Ciprofloxacin triggers the apoptosis of human triple-negative breast cancer MDA-MB-231 cells via the p53/Bax/Bcl-2 signaling pathway

Beberok,Artur; Wrześniok,Dorota; Rok,Jakub; Rzepka,Zuzanna; Respondek,Michalina; Buszman,Ewa

doi:10.3892/ijo.2018.4310

Ciprofloxacin triggers the apoptosis of human triple-negative breast cancer MDA-MB-231 cells via the p53/Bax/Bcl-2 signaling pathway

Authors:
- Artur Beberok
- Dorota Wrześniok
- Jakub Rok
- Zuzanna Rzepka
- Michalina Respondek
- Ewa Buszman
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Affiliations: Department of Pharmaceutical Chemistry, School of Pharmacy with the Division of Laboratory Medicine, Medical University of Silesia, 41-200 Sosnowiec, Poland
Published online on: March 8, 2018 https://doi.org/10.3892/ijo.2018.4310
Pages: 1727-1737

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Abstract

Fluoroquinolone antibiotics induce cytotoxicity in various cancer cell lines and may therefore represent a potentially important source of novel anticancer agents. The aim of the present study was to examine the effect of ciprofloxacin on the viability, redox balance, apoptosis, expression of p53, Bax and Bcl-2, cell cycle distribution and DNA fragmentation of triple-negative MDA-MB-231 breast cancer cells. The results of the present study demonstrated that ciprofloxacin decreases cell viability in a dose- and time-dependent manner. The half maximal inhibitory concentration values of ciprofloxacin in MDA-MB-231 cells following treatment for 24, 48 and 72 h were 0.83, 0.14 and 0.03 µmol/ml, respectively. Furthermore, it was demonstrated that ciprofloxacin altered the redox signaling pathway, as determined by intracellular glutathione depletion. The results of Annexin V/propidium iodide staining revealed that ciprofloxacin triggered the apoptosis of MDA-MB-231 cells. Furthermore, cipfloxacin treatment stimulated the loss of the mitochondrial transmembrane potential via the Bax/Bcl-2-dependent pathway, thus inducing apoptosis. Ciprofloxacin induced cell cycle arrest at the S-phase; therefore it was hypothesized that ciprofloxacin inhibits topoisomerase II. Oligonucleosomal DNA fragmentation and the elevation of p53 expression were observed in the present study, indicating that this late-apoptotic event may be mediated by the p53-dependent pathway. Therefore, the results of the current study provide important molecular data concerning the cellular cascade, which may explain the cytotoxicity induced by ciprofloxacin in human triple-negative breast cancer cells, thus providing a novel insight into the therapeutic properties of this drug.

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1	Torre LA, Siegel RL, Ward EM and Jemal A: Global cancer incidence and mortality rates and trends-An update. Cancer Epidemiol Biomarkers Prev. 25:16–27. 2016. View Article : Google Scholar
2	Yao H, He G, Yan S, Chen C, Song L, Rosol TJ and Deng X: Triple-negative breast cancer: Is there a treatment on the horizon? Oncotarget. 8:1913–1924. 2017.
3	Anders C and Carey LA: Understanding and treating triple-negative breast cancer. Oncology (Williston Park). 22:1233–1240. 12432008.
4	Wahba HA and El-Hadaad HA: Current approaches in treatment of triple-negative breast cancer. Cancer Biol Med. 12:106–116. 2015.PubMed/NCBI
5	Wang JC: Cellular roles of DNA topoisomerases: A molecular perspective. Nat Rev Mol Cell Biol. 3:430–440. 2002. View Article : Google Scholar : PubMed/NCBI
6	Tse-Dinh YC: Exploring DNA topoisomerases as targets of novel therapeutic agents in the treatment of infectious diseases. Infect Disord Drug Targets. 7:3–9. 2007. View Article : Google Scholar : PubMed/NCBI
7	Kaur P, Kaur V and Kaur S: DNA Topoisomerase II: promising target for anticancer drugs. Multi-Targeted Approach to Treatment of Cancer. Springer; pp. 323–338. 2015
8	Cowell IG and Austin CA: Mechanism of generation of therapy related leukemia in response to anti-topoisomerase II agents. Int J Environ Res Public Health. 9:2075–2091. 2012. View Article : Google Scholar : PubMed/NCBI
9	Aldred KJ, Kerns RJ and Osheroff N: Mechanism of quinolone action and resistance. Biochemistry. 53:1565–1574. 2014. View Article : Google Scholar : PubMed/NCBI
10	Seo K, Holt R, Jung YS, Rodriguez CO Jr, Chen X and Rebhun RB: Fluoroquinolone-mediated inhibition of cell growth, S-G2/M cell cycle arrest, and apoptosis in canine osteosarcoma cell lines. PLoS One. 7:e429602012. View Article : Google Scholar : PubMed/NCBI
11	Herold C, Ocker M, Ganslmayer M, Gerauer H, Hahn EG and Schuppan D: Ciprofloxacin induces apoptosis and inhibits proliferation of human colorectal carcinoma cells. Br J Cancer. 86:443–448. 2002. View Article : Google Scholar : PubMed/NCBI
12	Yadav V, Sultana S, Yadav J and Saini N: Gatifloxacin induces S and G2-phase cell cycle arrest in pancreatic cancer cells via p21/p27/p53. PLoS One. 7:e477962012. View Article : Google Scholar : PubMed/NCBI
13	Yadav V, Varshney P, Sultana S, Yadav J and Saini N: Moxifloxacin and ciprofloxacin induces S-phase arrest and augments apoptotic effects of cisplatin in human pancreatic cancer cells via ERK activation. BMC Cancer. 15:5812015. View Article : Google Scholar : PubMed/NCBI
14	Aranha O, Grignon R, Fernandes N, McDonnell TJ, Wood DP Jr and Sarkar FH: Suppression of human prostate cancer cell growth by ciprofloxacin is associated with cell cycle arrest and apoptosis. Int J Oncol. 22:787–794. 2003.PubMed/NCBI
15	Aranha O, Wood DP Jr and Sarkar FH: Ciprofloxacin mediated cell growth inhibition, S/G2-M cell cycle arrest, and apoptosis in a human transitional cell carcinoma of the bladder cell line. Clin Cancer Res. 6:891–900. 2000.PubMed/NCBI
16	Oliphant CM and Green GM: Quinolones: A comprehensive review. Am Fam Physician. 65:455–464. 2002.PubMed/NCBI
17	Talla V and Veerareddy P: Oxidative stress induced by fluoroquinolones on treatment for complicated urinary tract infections in Indian patients. J Young Pharm. 3:304–309. 2011. View Article : Google Scholar
18	Bisacchi GS and Hale MR: A 'Double-Edged' scaffold: Antitumor power within the antibacterial quinolone. Curr Med Chem. 23:520–577. 2016. View Article : Google Scholar :
19	Arriola E, Marchio C, Tan DS, Drury SC, Lambros MB, Natrajan R, Rodriguez-Pinilla SM, Mackay A, Tamber N, Fenwick K, et al: Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines. Lab Invest. 88:491–503. 2008. View Article : Google Scholar
20	Żaczek AJ, Markiewicz A, Seroczyńska B, Skokowski J, Jaśkiewicz J, Pieńkowski T, Olszewski WP, Szade J, Rhone P, Welnicka-Jaskiewicz M, et al: Prognostic significance of TOP2A gene dosage in HER-2-negative breast cancer. Oncologist. 17:1246–1255. 2012. View Article : Google Scholar : PubMed/NCBI
21	Shyur LF, Lee SH, Chang ST, Lo CP, Kuo YH and Wang SY: Taiwanin A inhibits MCF-7 cancer cell activity through induction of oxidative stress, upregulation of DNA damage checkpoint kinases, and activation of p53 and FasL/Fas signaling pathways. Phytomedicine. 18:16–24. 2010. View Article : Google Scholar
22	Panieri E and Santoro MM: ROS homeostasis and metabolism: A dangerous liason in cancer cells. Cell Death Dis. 7:e22532016. View Article : Google Scholar : PubMed/NCBI
23	Blaydes JP, Craig AL, Wallace M, Ball HM, Traynor NJ, Gibbs NK and Hupp TR: Synergistic activation of p53-dependent transcription by two cooperating damage recognition pathways. Oncogene. 19:3829–3839. 2000. View Article : Google Scholar : PubMed/NCBI
24	Burns TF and El-Deiry WS: The p53 pathway and apoptosis. J Cell Physiol. 181:231–239. 1999. View Article : Google Scholar : PubMed/NCBI
25	Pietenpol JA and Stewart ZA: Cell cycle checkpoint signaling: Cell cycle arrest versus apoptosis. Toxicology. 181–182:475–481. 2002. View Article : Google Scholar
26	Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007. View Article : Google Scholar : PubMed/NCBI
27	Chavez KJ, Garimella SV and Lipkowitz S: Triple negative breast cancer cell lines: One tool in the search for better treatment of triple negative breast cancer. Breast Dis. 32:35–48. 2010. View Article : Google Scholar
28	Beberok A, Wrześniok D, Szlachta M, Rok J, Rzepka Z, Respondek M and Buszman E: Lomefloxacin induces oxidative stress and apoptosis in COLO829 melanoma cells. Int J Mol Sci. 18:E21942017. View Article : Google Scholar : PubMed/NCBI
29	Bai L and Wang S: Targeting apoptosis pathways for new cancer therapeutics. Annu Rev Med. 65:139–155. 2014. View Article : Google Scholar
30	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar
31	Kloskowski T, Gurtowska N, Olkowska J, Nowak JM, Adamowicz J, Tworkiewicz J, Dębski R, Grzanka A and Drewa T: Ciprofloxacin is a potential topoisomerase II inhibitor for the treatment of NSCLC. Int J Oncol. 41:1943–1949. 2012. View Article : Google Scholar : PubMed/NCBI
32	Thadepalli H, Salem F, Chuah SK and Gollapudi S: Antitumor activity of trovafloxacin in an animal model. In Vivo. 19:269–276. 2005.PubMed/NCBI
33	Beberok A, Buszman E, Otręba M and Wrześniok D: Impact of lomefloxacin on antioxidant enzymes activity in normal melanocytes HEMa-LP. Curr Issues Pharm Med Sci. 25:426–429. 2012. View Article : Google Scholar
34	Beberok A, Wrześniok D, Otręba M, Miliński M, Rok J and Buszman E: Effect of norfloxacin and moxifloxacin on melanin synthesis and antioxidant enzymes activity in normal human melanocytes. Mol Cell Biochem. 401:107–114. 2015. View Article : Google Scholar :
35	Beberok A, Wrześniok D, Otręba M and Buszman E: Impact of sparfloxacin on melanogenesis and antioxidant defense system in normal human melanocytes HEMa-LP - An in vitro study. Pharmacol Rep. 67:38–43. 2015. View Article : Google Scholar : PubMed/NCBI
36	Liou GY and Storz P: Reactive oxygen species in cancer. Free Radic Res. 44:479–496. 2010. View Article : Google Scholar : PubMed/NCBI
37	Hall AG: Review: The role of glutathione in the regulation of apoptosis. Eur J Clin Invest. 29:238–245. 1999. View Article : Google Scholar : PubMed/NCBI
38	Mirkovic N, Voehringer DW, Story MD, McConkey DJ, McDonnell TJ and Meyn RE: Resistance to radiation-induced apoptosis in Bcl-2-expressing cells is reversed by depleting cellular thiols. Oncogene. 15:1461–1470. 1997. View Article : Google Scholar : PubMed/NCBI
39	Dai J, Weinberg RS, Waxman S and Jing Y: Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. Blood. 93:268–277. 1999.
40	Blau H, Klein K, Shalit I, Halperin D and Fabian I: Moxifloxacin but not ciprofloxacin or azithromycin selectively inhibits IL-8, IL-6, ERK1/2, JNK, and NF-kappaB activation in a cystic fibrosis epithelial cell line. Am J Physiol Lung Cell Mol Physiol. 292:L343–L352. 2007. View Article : Google Scholar
41	Beberok A, Wrześniok D, Minecka A, Rok J, Delijewski M, Rzepka Z, Respondek M and Buszman E: Ciprofloxacin-mediated induction of S-phase cell cycle arrest and apoptosis in COLO829 melanoma cells. Pharmacol Rep. 70:6–13. 2017. View Article : Google Scholar
42	Shah A, Lettieri J, Kaiser L, Echols R and Heller AH: Comparative pharmacokinetics and safety of ciprofloxacin 400 mg i.v. thrice daily versus 750 mg po twice daily. J Antimicrob Chemother. 33:795–801. 1994. View Article : Google Scholar : PubMed/NCBI
43	Rohwedder R, Bergan T, Caruso E, Thorsteinsson SB, Della Torre H and Scholl H: Penetration of ciprofloxacin and metabolites into human lung, bronchial and pleural tissue after 250 and 500 mg oral ciprofloxacin. Chemotherapy. 37:229–238. 1991. View Article : Google Scholar : PubMed/NCBI
44	Beberok A, Buszman E, Wrześniok D, Otręba M and Trzcionka J: Interaction between ciprofloxacin and melanin: The effect on proliferation and melanization in melanocytes. Eur J Pharmacol. 669:32–37. 2011. View Article : Google Scholar : PubMed/NCBI
45	d'Ischia M, Wakamatsu K, Cicoira F, Di Mauro E, Garcia-Borron JC, Commo S, Galván I, Ghanem G, Kenzo K, Meredith P, et al: Melanins and melanogenesis: From pigment cells to human health and technological applications. Pigment Cell Melanoma Res. 28:520–544. 2015. View Article : Google Scholar : PubMed/NCBI
46	Wyatt AJ, Agero ALC, Delgado R, Busam KJ and Marghoob AA: Cutaneous metastatic breast carcinoma with melanocyte colonization: A clinical and dermoscopic mimic of malignant melanoma. Dermatol Surg. 32:949–954. 2006.PubMed/NCBI