Inhibits the Rho/CCN2/extracellular matrix cascade in human fibrosis explants and improves radiation-induced intestinal fibrosis in rats. Clin Cancer Res. 13:5331–5340. 2007. View Article : Google Scholar : PubMed/NCBI
9	Haydont V, Gilliot O, Rivera S, Bourgier C, François A, Aigueperse J, Bourhis J and Vozenin-Brotons MC: Successful mitigation of delayed intestinal radiation injury using pravastatin is not associated with acute injury improvement or tumor protection. Int J Radiat Oncol Biol Phys. 68:1471–1482. 2007. View Article : Google Scholar : PubMed/NCBI
10	Gaugler MH, Vereycken-Holler V, Squiban C, Vandamme M, Vozenin-Brotons MC and Benderitter M: Pravastatin limits endothelial activation after irradiation and decreases the resulting inflammatory and thrombotic responses. Radiat Res. 163:479–487. 2005. View Article : Google Scholar : PubMed/NCBI
11	Mahmoudi M, Gorenne I, Mercer J, Figg N, Littlewood T and Bennett M: Statins use a novel Nijmegen breakage syndrome-1-dependent pathway to accelerate DNA repair in vascular smooth muscle cells. Circ Res. 103:717–725. 2008. View Article : Google Scholar : PubMed/NCBI
12	Nübel T, Damrot J, Roos WP, Kaina B and Fritz G: Lovastatin protects human endothelial cells from killing by ionizing radiation without impairing induction and repair of DNA double-strand breaks. Clin Cancer Res. 12:933–939. 2006. View Article : Google Scholar : PubMed/NCBI
13	Ostrau C, Hülsenbeck J, Herzog M, Schad A, Torzewski M, Lackner KJ and Fritz G: Lovastatin attenuates ionizing radiation-induced normal tissue damage in vivo. Radiother Oncol. 92:492–499. 2009. View Article : Google Scholar : PubMed/NCBI
14	Jenrow KA, Liu J, Brown SL, Kolozsvary A, Lapanowski K and Kim JH: Combined atorvastatin and ramipril mitigate radiation-induced impairment of dentate gyrus neurogenesis. J Neurooncol. 101:449–456. 2011. View Article : Google Scholar : PubMed/NCBI
15	Wedlake LJ, Silia F, Benton B, Lalji A, Thomas K, Dearnaley DP, Blake P, Tait D, Khoo VS and Andreyev HJ: Evaluating the efficacy of statins and ACE-inhibitors in reducing gastrointestinal toxicity in patients receiving radiotherapy for pelvic malignancies. Eur J Cancer. 48:2117–2124. 2012. View Article : Google Scholar : PubMed/NCBI
16	Withers HR and Elkind MM: Radiosensitivity and fractionation response of crypt cells of mouse jejunum. Radiat Res. 38:598–613. 1969. View Article : Google Scholar : PubMed/NCBI
17	Tian J, Doi H, Saar M, Santos J, Li X, Peehl DM and Knox SJ: Radioprotection and cell cycle arrest of intestinal epithelial cells by darinaparsin, a tumor radiosensitizer. Int J Radiat Oncol Biol Phys. 87:1179–1185. 2013. View Article : Google Scholar : PubMed/NCBI
18	Potten CS and Grant HK: The relationship between ionizing radiation-induced apoptosis and stem cells in the small and large intestine. Br J Cancer. 78:993–1003. 1998. View Article : Google Scholar : PubMed/NCBI
19	Johnston CJ, Hernady E, Reed C, Thurston SW, Finkelstein JN and Williams JP: Early alterations in cytokine expression in adult compared to developing lung in mice after radiation exposure. Radiat Res. 173:522–535. 2010. View Article : Google Scholar : PubMed/NCBI
20	Cho H, Matsumoto S, Fujita Y, Kuroda A, Menju T, Sonobe M, Kondo N, Torii I, Nakano T, Lara PN, et al: Trametinib plus 4-methylumbelliferone exhibits antitumor effects by ERK blockade and CD44 downregulation and affects PD1 and PD-L1 in malignant pleural mesothelioma. J Thorac Oncol. Nov 17–2016.(Epub ahead of print).
21	Rotolo JA, Kolesnick R and Fuks Z: Timing of lethality from gastrointestinal syndrome in mice revisited. Int J Radiat Oncol Biol Phys. 73:6–8. 2009. View Article : Google Scholar : PubMed/NCBI
22	Hauer-Jensen M, Denham JW and Andreyev HJ: Radiation enteropathy-pathogenesis, treatment and prevention. Nat Rev Gastroenterol Hepatol. 11:470–479. 2014. View Article : Google Scholar : PubMed/NCBI
23	Doi H, Kamikonya N, Takada Y, Fujiwara M, Tsuboi K, Miura H, Inoue H, Tanooka M, Nakamura T, Shikata T, et al: Long-term sequential changes of radiation proctitis and angiopathy in rats. J Radiat Res. 53:217–224. 2012. View Article : Google Scholar : PubMed/NCBI
24	Potten CS: Radiation, the ideal cytotoxic agent for studying the cell biology of tissues such as the small intestine. Radiat Res. 161:123–136. 2004. View Article : Google Scholar : PubMed/NCBI
25	Gomez DR, Hong DS, Allen PK, Welsh JS, Mehran RJ, Tsao AS, Liao Z, Bilton SD, Komaki R and Rice DC: Patterns of failure, toxicity, and survival after extrapleural pneumonectomy and hemithoracic intensity-modulated radiation therapy for malignant pleural mesothelioma. J Thorac Oncol. 8:238–245. 2013. View Article : Google Scholar : PubMed/NCBI
26	Soto DE, Daignault S, Sandler HM and Ray ME: No effect of statins on biochemical outcomes after radiotherapy for localized prostate cancer. Urology. 73:158–162. 2009. View Article : Google Scholar : PubMed/NCBI
27	Gauthaman K, Manasi N and Bongso A: Statins inhibit the growth of variant human embryonic stem cells and cancer cells in vitro but not normal human embryonic stem cells. Br J Pharmacol. 157:962–973. 2009. View Article : Google Scholar : PubMed/NCBI
28	Gabryś D, Dörfler A, Yaromina A, Hessel F, Krause M, Oertel R and Baumann M: Effects of lovastatin alone or combined with irradiation on tumor cells in vitro and in vivo. Strahlenther Onkol. 184:48–53. 2008. View Article : Google Scholar : PubMed/NCBI
29	Fritz G, Brachetti C and Kaina B: Lovastatin causes sensitization of HeLa cells to ionizing radiation-induced apoptosis by the abrogation of G2 blockage. Int J Radiat Biol. 79:601–610. 2003. View Article : Google Scholar : PubMed/NCBI
30	Zaorsky NG, Buyyounouski MK, Li T and Horwitz EM: Aspirin and statin nonuse associated with early biochemical failure after prostate radiation therapy. Int J Radiat Oncol Biol Phys. 84:e13–e17. 2012. View Article : Google Scholar : PubMed/NCBI
31	Larner J, Jane J, Laws E, Packer R, Myers C and Shaffrey M: A phase I–II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme. Am J Clin Oncol. 21:579–583. 1998. View Article : Google Scholar : PubMed/NCBI
32	Konings IR, van der Gaast A, van der Wijk LJ, de Jongh FE, Eskens FA and Sleijfer S: The addition of pravastatin to chemotherapy in advanced gastric carcinoma: A andomized phase II trial. Eur J Cancer. 46:3200–3204. 2010. View Article : Google Scholar : PubMed/NCBI
33	Kastan MB and Bartek J: Cell-cycle checkpoints and cancer. Nature. 432:316–323. 2004. View Article : Google Scholar : PubMed/NCBI
34	Koga T, Shimada Y, Kuroda M, Tsujita Y, Hasegawa K and Yamazaki M: Tissue-selective inhibition of cholesterol synthesis in vivo by pravastatin sodium, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Biochim Biophys Acta. 1045:115–120. 1990. View Article : Google Scholar : PubMed/NCBI
35	Alberton M, Wu P, Druyts E, Briel M and Mills EJ: Adverse events associated with individual statin treatments for cardiovascular disease: An indirect comparison meta-analysis. QJM. 105:145–157. 2012. View Article : Google Scholar : PubMed/NCBI