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Anti-Cancer Agents in Medicinal Chemistry

Author(s): Faisal Rashid, Sumera Zaib, Aliya Ibrar*, Syeda A. Ejaz, Aamer Saeed, Jamshed Iqbal* and Imtiaz Khan*

DOI: 10.2174/1871520620666200721110732

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New Hybrid Scaffolds Based on Carbazole-Chalcones as Potent Anticancer Agents

Page: [1082 - 1091] Pages: 10

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Abstract

Background and Objectives: Despite various technological advances for the treatment of cancer, the identification of new chemical entities with potent anticancer effects remain an indispensable requirement of the time due to multi-drug resistance exhibited by previously developed anticancer drugs. Particularly, the hybrid drugs incorporating two individual bioactive pharmacophores present medicinally important structural leads, thus improving the pharmacodynamic profile of the drug molecules. The antiproliferative and pro-apoptotic activity of the carbazole-chalcone hybrids on human breast and cervical cancer cells will be examined.

Materials and Methods: To overcome such complications, in the current study, we evaluated the cytotoxic effects of carbazole-chalcone hybrids on human breast adenocarcinoma (MCF-7), cervical adenocarcinoma (HeLa) cells and normal cells, i.e., Baby Hamster Kidney cells (BHK-21) using MTT (dimethyl-2-thiazolyl-2,5- diphenyl-2H-tetrazolium bromide) assay. The mechanistic studies were performed on potent compound 4g by fluorescent microscopic studies, release of Lactate Dehydrogenase (LDH) and mitochondrial membrane potential, activation of caspase-9 and -3 and flow cytometric analysis.

Results: As revealed by MTT assay, compound 4g was identified as the most potent derivative among the tested series with IC50 values of 5.64 and 29.15μM against HeLa and MCF-7 cells, respectively. The results were compared with cisplatin. Fluorescent microscopic studies using 4′,6-diamidino-2-phenylindole (DAPI) and Propidium Iodide (PI) staining confirmed the occurrence of apoptosis in HeLa cells treated with the most active compound 4g. Moreover, compound 4g also triggered the release of Lactate Dehydrogenase (LDH) in treated HeLa and MCF-7 cells while a fluorescence assay displayed a remarkable increase in the activity of caspase-9 and -3. Moreover, flow cytometric results revealed that compound 4g caused G0/G1 arrest in the treated HeLa cells.

Conclusion: Our results demonstrated that the compound 4g possesses chemotherapeutic properties against breast cancer and cervical adenocarcinoma cells, thus warranting further research to test the anticancer potential of this compound at preclinical and clinical level.

Keywords: Carbazole-chalcone hybrids, 4′, 6-diamidino-2-phenylindole (DAPI), caspase-3, caspase-9, flow cytometry, lactate dehydrogenase, HeLa cells, MCF-7.

Graphical Abstract

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