Document Type : Research articles
Authors
1 Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
2 Department of Physiology, Qom Branch, Islamic Azad University, Qom, Iran
Abstract
Background: Levofloxacin is a fluoroquinolone antibiotic with extensive anti-bacterial effects. Levofloxacin is widely used for treatment of urinary and vaginal infections.
Objectives: This research surveyed the cytotoxicity effects of levofloxacin on ovarian follicles of mice in both in vitro and in vivo conditions, as well as its anticancer effect on human ovarian cancer cell line (SKOV3).
Methods: For in vitro study, the ovaries of animals were isolated and treated with levofloxacin at doses of 1, 2, 5, and 10 µg/ml for 6 days. For in vivo study, animals were treated with levofloxacin at concentrations of 100, 200, 400, and 800 mg/kg for 24 days. Histopathological and morphological examinations of ovarian tissues were performed. Real-time PCR and Western Blot techniques were performed to analyze apoptosis-related genes and proteins of ovarian tissues.
Results: Levofloxacin at higher concentrations caused morphological changes and remarkably decreased the number of primary, secondary, and adult follicles compared to the control group. The percentage of viable SKOV3 cells was 10.12%, 7.63%, and 2.17% following exposure to levofloxacin (at a concentration of 800 ?g/ml) for 24, 48, and 72 h, respectively. The half-maximal inhibitory concentration of levofloxacin against SKOV3 was found to be 181.1, 74.84, and 27.58 ?g/ml at 24, 48, and 72 h, respectively. The percentage of SKOV3 cells apoptosis following exposure to levofloxacin after 72 h at 20, 80, and 200 ?g/ml doses was 11%, 42%, and 52%, respectively. Real-time PCR revealed up-regulation of Bax and Caspase-3 genes after exposure to levofloxacin in SKOV3 cells, whereas the expression of Bcl2 was significantly decreased in a concentration-depended manner.
Conclusion: The present study demonstrates that levofloxacin induces apoptosis of both ovarian follicles and human ovarian cancer cell lines.
Keywords
- Yadav V, Talwar P. Repositioning of fluoroquinolones from antibiotic to anti-cancer agents: An underestimated
- truth. Biomed Pharmacother. 2019;111:934-46. doi: 10.1016/j.biopha.2018.12.119.
- Bucaneve G, Micozzi A, Menichetti F, Martino P, Dionisi MS, Martinelli G, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med. 2005;353(10):977-87. doi: 10.1056/NEJMoa044097. [PubMed: 16148283].
- Carbon C. Levofloxacin adverse effects, data from clinical trials and pharmacovigilan. Therapie. 2001;56(1):35-40. [PubMed: 11322015].
- Tunitskaya VL, Khomutov AR, Kochetkov SN, Kotovskaya SK, Charushin VN. Inhibition of DNA gyrase by levofloxacin and related fluorine-containing heterocyclic compounds. Acta Naturae. 2011;3(4):94-9. [PubMed: 22649708].
- He X, Yao Q, Hall DD, Song Z, Fan D, You Y, et al. Levofloxacin exerts broad-spectrum anticancer activity via regulation of THBS1, LAPTM5, SRD5A3, MFAP5 and P4HA1. Anticancer Drugs. 2022;33(1):235-46. doi: 10.1097/cad.0000000000001194. [PubMed: 34419964].
- Song M, Wu H, Wu S, Ge T, Wang G, Zhou Y, et al. Antibiotic drug levofloxacin inhibits proliferation and induces apoptosis of lung cancer cells through inducing mitochondrial dysfunction and oxidative damage. Biomed Pharmacother. 2016;84:1137-43. doi: 10.1016/j.biopha.2016.10.034. [PubMed: 27780143].
- Kloskowski T, Szeliski K, Fekner Z, Rasmus M, Dąbrowski P, Wolska A, et al. Ciprofloxacin and Levofloxacin as Potential Drugs in Genitourinary Cancer Treatment-The Effect of Dose-Response on 2D and 3D Cell Cultures. Int J Mol Sci. 2021;22(21):1-27. doi: 10.3390/ijms222111970. [PubMed: 34769400].
- McCormick M, Friehling E, Kalpatthi R, Siripong N, Smith K. Cost-effectiveness of levofloxacin prophylaxis against bacterial infection in pediatric patients with acute myeloid
- leukemia. Pediatr Blood Cancer. 2020;67(10):1-19. doi: 10.1002/pbc.28469. [PubMed: 32710709].
- Urueta-Robledo J, Ariza H, Jardim JR, Caballero A, Garcia-Calderon A, Amabile-Cuevas CF, et al. Moxifloxacin versus levofloxacin against acute exacerbations of chronic bronchitis: the Latin American Cohort. Respir Med. 2006;100(9):1504-11. doi: 10.1016/j.rmed.2006.01.013. [PubMed: 16504492].
- Holtom PD, Pavkovic SA, Bravos PD, Patzakis MJ, Shepherd LE, Frenkel B. Inhibitory effects of the quinolone antibiotics trovafloxacin, ciprofloxacin, and levofloxacin on osteoblastic cells in vitro. J Orthop Res. 2000;18(5):721-7. doi: 10.1002/jor.1100180507. [PubMed: 11117292].
- Erden B, Ulak G, Yildiz F, Utkan T, Ozdemirci S, Gacar N. Antidepressant, anxiogenic, and antinociceptive properties of levofloxacin in rats and mice. Pharmacol Biochem Behav. 2001;68(3):435-41. doi: 10.1016/s0091-3057(00)00468-8. [PubMed: 11325396].
- Anderson VR, Perry CM. Levofloxacin : a review of its use
- as a high-dose, short-course treatment for bacterial infection. Drugs. 2008;68(4):535-65. doi: 10.2165/00003495-200868040-00011. [PubMed: 18318569].
- Johnson A. Intracellular mechanisms regulating cell survival in ovarian follicles. Anim Reprod Sci. 2003;78(3-4):185-201. doi: 10.1016/s0378-4320(03)00090-3. [PubMed: 12818644].
- Ahmadifar M, Vahidi N, Fathi R. The Study of Effect of Levofloxacin on Disorders of Female Hormones in Rats. Anat Sci J. 2014;11(2):71-4.
- Norrby SR, Petermann W, Willcox PA, Vetter N, Salewski E. A comparative study of levofloxacin and ceftriaxone in the treatment of hospitalized patients with pneumonia. Scand J Infect
- Dis. 1998;30(4):397-404. doi: 10.1080/00365549850160710. [PubMed: 9817522].
- Carbon C. Comparison of side effects of levofloxacin versus other fluoroquinolones. Chemotherapy. 2001;47(3):9-14. doi: 10.1159/000057839. [PubMed: 11549784].
- Claudio T, Marcelo RP, Susana C, Ernesto G, Alberto N. Study of sperm apoptosis and seminal oxidant capacity in infertile patients with genital tract infections evaluation of the efficacy of levofloxacin in two therapeutic protocols. Advanc Sex Med. 2012;2(2):21-4. doi: 10.4236/asm.2012.22004.
- Serebryakova VA, Urazova OI, Novitsky VV, Vengerovskii AI, Kononova TE, Vasil'eva OA, et al. Effects of levofloxacin on blood lymphocyte apoptosis in patients with pulmonary tuberculosis: an in vitro study. Bull Exp Biol Med. 2019;
- (1):109-12. doi: 10.1007/s10517-019-04659-x. [PubMed: 31773352].
- Wang L, Wu Y, Tan Y, Fei X, Deng Y, Cao H, et al. Cytotoxic effects of the quinolone levofloxacin on rabbit meniscus cells. J Appl Toxicol. 2014;34(8):870–7. doi: 10.1002/jat.2903. [PubMed: 23813946].
- Ahmadi R, Ahmadifar M, Safarpour E, Vahidi-Eyrisofla N, Darab M, Eini AM, et al. The Effects of Levofloxacin on Testis Tissue and Spermatogenesis in Rat. Cell J. 2016;18(1):112-6. doi: 10.22074/cellj.2016.3994. [PubMed: 27054126].
- Sun JP, Shi ZY, Liu SM, Kang YH, Hu GQ, Huangfu CS, et al. Trimethoxy-benzaldehyde levofloxacin hydrazone inducing the growth arrest and apoptosis of human hepatocarcinoma cells. Cancer Cell Int. 2013;13(1):1-10. doi: 10.1186/1475-2867-13-67. [PubMed: 23819802].
- Huo F, Tang N. Fan Y, Liu S, Zhang Y, L iang H, Hu G, al. e. Benzaldehyde levofloxacin schiff base induces apoptosis of human hepatocarcinoma cells. Chin Pharmacol Bull. 2015;6:821-6.
', './data/ircmj/coversheet/cover_en.jpg'))