Novel quinazoline-based sulfonamide derivative (3D) induces apoptosis in colorectal cancer by inhibiting JAK2–STAT3 pathway
| Autor: | Omar Al-Obeed, Rehan Ahmad, Ahmed M. Alafeefy, Ahmed M. Zubaidi, Khayal Al-Khayal, Wagdy M. Eldehna, Hatem A. Abdel-Aziz, Maha-Hamadien Abdulla, Amer Mahmood, Mansoor-Ali Vaali-Mohammed |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
colorectal cancer STAT3 pathway OncoTargets and Therapy Flow cytometry 03 medical and health sciences 0302 clinical medicine Cyclin D1 sulfonamide Survivin medicine Pharmacology (medical) Doxorubicin Viability assay Original Research Bcl2 proteins reactive oxygen species chemistry.chemical_classification Reactive oxygen species medicine.diagnostic_test Cell growth apoptosis 030104 developmental biology Oncology chemistry Apoptosis 030220 oncology & carcinogenesis Cancer research medicine.drug |
| Zdroj: | OncoTargets and therapy |
| ISSN: | 1178-6930 |
| Popis: | Omar Al-Obeed,1 Mansoor-Ali Vaali-Mohammed,1 Wagdy M Eldehna,2 Khayal Al-Khayal,1 Amer Mahmood,3 Hatem A Abdel-Aziz,4 Ahmed Zubaidi,1 Ahmed Alafeefy,5 Maha Abdulla,1 Rehan Ahmad1 1Colorectal Research Chair, Department of Surgery, King Khaled University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt; 3Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 4Department of Applied Organic Chemistry, National Research Center, Cairo, Egypt; 5Department of Chemistry, Kulliyyah of Science, International Islamic University, Kuantan, Malaysia Introduction: Colorectal cancer (CRC) is a major worldwide health problem owing to its high prevalence and mortality rate. Developments in screening, prevention, biomarker, personalized therapies and chemotherapy have improved detection and treatment. However, despite these advances, many patients with advanced metastatic tumors still succumb to the disease. New anticancer agents are needed for treating advanced stage CRC as most of the deaths occur due to cancer metastasis. A recently developed novel sulfonamide derivative 4-((2-(4-(dimethylamino) phenyl)quinazolin-4-yl)amino)benzenesulfonamide (3D) has shown potent antitumor effect; however, the mechanism underlying the antitumor effect remains unknown. Materials and methods: 3D-mediated inhibition on cell viability was evaluated by MTT and real-time cell proliferation was measured by xCelligence RTDP instrument. Western blotting was used to measure pro-apoptotic, anti-apoptotic proteins and JAK2-STAT3 phosphorylation. Flow cytometry was used to measure ROS production and apoptosis. Results: Our study revealed that 3D treatment significantly reduced the viability of human CRC cells HT-29 and SW620. Furthermore, 3D treatment induced the generation of reactive oxygen species (ROS) in human CRC cells. Confirming our observation, N-acetylcysteine significantly inhibited apoptosis. This is further evidenced by the induction of p53 and Bax; release of cytochrome c; activation of caspase-9, caspase-7 and caspase-3; and cleavage of PARP in 3D-treated cells. This compound was found to have a significant effect on the inhibition of antiapoptotic proteins Bcl2 and BclxL. The results further demonstrate that 3D inhibits JAK2–STAT3 pathway by decreasing the constitutive and IL-6-induced phosphorylation of STAT3. 3D also decreases STAT3 target genes such as cyclin D1 and survivin. Furthermore, a combination study of 3D with doxorubicin (Dox) also showed more potent effects than single treatment of Dox in the inhibition of cell viability. Conclusion: Taken together, these findings indicate that 3D induces ROS-mediated apoptosis and inhibits JAK2–STAT3 signaling in CRC. Keywords: sulfonamide, apoptosis, colorectal cancer, STAT3 pathway, Bcl2 proteins, reactive oxygen species |
| Databáze: | OpenAIRE |
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