Background
Cucurbitacin I is a selective inhibitor of JAK2/STAT3 signaling pathway with an IC50 value of 500 nM in A549 (a human lung?adenocarcinoma?cell?line). It suppressed phosphotyrosine levels of STAT3, restrained STAT3 DNA binding and STAT3-mediated gene expression but had no effects on the activation of Src, Akt, ERK and JNK [1].
JAK/STAT3 signaling is well known for its vital role in the regulation of tumor cell proliferation, survival, invasion and immunosuppression. It promotes the development of various types of cancer in different manners [2].
Cucurbitacin I is often used to investigate the role of STAT3 in tumor development. It can induce apoptosis and block cell cycle progression of various cancer cells. In addition, Cucurbitacin I can decrease cell viability through inhibiting cell migration and invasion and enhancing chemosensitivity in the colon cancer cell line COLO205 [3].
Recent research has showed that it also has anti-angiogenic effects in human breast cancer cells [4]. In vivo, matrigel plug assay showed dramatic decrease in vascularization and hemoglobin content in the plugs from Cucurbitacin-I-treated mice, compared with control mice [5]. Therefore, Cucurbitacin I has potent anticancer effect on a variety of cancer cell types.
However, exposing glioblastoma multiforme cells to Cucurbitacin I could up-regulate beclin1 and trigger a protective autophagy against the apoptosis. Deletion of beclin 1 or treatment with the autophagy inhibitor sensitized cancer cells to Cucurbitacin I-induced apoptosis [6]. Thus the role of Cucurbitacin I in the regulation of autophagy requires for further research.
参考文献:
Blaskovich MA, Sun J, Cantor A et al.? 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 Mar 15;63(6):1270-9.
Yu H, Lee H, Herrmann A et al.?Revisiting STAT3 signalling in cancer: new and unexpected biological functions.Nat Rev Cancer. 2014 Nov;14(11):736-46. doi: 10.1038/nrc3818.
Song J, Liu H, Li Z et al.? Cucurbitacin I inhibits cell migration and invasion and enhances chemosensitivity in colon cancer. Oncol Rep. 2015 Apr;33(4):1867-71.
Qi J, Xia G, Huang CR et al.? JSI-124 (Cucurbitacin I) inhibits tumor angiogenesis of human breast cancer through reduction of STAT3 phosphorylation. Am J Chin Med. 2015;43(2):337-47.
Kim HJ, Kim JK et al.?Antiangiogenic effects of cucurbitacin-I. Arch Pharm Res. 2015 Feb;38(2):290-8.
Yuan G, Yan SF, Xue H et al.? Cucurbitacin I induces protective autophagy in glioblastoma in vitro and in vivo. J Biol Chem. 2014 Apr 11;289(15):10607-19.
Protocol
| Cell experiment [1,2]: |
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Cell lines
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COLO205 colon cancer cell line
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Preparation method
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The solubility of this compound in DMSO is > 22.45 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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100 nM, 6 h
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Applications
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Cucurbitacin I (100 nM, 6 h) inhibited colon cancer cell COLO205 proliferation, migration and invasion in a dose-dependent manner. Cucurbitacin I sensitized the colon cancer cell line COLO205 to 5-FU treatment. Cucurbitacin (100 nM) decreased the protein level of phospho-STAT3 and MMP-9 expression. Cucurbitacin I (10 μM) suppressed phosphotyrosine levels of STAT3 and JAK2 but not Src in A549 and MDA-MB-468 cells. Cucurbitacin I inhibited cell proliferation and induced apoptosis in A549, MDA-MB-468, v-Src/3T3, H-Ras/3T3, vector/3T3, and Calu-1.
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| Animal experiment [2]: |
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Animal models
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Nude mice of A549 tumors, v-Src-transformed NIH 3T3 tumors, and the human breast carcinoma MDA-MB-468; Nude C57 BL-6 mice bearing A549, and MDA-MB-468 cells
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Dosage form
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1 mg/kg/day, 25 days
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Application
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Cucurbitacin I (1 mg/kg/day) potently inhibited the growth in nude mice of A549 tumors, v-Src-transformed NIH 3T3 tumors, and the human breast carcinoma MDA-MB-468. Cucurbitacin I inhibited tumor growth and significantly increased survival of immunologically competent mice bearing murine melanoma with constitutively activated STAT3. Cucurbitacin I inhibited A549 and MDA-MB-468 tumor growth with no effects on body weight, activity, or food intake.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1]. Song J, Liu H, Li Z, et al. Cucurbitacin I inhibits cell migration and invasion and enhances chemosensitivity in colon cancer[J]. Oncology reports, 2015, 33(4): 1867-1871.
[2]. Blaskovich M A, Sun J, Cantor A, et al. 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[J]. Cancer research, 2003, 63(6): 1270-1279.
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