Organoselenium-based Azomethines as Apoptosis Inducers in Colorectal Carcinoma via P53, BAX, Caspase-3, Caspase-6, and Caspase-9 Modulations

Author:

Shaaban Saad1,Hammouda Mohamed M.23,Althikrallah Hanan A.1,Al Nawah Jawaher Y.4,Ba-Ghazal Hussein1,Sharaky Marwa5,Abulkhair Hamada S.67,Al-Karmalawy Ahmed A.78

Affiliation:

1. Department of Chemistry, College of Science, King Faisal University, Al-Ahsa, 31982, Saudi Arabia

2. Department of Chemistry, Faculty of Science, Mansoura University, 35516, Mansoura, Egypt

3. Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia

4. King Faisal University, Ministry of health Al-Ahssa Psychiatry Hospital Department of Chemistry, College of Science, Ahssa Saudi Arabia

5. Cancer Biology Department, Pharmacology Unit, National Cancer Institute (NCI), Cairo University, Cairo, Egypt

6. Pharmaceutical Organic Chemistry Department, Al-Azhar University, Nasr City, 11884, Cairo, Egypt

7. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt

8. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, 12566, Egypt

Abstract

Background: Organoselenium (OSe) agents and Schiff bases have demonstrated immense potential in the pharmaceutical field due to their broad spectrum of medicinal activities. Methods: We herein report the antitumor activities of bis diselenide-based Schiff bases (3a-3c) derived from bis(4-aminophenyl)diselenide 2 and organoselenide-based Schiff bases (5a-c) derived from p-(methylselanyl)phenyl amine (4). The antitumor activity was estimated against fifteen cancer cell lines. Also, the growth inhibition percentage (GI%) of the Schiff bases tethered OSe compounds was evaluated against two normal cell lines, namely, human skin fibroblasts (HSF) and olfactory ensheathing cell line (OEC), to estimate the potential safety and selectivity. Furthermore, the cytotoxic inhibitory concentration 50 (IC50) was assessed against the cancer cell lines with the most outstanding GI% using the SRB assay. Results: Compounds 3a, 3b, 3c, and 5a showed the lowest IC50 values compared to those of doxorubicin (DOX) against HCT116, HEPG2, A549, MDA-MB-468, and FaDu cancer cell lines, respectively, especially against the HCT116 subtype, assuring their potential anticancer activity. On the other side, the apoptotic potentials of the most active compounds (3a, 3b, 3c, and 5a) were also evaluated for apoptosis-related genes (P53, BAX, caspases 3, 6, 8, and 9, MMP2, MMP9, and BCL-2). Interestingly, compounds 3a, 3b, 3c, and 5a upregulated P53, BAX, and caspases 3, 6, 8, and 9 by (2.66, 2.26, 2.44, and 2.57)-, (1.62, 1.52, 1.37, and 1.47)-, (1.87, 1.75, 2.02, and 1.75)-, (1.96, 1.74, 2.06, and 2.30)-, (4.25, 3.78, 3.53, and 3.96)-, and (2.04, 1.72, 1.90, and 1.63)-fold change, respectively. Furthermore, MMP2, MMP9, and BCL-2 were downregulated by (0.39, 0.51, 0.33, and 0.28)-, (0.29, 0.32, 0.37, and 0.41)-, and (0.42, 0.35, 0.29, and 0.38)-fold-change, upon treatment with compounds 3a, 3b, 3c, and 5a, respectively, assuring the apoptotic potentials. Finally, molecular docking also greatly recommends the potential activity of the examined candidates (especially 3a and 3c) against the GSTP1 receptor as a recommended mechanism for their antitumor activity. Conclusion: Our findings point to significant anticancer activities of Schiff bases tethered OSe agents, suggesting their promising potential for development as effective anticancer drugs.

Publisher

Bentham Science Publishers Ltd.

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