Cucurbitacin I

Cucurbitacin I is a selective Janus Kinase (JAK)/STAT3 signaling pathway inhibitor with an IC₅₀ value of 500nM in A549 ^[1]. A variety of cancers exhibit an aberrant activation of STAT3, which plays a pivotal role in malignant transformation and tumor cell survival. Cucurbitacin I can inhibit STAT3 expression, therefore it has a potent anticancer effect in a number of cancer cell lines and in vivo tumor models ^[2].

In vitro, 10μM Cucurbitacin I suppressed the levels of phosphotyrosine STAT3 in v-Src-transformed NIH3T3 cells and human cancer cells potently ^[1]. 100nM Cucurbitacin I treatment reduced COLO205 colon cancer cell proliferation, migration and invasion ^[2]. 100nM Cucurbitacin I sensitized the colon cancer cell line COLO205 to 5-FU treatment and decreased MMP-9 expression and phosphorylated STAT3 protein levels ^[2]. Treatment with 100nM Cucurbitacin I inhibited the growth of U251 and T98G cells with an IC₅₀ value of 170nM and 245nM, respectively ^[3]. 200nM Cucurbitacin I for 48h triggered autophagy and activated the autophagy-related gene Beclin 1 in GBM Cells ^[3]. 1μM Cucurbitacin I can prevent hypertrophic responses in PE-stimulated cardiomyocytes ^[4]. Cucurbitacin I significantly inhibited the cell viability and proliferation and prevented the tube formation of MDA-MB-468 in a dose-dependent manner from 0.2μmol/L to 1μmol/L ^[5].

In vivo, Cucurbitacin I (1mg/kg/d) potently inhibited the growth in nude mice of A549 tumors, v-Src-transformed NIH3T3 tumors, and the human breast carcinoma MDA-MB-468 and significantly increased survival of immunologically competent mice bearing murine melanoma with constitutively activated STAT3 ^[1]. Intraperitoneal administration of Cucurbitacin I (1mg/kg/d) for 18 days resulted in massive apoptotic cell death, and markedly inhibited tumor volume and tumor weight in mice with xenografted glioma cells ^[4].

References:
[1] Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM. Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res. 2003;63(6):1270-1279.
[2] Song J, Liu H, Li Z, Yang C, Wang C. Cucurbitacin I inhibits cell migration and invasion and enhances chemosensitivity in colon cancer. Oncol Rep. 2015;33(4):1867-1871. 
[3] Yuan G, Yan SF, Xue H, Zhang P, Sun JT, Li G. Cucurbitacin I induces protective autophagy in glioblastoma in vitro and in vivo. J Biol Chem. 2014;289(15):10607-10619.
[4] Jeong MH, Kim SJ, Kang H, et al. Cucurbitacin I Attenuates Cardiomyocyte Hypertrophy via Inhibition of Connective Tissue Growth Factor (CCN2) and TGF- β/Smads Signalings. PLoS One. 2015;10(8): e0136236.
[5] Qi J, Xia G, Huang CR, Wang JX, Zhang J. JSI-124 (Cucurbitacin I) inhibits tumor angiogenesis of human breast cancer through reduction of STAT3 phosphorylation. Am J Chin Med. 2015;43(2):337-347.

Cucurbitacin I是一种选择性的Janus激酶（JAK）/STAT3信号通路抑制剂，在A549细胞中的IC₅₀值为500nM ^[1]。多种癌症表现出STAT3的异常激活，而STAT3在恶性转化和肿瘤细胞存活中起着关键作用。Cucurbitacin I能够抑制STAT3的表达，因此在多种癌细胞系和体内肿瘤模型中具有强大的抗癌效果^[2]。

在体外，10μM的Cucurbitacin I能有效抑制v-Src转化后的NIH3T3细胞和人类癌细胞中磷酸化酪氨酸STAT3的水平^[1]。100nM的Cucurbitacin I处理能降低结肠癌细胞（COLO205）的增殖、迁移和侵袭能力，增强其对5-FU治疗的敏感性，并降低胞内MMP-9的表达和磷酸化STAT3的蛋白水平^[2]。100nM的Cucurbitacin I可以抑制U251和T98细胞的生长，IC₅₀值分别为170nM和245nM^[3]。200nM的Cucurbitacin I处理48小时后会触发GBM细胞的自噬，并激活与自噬相关的基因Beclin 1^[3]。1μM的Cucurbitacin I能抑制PE刺激后心肌细胞的肥大反应^[4]。Cucurbitacin I显著抑制细胞的存活和增殖，并以剂量依赖的方式（从0.2μmol/L到1μmol/L）抑制MDA-MB-468细胞管状结构生成^[5]。

在体内，Cucurbitacin I（1mg/kg/天）显著抑制了移植A549或v-Src转化的NIH3T3或MDA-MB-468细胞的裸鼠中肿瘤的生长，并显著提高了携带组成型激活STAT3的黑色素瘤的免疫功能健全小鼠的存活率^[1]。在移植了神经胶质瘤细胞的小鼠中，按照1mg/kg/天的剂量腹腔注射Cucurbitacin I，18天后，小鼠体内细胞大量凋亡，其体内肿瘤体积和肿瘤重量也显著减小^[4]。