Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity.

Abstract	Constitutive activation of the JAK/STAT3 pathway is a major contributor to oncogenesis. In the present study, structure-activity relationship (SAR) studies with five cucurbitacin (Cuc) analogs, A, B, E, I, and Q, led to the discovery of Cuc Q, which inhibits the activation of STAT3 but not JAK2; Cuc A which inhibits JAK2 but not STAT3 activation; and Cuc B, E, and I, which inhibit the activation of both. Furthermore, these SAR studies demonstrated that conversion of the C3 carbonyl of the cucurbitacins to a hydroxyl results in loss of anti-JAK2 activity, whereas addition of a hydroxyl group to C11 of the cucurbitacins results in loss of anti-STAT3 activity. Cuc Q inhibits selectively the activation of STAT3 and induces apoptosis without inhibition of JAK2, Src, Akt, Erk, or JNK activation. Furthermore, Cuc Q induces apoptosis more potently in human and murine tumors that contain constitutively activated STAT3 (i.e., A549, MDA-MB-435, and v-Src/NIH 3T3) as compared to those that do not (i.e., H-Ras/NIH 3T3, MDA-MB-453, and NIH 3T3 cells). Finally, in a nude mouse tumor xenograft model, Cuc Q, but not Cuc A, suppresses tumor growth indicating that JAK2 inhibition is not sufficient to inhibit tumor growth and suggesting that the ability of Cuc Q to inhibit tumor growth is related to its anti-STAT3 activity. These studies further validate STAT3 as a drug discovery target and provide evidence that pharmacological agents that can selectively reduce the P-STAT3 levels in human cancer cells result in tumor apoptosis and growth inhibition.
Authors	Jiazhi Sun, Michelle A Blaskovich, Richard Jove, Sandra K Livingston, Domenico Coppola, Saïd M Sebti
Journal	Oncogene (Oncogene) Vol. 24 Issue 20 Pg. 3236-45 (May 05 2005) ISSN: 0950-9232 [Print] England
PMID	15735720 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Antineoplastic Agents DNA-Binding Proteins Proto-Oncogene Proteins STAT3 Transcription Factor STAT3 protein, human Stat3 protein, mouse Trans-Activators Triterpenes cucurbitacin Q Phosphotyrosine Cucurbitacins Protein-Tyrosine Kinases JAK2 protein, human Jak2 protein, mouse Janus Kinase 2 src-Family Kinases AKT1 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt
Topics	3T3 Cells Animals Antineoplastic Agents (pharmacology) Apoptosis Blotting, Western Cell Line, Tumor Cell Proliferation Cucurbitacins DNA-Binding Proteins (antagonists & inhibitors, metabolism) Humans Immunohistochemistry Immunoprecipitation In Situ Nick-End Labeling Inhibitory Concentration 50 Janus Kinase 2 Mice Mice, Nude Models, Chemical NIH 3T3 Cells Neoplasm Transplantation Phosphotyrosine (chemistry) Protein Serine-Threonine Kinases (metabolism) Protein-Tyrosine Kinases (metabolism) Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-akt STAT3 Transcription Factor Signal Transduction Structure-Activity Relationship Time Factors Trans-Activators (antagonists & inhibitors, metabolism) Triterpenes (chemistry, pharmacology) src-Family Kinases (metabolism)

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