Anti-cancer Effects of MW-03, a Novel Indole Compound, by Inducing 15-Hydroxyprostaglandin Dehydrogenase and Cellular Growth Inhibition in the LS174T Human Colon Cancer Cell Line.

Increases in the expression of prostaglandin E2 (PGE2) are widely known to be involved in aberrant growth in the early stage of colon cancer development. We herein demonstrated that the novel indole compound MW-03 reduced PGE2-induced cAMP formation by catalization to an inactive metabolite by inducing 15-hydroxyprostaglandin dehydrogenase through the activation of peroxisome proliferator-activated receptor-γ. MW-03 also inhibited colon cancer cell growth by arresting the cell cycle at the S phase. Although the target of MW-03 for cell cycle inhibition has not yet been identified, these dual anti-cancer effects of MW-03 itself and/or its leading compound(s) on colon cancer cells may reduce colon cancer development and, thus, have potential as a novel treatment for the early stage of this disease.

[1]  K. Ahmed,et al.  Indoles as anticancer agents , 2015 .

[2]  J. Regan,et al.  Cellular density-dependent down-regulation of EP4 prostanoid receptors via the up-regulation of hypoxia-inducible factor-1α in HCA-7 human colon cancer cells , 2014, Pharmacology research & perspectives.

[3]  J. Eeckhoute,et al.  Coordinated Regulation of PPARγ Expression and Activity through Control of Chromatin Structure in Adipogenesis and Obesity , 2012, PPAR research.

[4]  K. Büssow,et al.  Amorfrutins are potent antidiabetic dietary natural products , 2012, Proceedings of the National Academy of Sciences.

[5]  H. Fujino,et al.  Indomethacin antagonizes EP(2) prostanoid receptor activation in LS174T human colon cancer cells. , 2012, European journal of pharmacology.

[6]  Y. Surh,et al.  15-Hydroxyprostaglandin dehydrogenase as a novel molecular target for cancer chemoprevention and therapy. , 2011, Biochemical pharmacology.

[7]  T. Arai,et al.  Easy access to fully functionalized chiral tetrahydro-β-carboline alkaloids. , 2011, The Journal of organic chemistry.

[8]  A. Cullen,et al.  NSAIDs and Cell Proliferation in Colorectal Cancer , 2010, Pharmaceuticals.

[9]  Wael A Sakr,et al.  Anticancer properties of indole compounds: mechanism of apoptosis induction and role in chemotherapy. , 2010, Current drug targets.

[10]  Y. Daaka,et al.  Prostaglandin E2 Promotes Lung Cancer Cell Migration via EP4-βArrestin1-c-Src Signalsome , 2010, Molecular Cancer Research.

[11]  H. Fujino,et al.  Decrease in uptake of arachidonic acid by indomethacin in LS174T human colon cancer cells; a novel cyclooxygenase-2-inhibition-independent effect. , 2010, Archives of biochemistry and biophysics.

[12]  M. Giembycz,et al.  Prostanoid receptor antagonists: development strategies and therapeutic applications , 2009, British journal of pharmacology.

[13]  J. Regan,et al.  Indomethacin decreases EP2 prostanoid receptor expression in colon cancer cells. , 2007, Biochemical and biophysical research communications.

[14]  N. Horikoshi,et al.  Combined inhibition of extracellular signal-regulated kinases and HSP90 sensitizes human colon carcinoma cells to ionizing radiation , 2005, Oncogene.

[15]  R. DuBois,et al.  COX-2: a molecular target for colorectal cancer prevention. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  H. Tai,et al.  15-Hydroxyprostaglandin Dehydrogenase Is Down-regulated in Colorectal Cancer* , 2005, Journal of Biological Chemistry.

[17]  M. Toda,et al.  Discovery of new chemical leads for prostaglandin D2 receptor antagonists. , 2004, Bioorganic & medicinal chemistry letters.

[18]  M. Hull,et al.  Prostaglandin EP receptors: targets for treatment and prevention of colorectal cancer? , 2004, Molecular cancer therapeutics.

[19]  T. Warner,et al.  PPARγ ligands induce prostaglandin production in vascular smooth muscle cells: indomethacin acts as a peroxisome proliferator‐activated receptor‐γ antagonist , 2003 .

[20]  M. Hull,et al.  Activation of Peroxisome Proliferator-Activated Receptor γ Does Not Explain the Antiproliferative Activity of the Nonsteroidal Anti-Inflammatory Drug Indomethacin on Human Colorectal Cancer Cells , 2003, Journal of Pharmacology and Experimental Therapeutics.

[21]  H. Tai,et al.  Inhibition of NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) by cyclooxygenase inhibitors and chemopreventive agents. , 2002, Prostaglandins, leukotrienes, and essential fatty acids.

[22]  Masataka Nakamura,et al.  Cutting Edge: Agonistic Effect of Indomethacin on a Prostaglandin D2 Receptor, CRTH2 , 2002, The Journal of Immunology.

[23]  J. Regan,et al.  Phosphorylation of Glycogen Synthase Kinase-3 and Stimulation of T-cell Factor Signaling following Activation of EP2 and EP4 Prostanoid Receptors by Prostaglandin E2 * , 2002, The Journal of Biological Chemistry.

[24]  J. Morrow,et al.  Regulation of Constitutive Cyclooxygenase-2 Expression in Colon Carcinoma Cells* , 2000, The Journal of Biological Chemistry.

[25]  D. Inzé,et al.  Indomethacin‐induced G1/S phase arrest of the plant cell cycle , 1999, FEBS letters.

[26]  S. Tafuri,et al.  PPARγ activators down‐regulate the expression of PPARγ in 3T3‐L1 adipocytes , 1999 .

[27]  J. Lehmann,et al.  Peroxisome Proliferator-activated Receptors α and γ Are Activated by Indomethacin and Other Non-steroidal Anti-inflammatory Drugs* , 1997, The Journal of Biological Chemistry.

[28]  B. Rigas,et al.  Nonsteroidal antiinflammatory drugs inhibit the proliferation of colon adenocarcinoma cells: effects on cell cycle and apoptosis. , 1996, Experimental cell research.

[29]  J. Regan,et al.  A novel indole compound, AWT-489, inhibits prostaglandin D2-induced CD55 expression by acting on DP prostanoid receptors as an antagonist in LS174T human colon cancer cells. , 2014, Archives of biochemistry and biophysics.

[30]  David A Jones,et al.  The role of cyclooxygenase-2 and prostaglandins in colon cancer. , 2007, Prostaglandins & other lipid mediators.

[31]  M. Kralj,et al.  Effect of the nonsteroidal anti-inflammatory drug indomethacin on proliferation and apoptosis of colon carcinoma cells , 2001, Journal of Cancer Research and Clinical Oncology.