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

• Published in: International journal of molecular medicine 2019-10, Vol.44 (4), p.1552-1562
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Antibiotics; Apoptosis; Biochemistry; Cancer; Cancer cells; Cancer metastasis; Cancer research; Cancer therapies; Cancer treatment; Cell death; Cell growth; Colorectal cancer; Cysteine; Cystine; Cytochrome c; Experiments; Fluorescent antibody technique; Health aspects; Industrialized countries; Instrument industry (Equipment); Kinases; Monosaccharides; Natural products; Necrosis; Novels; Obesity; Penicillin; Physical fitness; Protein expression; Proteins; Reactive oxygen species; Scientific equipment industry; Sulfonamides; Tumorigenesis
• ISSN: 1107-3756; 1791-244X
• DOI: 10.3892/ijmm.2019.4284

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.