Archives of Pharmacal Research

, Volume 36, Issue 8, pp 1023–1028 | Cite as

Methoxyphenylcipro induces antitumor activity in human cancer cells

  • Nizar M. Mhaidat
  • Amjad M. Qandil
  • Qosay A. Al-Balas
  • Mohammad A. Hassan
  • Saied A. Jaradat
  • Ahmad M. Matalkah
  • Rick T. Thorne
Research Article

Abstract

To examine the antitumor activity of a new derivative of ciprofloxacin called methoxyphenylcipro (CMPP). Cell viability was assessed using the MTT assay and apoptotic cells and reactive oxygen species were evaluated using flow cytometry. Results revealed that CMPP induces antiproliferative activity against breast cancer cells and melanoma and to a lesser extent against colorectal cancer cells. Interestingly, compared to ciprofloxacin, CMPP-induced a selective cytotoxicity against human cancer cells but not human normal fibroblasts. The potential of CMPP to inhibit cellular growth in MD-MB-486 breast cancer cells and MV3 melanoma cells was largely due to induction of caspase-dependent apoptosis, as confirmed by caspase-3 activation and cleavage of its substrate PARP. In addition, results indicated that CMPP-induced apoptosis is mediated by generation of reactive oxygen species. These findings revealed that CMPP has a selective antitumor activity against cancer cells and warrants further clinical evaluation.

Keywords

Apoptosis Breast cancer CMPP Colorectal cancer Melanoma 

References

  1. Anderson, V.A., and N. Osheroff. 2001. Type II topoisomerases as targets for quinolone antibacterials: turning Dr. Jekyll into Mr. Hyde. Current Pharmaceutical Design 7: 339–355.CrossRefGoogle Scholar
  2. Appelbaum, P.C., and P.A. Hunter. 2000. The fluoroquinolone antibacterials: Past, present and future perspectives. International Journal of Antimicrobial Agents 16: 5–15.PubMedCrossRefGoogle Scholar
  3. Aranha, O., R. Grignon, N. Fernandes, T.J. McDonnell, D.P. Wood Jr, and F.H. Sarkar. 2003. Suppression of human prostate cancer cell growth by ciprofloxacin is associated with cell cycle arrest and apoptosis. International Journal of Oncology 22: 787–794.PubMedGoogle Scholar
  4. Aranha, O., D.P. Wood Jr, and F.H. Sarkar. 2000. Ciprofloxacin mediated cell growth inhibition, S/G2-M cell cycle arrest, and apoptosis in a human transitional cell carcinoma of the bladder cell line. Clinical Cancer Research 6: 891–900.PubMedGoogle Scholar
  5. Ashkenazi, A., and V.M. Dixit. 1998. Death receptors: Signaling and modulation. Science 281: 1305–1308.PubMedCrossRefGoogle Scholar
  6. Bardia, A., J.O. Ebbert, R.A. Vierkant, P.J. Limburg, K. Anderson, A.H. Wang, J.E. Olson, C.M. Vachon, and J.R. Cerhan. 2007. Association of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs with cancer incidence and mortality. Journal of the National Cancer Institute 99: 881–889.PubMedCrossRefGoogle Scholar
  7. Bredberg, A., M. Brant, and M. Jaszyk. 1991. Ciprofloxacin-induced inhibition of topoisomerase II in human lymphoblastoid cells. Antimicrobial Agents and Chemotherapy 35: 448–450.PubMedCrossRefGoogle Scholar
  8. Bromberg, K.D., A.B. Burgin, and N. Osheroff. 2003. Quinolone action against human topoisomerase II alpha: Stimulation of enzyme-mediated double-stranded DNA cleavage. Biochemistry 42: 3393–3398.PubMedCrossRefGoogle Scholar
  9. Chau, Y.P., S.G. Shiah, M.J. Don, and M.L. Kuo. 1998. Involvement of hydrogen peroxide in topoisomerase inhibitor beta-lapachone-induced apoptosis and differentiation in human leukemia cells. Free Radical Biology and Medicine 24: 660–670.PubMedCrossRefGoogle Scholar
  10. Cryns, V., and J. Yuan. 1998. Proteases to die for. Genes and Development 12(11): 1551–1570.PubMedCrossRefGoogle Scholar
  11. Debatin, K.M., D. Poncet, and G. Kroemer. 2002. Chemotherapy: Targeting the mitochondrial cell death pathway. Oncogene 21: 8786–8803.PubMedCrossRefGoogle Scholar
  12. Green, D.R., and J.C. Reed. 1998. Mitochondria and apoptosis. Science 281: 1309–1312.PubMedCrossRefGoogle Scholar
  13. Herbold, B.A., S.Y. Brendler-Schwaab, and H.J. Ahr. 2001. Ciprofloxacin: In vivo genotoxicity studies. Mutation Research 498: 193–205.PubMedCrossRefGoogle Scholar
  14. Herold, C., M. Ocker, M. Ganslmayer, H. Gerauer, E.G. Hahn, and D. Schuppan. 2002. Ciprofloxacin induces apoptosis and inhibits proliferation of human colorectal carcinoma cells. British Journal of Cancer 86: 443–448.PubMedCrossRefGoogle Scholar
  15. Higuchi, M., R.J. Proske, and E.T. Yeh. 1998. Inhibition of mitochondrial respiratory chain complex I by TNF results in cytochrome c release, membrane permeability transition, and apoptosis. Oncogene 17: 2515–2524.PubMedCrossRefGoogle Scholar
  16. Ikeda, K., K. Kajiwara, E. Tanabe, S. Tokumaru, E. Kishida, and Y. Masuzawa. 1999. Involvement of hydrogen peroxide and hydroxyl radical in chemically induced apoptosis of HL-60 cells. Biochemical Pharmacology 57: 1361–1365.PubMedCrossRefGoogle Scholar
  17. Inoue, M., N. Sakaguchi, K. Isuzugawa, H. Tani, and Y. Ogihara. 2000. Role of reactive oxygen species in gallic acid-induced apoptosis. Biological and Pharmaceutical Bulletin 23: 1153–1157.PubMedCrossRefGoogle Scholar
  18. Itoh, T., K. Mitsumori, S. Kawaguchi, and Y.F. Sasaki. 2006. Genotoxic potential of quinolone antimicrobials in the in vitro comet assay and micronucleus test. Mutation Research 603: 135–144.PubMedCrossRefGoogle Scholar
  19. Jacobs, E.J., M.J. Thun, E.B. Bain, C. Rodriguez, S.J. Henley, and E.E. Calle. 2007. A large cohort study of long-term daily use of adult-strength aspirin and cancer incidence. Journal of the National Cancer Institute 99: 608–615.PubMedCrossRefGoogle Scholar
  20. Lewanski, C.R., and W.J. Gullick. 2001. Radiotherapy and cellular signalling. Lancet Oncol 2: 366–370.PubMedCrossRefGoogle Scholar
  21. Mhaidat, N.M., Y.F. Wang, K.A. Kiejda, X.D. Zhang, and P. Hersey. 2007. Docetaxel-induced apoptosis in melanoma cells is dependent on activation of caspase-2. Molecular Cancer Therapeutics 6: 752–761.PubMedCrossRefGoogle Scholar
  22. Miclau, T., M.L. Edin, G.E. Lester, R.W. Lindsey, and L.E. Dahners. 1998. Effect of ciprofloxacin on the proliferation of osteoblast-like MG-63 human osteosarcoma cells in vitro. Journal of Orthopaedic Research 16: 509–512.PubMedCrossRefGoogle Scholar
  23. Mukherjee, A., S. Sen, and K. Agarwal. 1993. Ciprofloxacin: Mammalian DNA topoisomerase type II poison in vivo. Mutation Research 301: 87–92.PubMedGoogle Scholar
  24. Scorrano, L., S.A. Oakes, J.T. Opferman, E.H. Cheng, M.D. Sorcinelli, and T. Pozzan. 2003. BAX and BAK regulation of endoplasmic reticulum Ca2+: A control point for apoptosis. Science 300: 135–139.PubMedCrossRefGoogle Scholar
  25. Shalit, I., N. Nasrallah, S. Bar-On, and M. Rabau. 1995. In vitro effect of ciprofloxacin and ofloxacin on murine and human colon carcinoma cell lines. Drugs 49: 296–297.PubMedCrossRefGoogle Scholar
  26. Shen, L.L., W.E. Kohlbrenner, D. Weigl, and J. Baranowski. 1989. Mechanism of quinolone inhibition of DNA gyrase: Appearance of unique norfloxacin binding sites in enzyme-DNA complexes. Journal of Biological Chemistry 264: 2973–2978.PubMedGoogle Scholar
  27. Smart, D.J., H.D. Halicka, F. Traganos, Z. Darzynkiewicz, and G.M. Williams. 2008. Ciprofloxacin-induced G2 arrest and apoptosis in TK6 lymphoblastoid cells is not dependent on DNA double-strand break formation. Cancer Biology and Therapy 7: 113–119.PubMedCrossRefGoogle Scholar
  28. Somekh, E., D. Douer, N. Shaked, and E. Rubinstein. 1989. In vitro effects of ciprofloxacin and pefloxacin on growth of normal human hematopoietic progenitor cells and on leukemic cell lines. Journal of Pharmacology and Experimental Therapeutics 248: 415–418.PubMedGoogle Scholar
  29. Thornberry, N.A., and Y. Lazebnik. 1998. Caspases: Enemies within. Science 281: 1312–1316.PubMedCrossRefGoogle Scholar
  30. Wesselborg, S., I.H. Engels, E. Rossmann, M. Los, and K. Schulze-Osthoff. 1999. Anticancer drugs induce caspase-8/FLICE activation and apoptosis in the absence of CD965 receptor/ligand interaction. Blood 93: 3053–3063.PubMedGoogle Scholar
  31. Wu, J., X. Zhang, S. Gillespie, and P. Hersey. 2005. Selection for TRAIL resistance in melanoma cells with high proliferative potential. FEEBS Letters 579: 1940–1944.CrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2013

Authors and Affiliations

  • Nizar M. Mhaidat
    • 4
  • Amjad M. Qandil
    • 1
    • 2
  • Qosay A. Al-Balas
    • 1
  • Mohammad A. Hassan
    • 1
  • Saied A. Jaradat
    • 1
  • Ahmad M. Matalkah
    • 1
  • Rick T. Thorne
    • 3
  1. 1.Jordan University of Science & TechnologyIrbidJordan
  2. 2.King Saud Bin Abdulaziz University for Health SciencesRiyadhSaudi Arabia
  3. 3.Faculty of Health, The Newcastle UniversityOurimbahAustralia
  4. 4.Department of Clinical PharmacyFaculty of Pharmacy, Jordan University of Science & TechnologyIrbidJordan

Personalised recommendations