3,3'-Diindolylmethane inhibits patient-derived xenograft colon tumor growth by targeting COX1/2 and ERK1/2.

Abstract

3,3'-Diindolymethane (DIM) is a dimeric condensation product of indole-3-carbinol (I3C) that is found in broccoli and cabbage. Although DIM has been reported to exhibit anticancer properties against multiple tumor types, the direct target proteins of DIM have not been fully investigated. In the present study, we report that DIM is a novel COX1/2 and ERK1/2 inhibitor that suppresses growth of colon cancer in vitro and in vivo. To identify possible molecular targets of DIM, 11 potential candidate proteins were validated by an in vitro kinase or enzyme assay. We found that DIM directly inhibits COX1/2 and ERK1/2 protein activities in vitro. Additionally, the PGE2 production (COX-mediated metabolite) and phosphorylated RSK expression (ERK1/2 direct downstream kinase) were strongly suppressed by DIM in colon cancer cells. The inhibition of cell growth by DIM is dependent on the expression of COX1/2 or ERK1/2 proteins. Notably, oral administration of DIM suppressed patient-derived xenograft colon tumor growth in an in vivo mouse model. Overall these results suggest that DIM is a potent and dual COX1/2 and ERK1/2 inhibitor that might be used for chemotherapy against colon cancer.

• Authors: Xueli Tian, KangDong Liu, Xueyin Zu, Fayang Ma, Zhi Li, MeeHyun Lee, Hanyong Chen, Yan Li, Yuzhou Zhao, Fangfang Liu, Naomi Oi, Ann M Bode, Zigang Dong, Dong Joon Kim
• Journal: Cancer letters (Cancer Lett) Vol. 448 Pg. 20-30 (04 28 2019) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 30716361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Anticarcinogenic Agents
• Cyclooxygenase Inhibitors
• Indoles
• Cyclooxygenase 2
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• 3,3'-diindolylmethane

Topics

• Animals
• Anticarcinogenic Agents (pharmacology)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase Inhibitors (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Humans
• Indoles (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Mice
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured