Induction of ROS‑mediated cell death and activation of the JNK pathway by a sulfonamide derivative

Ahmad,Rehan; Vaali‑Mohammed,Mansoor‑Ali; Elwatidy,Mohammed; Al‑Obeed,Omar; Al‑Khayal,Khayal; Eldehna,Wagdy   M.; Abdel‑Aziz,Hatem   A.; Alafeefy,Ahmed; Abdulla,Maha

doi:10.3892/ijmm.2019.4284

Induction of ROS‑mediated cell death and activation of the JNK pathway by a sulfonamide derivative

Authors:
- Rehan Ahmad
- Mansoor‑Ali Vaali‑Mohammed
- Mohammed Elwatidy
- Omar Al‑Obeed
- Khayal Al‑Khayal
- Wagdy M. Eldehna
- Hatem A. Abdel‑Aziz
- Ahmed Alafeefy
- Maha Abdulla
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Affiliations: Colorectal Research Chair, Department of Surgery, King Khaled University Hospital, College of Medicine, King Saud University, Riyadh 11472, Saudi Arabia, CMRC, College of Medicine, King Saud University, Riyadh 11472, Saudi Arabia, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33511, Egypt, Department of Applied Organic Chemistry, National Research Center, Cairo 12622, Egypt, Department of Chemistry, Kulliyyah of Science, International Islamic University, Kuantan 25200, Malaysia
Published online on: July 23, 2019 https://doi.org/10.3892/ijmm.2019.4284
Pages: 1552-1562

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Abstract

The emergence of colorectal cancer in developed nations can be attributed to dietary habits, smoking, a sedentary lifestyle and obesity. Several treatment regimens are available for primary and metastatic colorectal cancer; however, these treatment options have had limited impact on cure and disease‑free survival, and novel agents need to be developed for treating colorectal cancer. Thus, the objective of this study was to explore the anticancer mechanism of a benzo(1,3)dioxol‑based derivative of sulfonamide. The compound's inhibitory effect on cell proliferation was determined using the MTT assay and the xCelligence RTDP machine. Alternations in the expression of Bcl‑2 and inhibitor of apoptosis protein families were detected by western blotting. Apoptotic marker protein expression, including cytochrome c and cleaved poly(ADP‑ribose)polymerase was measured in the cytosolic extract of cells. Apoptosis and necrosis were detected by flow cytometry and immunofluorescence. Reactive oxygen species (ROS), and activation of caspase‑3 and caspase‑7 were measured using flow cytometry. Activation of the JNK pathway was detected by western blotting. We investigated the molecular mechanism of action of the sulfonamide derivative on colorectal cancer cells and found that the compound possesses a potent anticancer effect, which is primarily exerted by inducing apoptosis and necrosis. Interestingly, this compound exhibited little antiproliferative effect against the normal colonic epithelial cell line FHC. Furthermore, our results showed that the compound could significantly increase ROS production. Apoptosis induction could be attenuated by the free oxygen radical scavenger N‑acetyl cysteine (NAC), indicating that the antiproliferative effect of this compound on colorectal cancer cells is at least partially dependent on the redox balance. In addition, JNK signaling was activated by treatment with this derivative, which led to the induction of apoptosis. On the contrary, a JNK inhibitor could suppress the cell death induced by this compound. Our findings thus suggested a novel anticancer mechanism of a benzo(1,3)dioxol‑based derivative of sulfonamide for colorectal cancer cells and may have therapeutic potential for the treatment of colorectal cancer; however, further investigation is required.

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1	American Cancer Society: Cancer Facts & Figures 2018. Atlanta, GA: American Cancer Society; 2018, https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2018.html. Accessed November 22, 2018.
2	Zubaidi AM, AlSubaie NM, AlHumaid AA, Shaik SA, AlKhayal KA and AlObeed OA: Public awareness of colorectal cancer in Saudi Arabia: A survey of 1070 participants in Riyadh. Saudi J Gastroenterol. 21:78–83. 2015. View Article : Google Scholar : PubMed/NCBI
3	Kuipers EJ, Grady WM, Lieberman D, Seufferlein T, Sung JJ, Boelens PG, van de Velde CJ and Watanabe T: Colorectal cancer. Nat Rev Dis Primers. 1:150652015. View Article : Google Scholar : PubMed/NCBI
4	Sreevalsan S and Safe S: Reactive oxygen species and colorectal cancer. Curr Colorectal Cancer Rep. 9:350–357. 2013. View Article : Google Scholar
5	Trachootham D, Alexandre J and Huang P: Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach? Nat Rev Drug Discov. 8:579–591. 2009. View Article : Google Scholar : PubMed/NCBI
6	Larocque K, Ovadje P, Djurdjevic S, Mehdi M, Green J and Pandey S: Novel analogue of colchicine induces selective pro-death autophagy and necrosis in human cancer cells. PLoS One. 9:e870642014. View Article : Google Scholar : PubMed/NCBI
7	Kim AD, Kang KA, Kim HS, Kim DH, Choi YH, Lee SJ, Kim HS and Hyun JW: A ginseng metabolite, compound K, induces autophagy and apoptosis via generation of reactive oxygen species and activation of JNK in human colon cancer cells. Cell Death Dis. 4:e7502013. View Article : Google Scholar : PubMed/NCBI
8	Kim JY, Yu SJ, Oh HJ, Lee JY, Kim Y and Sohn J: Panaxydol induces apoptosis through an increased intracellular calcium level, activation of JNK and p38 MAPK and NADPH oxidase-dependent generation of reactive oxygen species. Apoptosis. 16:347–358. 2011. View Article : Google Scholar
9	Ramiro-Cortés Y, Guemez-Gamboa A and Morán J: Reactive oxygen species participate in the p38-mediated apoptosis induced by potassium deprivation and staurosporine in cerebellar granule neurons. Int J Biochem Cell Biol. 43:1373–1382. 2011. View Article : Google Scholar : PubMed/NCBI
10	Hsieh CJ, Kuo PL, Hsu YC, Huang YF, Tsai EM and Hsu YL: Arctigenin, a dietary phytoestrogen, induces apoptosis of estrogen receptor-negative breast cancer cells through the ROS/p38 MAPK pathway and epigenetic regulation. Free Radic Biol Med. 67:159–170. 2014. View Article : Google Scholar
11	Alafeefy AM, Ahmad R, Abdulla M, Eldehna WM, Al-Tamimi AM, Abdel-Aziz HA, Al-Obaid O, Carta F, Al-Kahtani AA and Supuran CT: Development of certain new 2-substituted-quinazolin-4-yl-aminobenzenesulfonamide as potential antitumor agents. Eur J Med Chem. 109:247–253. 2016. View Article : Google Scholar : PubMed/NCBI
12	Al-Khayal K, Alafeefy A, Vaali-Mohammed MA, Mahmood A, Zubaidi A, Al-Obeed O, Khan Z, Abdulla M and Ahmad R: Novel derivative of aminobenzenesulfonamide (3c) induces apoptosis in colorectal cancer cells through ROS generation and inhibits cell migration. BMC Cancer. 17:42017. View Article : Google Scholar : PubMed/NCBI
13	Al-Obeed O, Vaali-Mohammed MA, Eldehna WM, Al-Khayal K, Mahmood A, Abdel-Aziz HA, Zubaidi A, Alafeefy A, Abdulla M and Ahmad R: Novel quinazoline-based sulfonamide derivative (3D) induces apoptosis in colorectal cancer by inhibiting JAK2-STAT3 pathway. Onco Targets Ther. 11:3313–3322. 2018. View Article : Google Scholar : PubMed/NCBI
14	Olovnikov IA, Kravchenko JE and Chumakov PM: Homeostatic function of the p53 tumor suppressor: Regulation of energy metabolism and antioxidant defence. Semin Cancer Biol. 19:32–41. 2009. View Article : Google Scholar
15	Shamas-Din A, Kale J, Leber B and Andrews DW: Mechanism of action of Bcl-2 family proteins. Cold Spring Harb Perspect Biol. 5:a0087142013. View Article : Google Scholar
16	Casimiro MC, Crosariol M, Loro E, Li Z and Pestell RG: Cyclins and cell cycle control in cancer and disease. Genes Cancer. 3:649–657. 2012. View Article : Google Scholar
17	Altieri DC: Survivin and IAP proteins in cell death mechanisms. Biochem J. 430:199–205. 2010. View Article : Google Scholar : PubMed/NCBI
18	Soldani C and Scovassi AI: Poly(ADP-ribose) polymerase-1 cleavage during apoptosis: An update. Apoptosis. 7:321–328. 2002. View Article : Google Scholar : PubMed/NCBI
19	Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li X, Tolliday NJ, Golub TR, Carr SA, Shamji AF, et al: Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature. 475:231–234. 2011. View Article : Google Scholar : PubMed/NCBI
20	Zikaki K, Aggeli IK, Gaitanaki C and Beis I: Curcumin induces the apoptotic intrinsic pathway via upregulation of reactive oxygen species and JNKs in H9c2 cardiac myoblasts. Apoptosis. 19:958–974. 2014. View Article : Google Scholar : PubMed/NCBI
21	Liu Z, Liang C, Zhang Z, Pan J, Xia H, Zhong N and Li L: Para-toluenesulfonamide induces tongue squamous cell carcinoma cell death through disturbing lysosomal stability. Anticancer Drugs. 26:1026–1033. 2015. View Article : Google Scholar : PubMed/NCBI
22	Saha T, Hossain MS, Saha D, Lahiri M and Talukdar P: Chloride-mediated apoptosis-inducing activity of bis(sulfonamide) anionophores. J Am Chem Soc. 138:7558–7567. 2016. View Article : Google Scholar : PubMed/NCBI
23	Agudo-López A, Prieto-García E, Alemán J, Pérez C, Díaz-García CV, Parrilla-Rubio L, Cabrera S, Navarro-Ranninger C, Cortés-Funes H, López-Martín JA and Agulló-Ortuño MT: Mechanistic added value of a trans-Sulfonamide-Platinum-Complex in human melanoma cell lines and synergism with cis-Platin. Mol Cancer. 16:452017. View Article : Google Scholar : PubMed/NCBI
24	Armaghany T, Wilson JD, Chu Q and Mills G: Genetic alterations in colorectal cancer. Gastrointest Cancer Res. 5:19–27. 2012.PubMed/NCBI
25	Cherbonnel-Lasserre C and Dosanjh ML: Suppression of apoptosis by overexpression of Bcl-2 or Bcl-xL promotes survival and mutagenesis after oxidative damage. Biochimie. 79:613–617. 1997. View Article : Google Scholar
26	Sinicrope FA, Ruan SB, Cleary KR, Stephens LC, Lee JJ and Levin B: Bcl-2 and p53 expression during colorectal tumorigenesis. Cancer Res. 55:237–241. 1995.PubMed/NCBI
27	Scherr AL, Gdynia G, Salou M, Radhakrishnan P, Duglova K, Heller A, Keim S, Kautz N, Jassowicz A, Elssner C, et al: Bcl-xL is an oncogenic driver in colorectal cancer. Cell Death Dis. 7:e23422016. View Article : Google Scholar : PubMed/NCBI
28	Mermelshtein A, Gerson A, Walfisch S, Delgado B, Shechter-Maor G, Delgado J, Fich A and Gheber L: Expression of D-type cyclins in colon cancer and in cell lines from colon carcinoma. Br J Cancer. 93:338–345. 2005. View Article : Google Scholar : PubMed/NCBI
29	Takeuchi H, Kim J, Fujimoto A, Umetani N, Mori T, Bilchik A, Turner R, Tran A, Kuo C and Hoon DS: X-Linked inhibitor of apoptosis protein expression level in colorectal cancer is regulated by hepatocyte growth factor/C-met pathway via Akt signaling. Clin Cancer Res. 11:7621–7628. 2005. View Article : Google Scholar : PubMed/NCBI
30	Kalliakmanis JG, Kouvidou CH, Latoufis C, Kouvatseas G, Anagnostakis D, Papatheodoridis G, Koskinas J and Archimandritis A: Survivin expression in colorectal carcinomas: Correlations with clinicopathological parameters and survival. Dig Dis Sci. 55:2958–2964. 2010. View Article : Google Scholar
31	Arihara Y, Takada K, Kamihara Y, Hayasaka N, Nakamura H, Murase K, Ikeda H, Iyama S, Sato T, Miyanishi K, et al: Small molecule CP-31398 induces reactive oxygen species-dependent apoptosis in human multiple myeloma. Oncotarget. 8:65889–65899. 2017. View Article : Google Scholar : PubMed/NCBI
32	Adams DJ, Boskovic ZV, Theriault JR, Wang AJ, Stern AM, Wagner BK, Shamji AF and Schreiber SL: Discovery of small-molecule enhancers of reactive oxygen species that are nontoxic or cause genotype-selective cell death. ACS Chem Biol. 8:923–929. 2013. View Article : Google Scholar : PubMed/NCBI
33	Weidner C, Rousseau M, Plauth A, Wowro SJ, Fischer C, Abdel-Aziz H and Sauer S: Iberis amara extract induces intracellular formation of reactive oxygen species and inhibits colon cancer. PLoS One. 11:e01523982016. View Article : Google Scholar : PubMed/NCBI
34	Marathe SA, Dasgupta I, Gnanadhas DP and Chakravortty D: Multifaceted roles of curcumin: Two sides of a coin! Expert Opin Biol Ther. 11:1485–1499. 2011. View Article : Google Scholar : PubMed/NCBI
35	Muqbil I, Beck FW, Bao B, Sarkar FH, Mohammad RM, Hadi SM and Azmi AS: Old wine in a new bottle: The warburg effect and anticancer mechanisms of resveratrol. Curr Pharm Des. 18:1645–1654. 2012. 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	Cargnello M and Roux PP: Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 75:50–83. 2011. View Article : Google Scholar : PubMed/NCBI
38	Cumaoglu A, Dayan S, Agkaya AO, Ozkul Z and Ozpozan NK: Synthesis and pro-apoptotic effects of new sulfonamide derivatives via activating p38/ERK phosphorylation in cancer cells. J Enzyme Inhib Med Chem. 30:413–419. 2015. View Article : Google Scholar
39	Kwon Y, Song J, Lee H, Kim EY, Lee K, Lee SK and Kim S: Design, synthesis, and biological activity of sulfonamide analogues of antofine and cryptopleurine as potent and orally active antitumor agents. J Med Chem. 58:7749–7762. 2015. View Article : Google Scholar : PubMed/NCBI
40	Tülüce Y, Ahmed BA, Koyuncu İ and Durgun M: The cytotoxic, apoptotic and oxidative effects of carbonic anhydrase IX inhibitor on colorectal cancer cells. J Bioenerg Biomembr. 50:107–116. 2018. View Article : Google Scholar : PubMed/NCBI