3-Bromopyruvate potentiates TRAIL-induced apoptosis in human colon cancer cells through a reactive oxygen species- and caspase-dependent mitochondrial pathway

• Published in: Canadian journal of physiology and pharmacology 2019-12, Vol.97 (12), p.1176-1184
• Main Authors: Abbaszadeh, Hassan, Valizadeh, Armita, Mahdavinia, Masoud, Teimoori, Ali, Pipelzadeh, Mohammad Hassan, Zeidooni, Leila, Alboghobeish, Soheila
• Format: Article
• Language: English
• Subjects: 3-BP; Activation; Antineoplastic Agents - pharmacology; apoptose; Apoptosis; Apoptosis - drug effects; Bcl-2 protein; bcl-2-Associated X Protein - metabolism; Cancer; Cancer cells; cancer colorectal; Care and treatment; Caspase-3; Caspases - metabolism; Cell proliferation; Cells; Colon cancer; Colonic Neoplasms - pathology; Colorectal cancer; Combined treatment; Cytochrome; Cytochrome c; Cytochromes c - metabolism; Cytokines; Cytosol; Down-Regulation - drug effects; Drug Synergism; Drug therapy; Enzyme Activation - drug effects; HEK293 Cells; HT29 Cells; Humans; Inhibitor drugs; Ligands; Membrane Potential, Mitochondrial - drug effects; Mitochondria; Mitochondria - drug effects; Mitochondria - pathology; Pharmacology; Physiology; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyruvates - pharmacology; Reactive oxygen species; Reactive Oxygen Species - metabolism; résistance à TRAIL; Studies; Survivin; Survivin - metabolism; TNF-Related Apoptosis-Inducing Ligand - pharmacology; Toxicity; TRAIL; TRAIL protein; TRAIL resistance; Tumor necrosis factor; Tumor necrosis factor-TNF; Up-Regulation - drug effects
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/cjpp-2019-0131

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising anticancer cytokine with minimal toxicity towards normal cells. Nevertheless, most primary cancers are often intrinsically TRAIL-resistant or can acquire resistance after TRAIL therapy. This study aimed to investigate the inhibitory effect of co-treatment of 3-bromopyruvate (3-BP) as a potent anticancer agent with TRAIL on colon cancer cells (HT-29). The results of present study indicated that combined treatment with 3-BP and TRAIL inhibited the proliferation of HT-29 cells to a greater extent (88.4%) compared with 3-BP (54%) or TRAIL (11%) treatment alone. In contrast, the combination of 3-BP and TRAIL had no significant inhibitory effect on the proliferation of normal cells (HEK-293) (8.4%). At a cellular mechanistic level, the present study showed that 3-BP sensitized human colon cancer cells to TRAIL-induced apoptosis via reactive oxygen species generation, upregulation of Bax, downregulation of Bcl-2 and survivin, release of cytochrome c into the cytosol, and activation of caspase-3. In normal cells, 3-BP, TRAIL, or combination of both had no significant effect on the reactive oxygen species levels, release of cytochrome c, and caspase-3 activity. Therefore, the combination of 3-BP and TRAIL can be a promising therapeutic strategy for treatment of colon cancer.