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ORIGINAL ARTICLE
Year : 2016  |  Volume : 2  |  Issue : 6  |  Page : 163-174

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


1 Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain
2 Laboratory of Cell Signaling and Apoptosis, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic

Correspondence Address:
Prof. Juan Carlos Lacal
Instituto de Investigación Sanitaria IdiPAZ, Paseo de la Castellana, 261, 28046 Madrid
Spain
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-3977.196910

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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.


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