The cytotoxic, apoptotic and oxidative effects of carbonic anhydrase IX inhibitor on colorectal cancer cells
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.
KeywordsCarbonic Anhydrase-9 inhibitor Colorectal cancer Apoptosis Cytotoxicity And oxidative stress
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
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.
- 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
- 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
- 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
- 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
- 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
- Hanahan D, Weinberg R, Francisco S (2000) The hallmarks of cancer review University of California at San Francisco. Horm Res 100:57–70Google Scholar
- Kampa M, Nifli A, Notas G, Castanas E (2007) Polyphenols and cancer cell growth. Rev Physiol Biochem Pharmacol 159:79–113Google Scholar
- Kosova F, Arı Z (2008) Adipositokinler ve meme kanseri. Fırat Üniv Sağlık Bilim Tıp Dergisi 22:377–384Google Scholar
- 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
- 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
- Maren T (1995) Glaucoma hereditary nonpolyposis colorectal cancer. Am J Ophthalmol 4:42–49Google Scholar
- 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
- 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
- Slattery M (2000) Diet, lifestyle, and colon cancer. Semin Gastrointest Dis 11:142–146Google Scholar
- Suzuki T, Motohashi H, Yamamoto M (2013) Toward clinical application of the Keap1-Nrf 2 pathway. Trends Biochem Sci 34:340–346Google Scholar