Advertisement

Journal of Bioenergetics and Biomembranes

, Volume 50, Issue 2, pp 107–116 | Cite as

The cytotoxic, apoptotic and oxidative effects of carbonic anhydrase IX inhibitor on colorectal cancer cells

  • Yasin Tülüce
  • Bewar Ali Ahmed
  • İsmail Koyuncu
  • Mustafa Durgun
Article
  • 141 Downloads

Abstract

Colorectal cancer (CRC) is the third most common tumor, malignant and has developed one of the main reasons of cancer mortality. According to studies conducted recently; carbonic anhydrase 9 (CAIX) is an especially attractive target for cancer therapy, in part since it is limited way expressed in normal tissues on the other hand in a wide variety of solid neoplasia are overexpressed. The aim of this study was to appreciate the effects of CAIX inhibitor, namely novel synthesized sulfonamide derivative (H-4i) with high affinity for CAIX, in CAIX-positive human colorectal cancer cell (HT-29) and CAIX-negative human normal embryonic kidney cell line (HEK-293). For this reason, we planned to investigate apoptotic, cytotoxic and oxidative stress activity of H-4i on HT-29 and HEK-293 cell lines. Cell viability determined by WST-1 assay afterwards IC50 values, apoptosis and cell cycle induction measured by flow cytometric analysis, intracellular free radical induction performed by reactive oxygen species (ROS) analyses. The IC50 value of the sulfonamide derivative compound was found to be very low, especially in HT-29 cells, when compared to human normal cells. This research found that H-4i significantly increased cytotoxicity and ROS production, caused significant signs of apoptosis level. High level of ROS and apoptosis lead to arrest the cell cycle and reduce cell survival. The most obvious finding to emerge from the analysis that novel synthesized sulfonamide derivative H-4i is effective on HT-29 more than HEK-293. Therefore, novel derivative H-4i might be used as an anti-cancer potential compound on CRC.

Keywords

Carbonic Anhydrase-9 inhibitor Colorectal cancer Apoptosis Cytotoxicity And oxidative stress 

Notes

Acknowledgements

This study was supported by the research fund of Yuzuncu Yil University and TUBITAK. Project No: TYL-2017-5559 and TUBITAK No: 115Z681.

Compliance with ethical standards

Ethical statement

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Afaq F, Saleem M, Krueger CG, Reed JD, Mukhtar H (2005) Anthocyanin and hydrolyzable tannin-rich pomegranate fruit extract modulates MAPK and NF-kappaB pathways and inhibits skin tumorigenesis in CD-1 mice. Int J Cancer 113:423–433CrossRefGoogle Scholar
  2. Bernardi P, Krauskopf A, Basso E, Petronilli V, Blalchy-Dyson E, Di Lisa F, Forte M (2006) The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J 273:2077–2099CrossRefGoogle Scholar
  3. Capasso C, Supuran CT (2017). Bacterial carbonic anhydrases, in zinc enzyme inhibitors - volume 1: enzymes from microorganisms, C.T. Supuran, C. Capasso, Eds., Topics in Medicinal Chemistry, 22:135–152Google Scholar
  4. Choi E, Lee J, Kim G (2012) Evaluation of the anticancer activities of thioflavanone and thioflavone in human breast cancer cell lines. Int J Mol Med 29:252–256Google Scholar
  5. Chung TP, Fleshman JW (2005) The genetics of sporadic colon cancer. Colo and Rect Surg 15:128–135CrossRefGoogle Scholar
  6. Dikilitas M, Guldur ME, Deryaoglu A, Erel O (2011) Antioxidant and oxidant levels of pepper infected with pepper mild mottle virus. Not Bot Horti Agrobot Cluj Napoca 39:58–63CrossRefGoogle Scholar
  7. Dubois L, Peeters S, Lieuwes NG, Geusens N, Thiry A, Wigfield S, Carta F, McIntyre A, Scozzafava A, Dogné JM, Supuran CT, Harris AL, Masereel B, Lambin P (2011) Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation. Radiother Oncol 99:424–431CrossRefGoogle Scholar
  8. Durgun M, Turkmen H, Ceruso M, Supuran CT (2015) Synthesis of Schiff base derivatives of 4-(2-aminoethyl)-benzenesulfonamide with inhibitory activity against carbonic anhydrase isoforms I, II, IX and XII. Bioorg Med Chem Lett 25(11):2377–2381CrossRefGoogle Scholar
  9. Erel O (2004) A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Chem 37:277–285Google Scholar
  10. Erel O (2005) A new automated colorimetric method for measuring total oxidant status. Clin Biochem 38:1103–1111CrossRefGoogle Scholar
  11. Fadok V, Voelker D, Campbell P, Cohen J, Bratton D, Henson P (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148:2207–2216Google Scholar
  12. Fearon ER (2011) Molecular genetics of colorectal cancer. Annu Rev Pathol 6:479–507CrossRefGoogle Scholar
  13. Gach K, Dlugosz A, Janecka A (2015) The role of oxidative stress in anticancer activity of sesquiterpene lactones. Naunyn Schmiedeberg's Arch Pharmacol 388:477–486CrossRefGoogle Scholar
  14. Galati G, Teng S, Moridani M, Chan T, O’Brien P (2000) Cancer chemoprevention and apoptosis mechanisms induced by dietary polyphenolics. Drug Metabol Drug Interact 17:311–349CrossRefGoogle Scholar
  15. Halliwell B (2007) Oxidative stress and cancer: have we moved forward. Biochem J 401:1–11CrossRefGoogle Scholar
  16. Hanahan D, Weinberg R, Francisco S (2000) The hallmarks of cancer review University of California at San Francisco. Horm Res 100:57–70Google Scholar
  17. Hawk ET, Levin B (2005) Colorectal cancer prevention. J Clin Oncol 23:378–391CrossRefGoogle Scholar
  18. Jansen EH, Ruskovska T (2013) Comparative analysis of serum (anti) oxidative status parameters in healthy persons. Int J Mol Sci 14:6106–6115CrossRefGoogle Scholar
  19. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics 2009. CA Cancer J Clin 59:225–249CrossRefGoogle Scholar
  20. Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90CrossRefGoogle Scholar
  21. Jiang QL, Zhang S, Tian M, Zhang SY, Xie T, Chen DY (2015) Plant lectins, from ancient sugar-binding proteins to emerging anticancer drugs in apoptosis and autophagy. Cell Prolif 48:17–28CrossRefGoogle Scholar
  22. Kampa M, Nifli A, Notas G, Castanas E (2007) Polyphenols and cancer cell growth. Rev Physiol Biochem Pharmacol 159:79–113Google Scholar
  23. Kaplan M, Hayek T, Raz A, Coleman R, Dornfeld L, Vaya J, Aviram M (2001) Pomegranate juice supplementation to atherosclerotic mice reduces macrophage lipid peroxidation, cellular cholesterol accumulation and development of atherosclerosis. J Nutr 131:2082–2089CrossRefGoogle Scholar
  24. Kerr JFR, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 4:239–257CrossRefGoogle Scholar
  25. Khan M, Maryam A, Qazi JI, Ma T (2015) Targeting apoptosis and multiple signaling pathways with icariside II in cancer cells. Int J Biol Sci 11:1100–1112CrossRefGoogle Scholar
  26. Kosova F, Arı Z (2008) Adipositokinler ve meme kanseri. Fırat Üniv Sağlık Bilim Tıp Dergisi 22:377–384Google Scholar
  27. Lee SH, Meng XW, Flatten KS, Loegering DA, Kaufmann SH (2013) Phosphatidylserine exposure during apoptosis reflects bidirectional trafficking between plasma membrane and cytoplasm. Cell Death Differ 20:64–76CrossRefGoogle Scholar
  28. Li H, Wu W, Zheng Z, Che C, Yu L, Wang M (2009) 2, 3, 4, 4, 5-Pentamethoxy-trans-stilbene, a resveratrol derivative, is a potent inducer of apoptosis in colon cancer cells via targeting microtubules. Biochem Pharmacol 78:1224–1232CrossRefGoogle Scholar
  29. Lou Y, McDonald PC, Oloumi A, Chia S, Ostlund C, Ahmadi A, Kyle A, Auf dem Keller U, Leung S, Huntsman D, Clarke B, Sutherland BW, Waterhouse D, Bally M, Roskelley C, Overall CM, Minchinton A, Pacchiano F, Carta F, Scozzafava A, Touisni N, Winum JY, Supuran CT, Dedhar S (2011) Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res 71(9):3364–3376CrossRefGoogle Scholar
  30. Low J, Chakravartty A, Blosser W, Dowless M, Chalfant C, Bragger P, Stancato L (2009) Phenotypic fingerprinting of small molecule cell cycle kinase inhibitors for drug discovery. Curr Chem Genomics 3:12–13CrossRefGoogle Scholar
  31. Mahassni SH, Al-Reemi RM (2013) Apoptosis and necrosis of human breast cancer cells by an aqueous extract of garden cress (Lepidium sativum) seeds. J Biol Sci 20:131–139Google Scholar
  32. Maren T (1995) Glaucoma hereditary nonpolyposis colorectal cancer. Am J Ophthalmol 4:42–49Google Scholar
  33. Martinez ME, Willett WC (1998) Calcium, vitamin D, and colorectal cancer: a review of the epidemiologic evidence. Cancer Epidemiol Biomark Prev 7:163–168Google Scholar
  34. McCarthy DA, Marcey MG (2001) Cytometric analysis of cell phenotype and function, chapter 10 - cell cycle, DNA and DNA ploidy analysis Paul D. Allen and Adrian C. Newland, 186–188Google Scholar
  35. McDonald PC, Winum JY, Supuran CT, Dedhar S (2012) Recent developments in targeting carbonic anhydrase IX for cancer therapeutics. Oncotarget 3:84–97CrossRefGoogle Scholar
  36. Neri D, Supuran CT (2011) Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov 10(10):767–777CrossRefGoogle Scholar
  37. Ozyurek M, Akpınar D, Bener M, Türkkan B, Güçlü K, Apak R (2014) Novel oxime based flavanone, naringin-oxime: synthesis, characterization and screening for antioxidant activity. Chem Biol Interact 212:40–46CrossRefGoogle Scholar
  38. Park JH, Jin CY, Lee BK, Kim GY, Choi YH, Jeong YK (2008) Naringenin induces apoptosis through downregulation of Akt and caspase-3 activation in human leukemia THP-1 cells. Food Chem Toxicol 46:3684–3690CrossRefGoogle Scholar
  39. Perego S, Cosentino S, Fiorilli A, Tettamanti G, Ferraretto A (2012) Casein phosphopeptides modulate proliferation and apoptosis in HT-29 cell line through their interaction with voltage-operated L-type calcium channels. J Nutr Biochem 23:808–816CrossRefGoogle Scholar
  40. Prokhorova EA, Zamaraev AV, Kopeina GS, Zhivotovsky B, Lavrik IN (2015) Role of the nucleus in apoptosis: signaling and execution. Cell Mol Life Sci 72:4593–4612CrossRefGoogle Scholar
  41. Renschler MF (2004) The emerging role of reactive oxygen species in cancer therapy. Eur J Cancer 40:1934–1940CrossRefGoogle Scholar
  42. Sakihama Y, Mano J, Sano S, Asada K, Yamasaki H (2000) Reduction of phenoxyl radicals mediated by monodehydroascorbate reductase. Biochem Biophys Res Commun 279:949–954CrossRefGoogle Scholar
  43. Salomons G, Smets L, Verwijs-Janssen M, Hart A, Haarman E, Kaspers G (1999) Bcl-2 family members in childhood acute lymphoblastic leukemia: relationships with features at presentation, in vitro and in vivo drug response and long-term clinical outcome. Leukemia 13:1574–1580CrossRefGoogle Scholar
  44. Scherz-Shouval R, Elazar Z (2011) Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 36:30–38CrossRefGoogle Scholar
  45. Slattery M (2000) Diet, lifestyle, and colon cancer. Semin Gastrointest Dis 11:142–146Google Scholar
  46. Supuran CT (2008) Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7(2):168–181CrossRefGoogle Scholar
  47. Supuran CT (2017) Carbonic anhydrase inhibition and the management of hypoxic tumors. Meta 16:7(3).  https://doi.org/10.3390/metabo7030048 Google Scholar
  48. Supuran C, Conroy C, Maren T (1996) Sulfonamides are powerful CA inhibitors. Eur J Med Chem 831:843CrossRefGoogle Scholar
  49. Suzuki T, Motohashi H, Yamamoto M (2013) Toward clinical application of the Keap1-Nrf 2 pathway. Trends Biochem Sci 34:340–346Google Scholar
  50. Taylor DP, Burt RW, Williams MS, Haug PJ, Cannon-Albright LA (2010) Population-based family history-specific risks for colorectal cancer: a constellation approach. Gastroenterology 138:877–885CrossRefGoogle Scholar
  51. Tompkins WA, Watrach AM, Schmale JD, Schultz RM, Harris JA (1974) Cultural and antigenic properties of newly established cell strains derived from adenocarcinomas of the human colon and rectum. J Natl Cancer Inst 52:1101–1110CrossRefGoogle Scholar
  52. Vermeulen K, Van Bockstaele DR, Berneman ZN (2003) The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36:131–149CrossRefGoogle Scholar
  53. Wong RS (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30:87CrossRefGoogle Scholar
  54. Xie C, Chan W, Zhao S, Cheng C (2011) Bufalin induces autophagy-mediated cell death in human colon cancer cells through reactive oxygen species generation and JNK activation. Free Radical Bio Med 51:365–1375CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Faculty of Medicine, Department of Medical BiologyVan Yuzuncu Yil UniversityVanTurkey
  2. 2.Faculty of Medicine, Department of BiochemistryHarran UniversityŞanlıurfaTurkey
  3. 3.Faculty of Science and Art, Department of ChemistryHarran UniversityŞanlıurfaTurkey

Personalised recommendations