Choline kinase inhibitors synergize with TRAIL in the treatment of colorectal tumors and overcomes TRAIL resistance

• Main Authors: Juan Carlos Lacal, Ladislav Andera
• Format: Article
• Language: English
• Published: Wolters Kluwer Medknow Publications 2016-01-01
• Series: Cancer Translational Medicine
• Subjects: Choline kinase inhibitors; colon cancer; combinatorial chemotherapy; DR5; tumor necrosis factor-related apoptosis inducing ligand; tumor necrosis factor-related apoptosis inducing ligand resistance
• Online Access: http://www.cancertm.com/article.asp?issn=2395-3977;year=2016;volume=2;issue=6;spage=163;epage=174;aulast=Lacal

Aim: The aim of this study was to investigate the effects of the combination of choline kinase inhibitor MN58b and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) against colon cancer cells. Methods: TRAIL-sensitive (DLD-1) and TRAIL-resistant (SW620) cells were treated with MN58b and/or TRAIL. Cell viability and induction of apoptosis were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide and flow cytometry. Posttreatment expression levels of different proteins (PARP, caspase-3, X-linked inhibitor of apoptosis protein [XIAP], CHOP, DR5, DR4, CHOP) were analyzed by quantitative reverse transcription polymerase chain reaction, Western blot, and flow cytometry.In vivo antitumoral activity was assessed by xenograft models. Results: A strong synergistic effect of TRAIL and MN58b was observed in both TRAIL-sensitive and resistant cells. The combinatory treatment induced an increase in PARP and active-caspase 3 fragments along with a decrease in XIAP, enhancing TRAIL sensitivity. Reduced cellular viability and increased cell death correlated with increased DR5 expression and membrane surface recruitment, an effect that was concomitant with CHOP expression. Conclusion: MN58b, which alone exhibits anticancer activities against a wide variety of tumor-derived cell lines, synergizes with TRAIL through a mechanism that involves DR5 upregulation. This study supports the use of MN58b in combination with TRAIL on colorectal tumors, including those that develop TRAIL resistance.