Sun Jiazhi, Blaskovich Michelle A, Jove Richard, Livingston Sandra K, Coppola Domenico, Sebti Saïd M
Department of Interdisciplinary Oncology, Drug Discovery and Molecular Oncology Programs, H Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, MRC-DRDIS, Tampa, FL 33612-9497, USA.
Oncogene. 2005 May 5;24(20):3236-45. doi: 10.1038/sj.onc.1208470.
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.
JAK/STAT3信号通路的组成性激活是肿瘤发生的主要原因。在本研究中，对五种葫芦素（Cuc）类似物A、B、E、I和Q进行的构效关系（SAR）研究发现，葫芦素Q可抑制STAT3的激活，但不抑制JAK2；葫芦素A可抑制JAK2，但不抑制STAT3的激活；葫芦素B、E和I则可同时抑制两者的激活。此外，这些SAR研究表明，将葫芦素的C3羰基转化为羟基会导致抗JAK2活性丧失，而在葫芦素的C11处添加羟基会导致抗STAT3活性丧失。葫芦素Q选择性地抑制STAT3的激活并诱导细胞凋亡，而不抑制JAK2、Src、Akt、Erk或JNK的激活。此外，与不含有组成性激活STAT3的细胞（即H-Ras/NIH 3T3、MDA-MB-453和NIH 3T3细胞）相比，葫芦素Q在含有组成性激活STAT3的人源和鼠源肿瘤细胞（即A549、MDA-MB-435和v-Src/NIH 3T3）中诱导细胞凋亡的能力更强。最后，在裸鼠肿瘤异种移植模型中，葫芦素Q而非葫芦素A可抑制肿瘤生长，这表明抑制JAK2不足以抑制肿瘤生长，并提示葫芦素Q抑制肿瘤生长的能力与其抗STAT3活性有关。这些研究进一步验证了STAT3作为药物研发靶点的地位，并提供了证据表明能够选择性降低人癌细胞中P-STAT3水平的药物可导致肿瘤细胞凋亡和生长抑制。
