Activation of death receptor, DR5 and mitochondria-mediated apoptosis by a 3,4,5-trimethoxybenzyloxy derivative in wild-type and p53 mutant colorectal cancer cell lines

• Published in: Naunyn-Schmiedeberg's archives of pharmacology 2020-03, Vol.393 (3), p.405-417
• Main Authors: Chan, Zachariah Chee Ken, Leong, Kok Hoong, Kareem, Huda Salah, Norazit, Anwar, Noor, Suzita Mohd, Ariffin, Azhar
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antioxidants; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Biomedical and Life Sciences; Biomedicine; Cell cycle; Chemotherapy; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Cytotoxicity; Dose-Response Relationship, Drug; Gallic Acid - analogs & derivatives; Gallic Acid - chemistry; Gallic Acid - pharmacology; Gallic Acid - therapeutic use; HCT116 Cells; HT29 Cells; Humans; Mitochondria; Mitochondria - drug effects; Mitochondria - genetics; Mitochondria - metabolism; Mutants; Mutation - drug effects; Mutation - genetics; Neurosciences; Original Article; p53 Protein; Pharmacology/Toxicology; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Structure-Activity Relationship; Triazoles; Tumor cell lines; Tumor Suppressor Protein p53 - genetics
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-019-01730-2

The rationale of designing compounds containing a (3,4,5-trimethoxybenzyloxy) phenyl moiety is largely due to its potential antioxidant and cytotoxic activities. A previous study focused on its antioxidant mechanism, whereas in this study, we investigated the cytotoxicity of a series of 28 analogues and the mechanism of apoptosis of the most cytotoxic compound against wild-type (HCT-116) and p53 mutant (HT-29) colorectal cancer cell lines. The series of analogues comprise of different families, namely hydrazone, oxadiazole, thiosemicarbazides and triazoles. In the initial cytotoxicity screening, N-(3,4,5-trimethoxybenzylidene)-4-(3,4,5-trimethoxybenzyloxy) benzohydrazide, henceforth known as, P5H, was found to be most cytotoxic against human colorectal cancer cell lines (IC 50 for HCT-116 = 11.79 μM and HT-29 = 18.52 μM). Additionally, P5H was found to have some degree of selectivity towards cancer cells compared to normal human colon cells (CCD-112 CoN). Subsequent investigation had brought insight on P5H ability to induce apoptosis in both HCT-116 and HT-29 cell lines. Cell cycle analysis showed both cell lines were arrested at the G2/M phase upon treatment. Our study concluded that P5H induced the death receptor, DR5 in HCT-116 and mitochondria-mediated apoptosis pathway in HT-29. Therefore, P5H may be a promising candidate as a chemotherapy agent against colon cancer. Graphical abstract The apoptotic pathways induced in HT-29 and HCT-116 cells upon P5H treatment.