Abstract
Purpose: Aim of this study is to assess the anti-proliferative effect of the thiazole analogue (5-acetyl-4-methyl-2-(3-pyridyl) thiazole) with different human carcinoma cell lines and to postulate its possible mechanism of action using molecular modeling. Methods: Three different human carcinoma cell lines were used namely hepatocyte carcinoma (HEPG2), breast adenocarcinoma (MCF7) and colon cancer (HCT116). Molecular docking simulations for tested thiazole analogue and its virtual analogues against the cytochrome P-450 2A6 enzyme and mutated SOD were performed. Results: Cell lines cytotoxicity revealed that the tested thiazole analogue exerts a significant anti-proliferative activity in all the used human carcinoma cell lines with a pronounced anti-proliferative effect in liver carcinoma cell line HEPG2 (IC50 = 23.8 μg/ml) whereas the anti-proliferative effect in colon carcinoma and breast cancer cell lines was poor with IC50 = 50 μg/ml and IC50 > 50 μg/ml respectively. The postulated mechanism of action revealed the high affinity to inhibit SOD and CYP2A6 enzymes in the liver. Conclusion: The thiazole analogue (5-acetyl-4-methyl-2-(3-pyridyl)thiazole) is a potential liver specific anticancer agent capable of interfering with both apoptotic signaling pathway and the free radical processing in liver which leads to more studies on liver cancer from different perspective rather than the apoptotic signaling pathway.
Highlights
Cancer has become the leading disease-related cause of deaths of humans [1]
Cell lines cytotoxicity revealed that the tested thiazole analogue exerts a significant anti-proliferative activity in all the used human carcinoma cell lines with a pronounced anti-proliferative effect in liver carcinoma cell line HEPG2 (IC50 = 23.8 μg/ml) whereas the anti-proliferative effect in colon carcinoma and breast cancer cell lines was poor with IC50 = 50 μg/ml and IC50 > 50 μg/ml respectively
Performance of cytotoxicity tests has shown that the tested thiazole analogue 5-acetyl-4-methyl-2-(3-pyridyl) thiazole demonstrates considerable cytotoxicity against all used cell lines
Summary
Cancer has become the leading disease-related cause of deaths of humans [1]. Radiation therapy and surgery treatments are only successful when cancer is localized in the early stage whereas chemotherapy has the ability to cure widespread or metastatic cancers. 74% of anti-cancer drugs are either natural products, semi synthetic compounds or their mimetics [2]. Inhibition of hemoproteins such as cytochromes P450 is a widely pursued area of research for cancer treatment and prevention [3]. CYP proteins in general have about 500 amino acid residues with 2 main domains: the α-domain (13 α-helices) and the β-domain (5 β-sheets). The α-domain contains the heme binding pocket and β-domain has the N-terminus [4]. The enzyme compact structure stability is due to phenylalanine residues (Phe107, Phe111, Phe118, Phe209 and Phe480) located above the haem to form the upper surface of the enzyme active site pocket. The π-π stacking because of the aromatic residues leads to the formation of a hydrogen bond with the ligands, such as methoxsalen, coumarin and amine derivatives due to the interaction with Asn297 residue and aromatic ligands [5] [6]
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