The combination of cantharidin and antiangiogenic therapeutics presents additive antitumor effects against pancreatic cancer.
The combination of cantharidin and antiangiogenic therapeutics presents additive antitumor effects against pancreatic cancer.
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斑蝥素和抗血管生成疗法的组合对胰腺癌具有额外的抗肿瘤作用
DOI：
10.1038/s41389-018-0102-2
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发表时间：
2018-11-26
期刊：
影响因子：
6.2
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Xu MD;Liu L;Wu MY;Jiang M;Shou LM;Wang WJ;Wu J;Zhang Y;Gong FR;Chen K;Tao M;Zhi Q;Li W
斑蝥素是斑蝥的活性成分之一，被认为具有抗肿瘤活性。斑蝥素选择性抑制蛋白磷酸酶 2A (PP2A)，从而抑制多种致癌激酶（ERK、JNK、PKC 和 NF-κB）。体外研究表明斑蝥素可抑制胰腺癌细胞的细胞活力和转移。本研究旨在探讨斑蝥素对体内胰腺癌异种移植物的影响。使用稳定表达荧光素酶的细胞建立异种移植模型。通过活体成像评估异种移植物的生长。使用微阵列、实时 PCR、RayBiotech 抗体阵列和 Milliplex 测定法测定基因表达。令人惊讶的是，斑蝥素显着加速异种移植物的生长。活体成像显示 D-荧光素在斑蝥素处理的异种移植物中快速分布，表明血液供应丰富。免疫组织化学证实血管生成增加。微阵列和抗体阵列鉴定了上调的促血管生成因子和下调的抗血管生成因子。 Milliplex 测定表明 IL-6、IL-8、TNF-α 和 VEGF 的分泌增加。 ERK、JNK、PKC 和 NF-κB 通路抑制剂可减弱斑蝥素诱导的促血管生成基因表达的变化。 PKC 通路抑制他莫昔芬或抗血管生成治疗药物，包括人参皂苷 Rg3、贝伐珠单抗、阿帕替尼和恩度，可以拮抗斑蝥素或其衍生物的促血管生成作用。这些方案在体内表现出显着的附加抗肿瘤作用。尽管斑蝥素在体外表现出抗肿瘤作用并已应用于临床实践，但我们发现了不利的促血管生成副作用。我们建议斑蝥素的临床应用应以抗血管治疗为前提。
Cantharidin, one of the active components of mylabris, is believed to have antitumor activity. Cantharidin selectively inhibits protein phosphatase 2A (PP2A), which can repress multiple oncogenic kinases (ERK, JNK, PKC, and NF-κB). Researches in vitro have shown that cantharidin suppresses cell viability and metastasis in pancreatic cancer cells. This study aims to investigate the effects of cantharidin on pancreatic cancer xenografts in vivo. Xenograft models were established using cells stably expressing luciferase. Xenograft growth was evaluated by living imaging. Gene expression was determined using a microarray, real-time PCR, a RayBiotech antibody array, and the Milliplex assay. Surprisingly, cantharidin significantly accelerated xenograft growth. Living imaging showed a rapid distribution of D-luciferin in cantharidin-treated xenografts, suggesting a rich blood supply. Immunohistochemistry confirmed increased angiogenesis. Microarray and antibody array identified upregulated proangiogenic and downregulated antiangiogenic factors. The Milliplex assay suggested elevated secretion of IL-6, IL-8, TNF-α, and VEGF. Inhibitors of ERK, JNK, PKC, and NF-κB pathway attenuated the cantharidin-induced changes to proangiogenic gene expression. PKC pathway-inhibiting tamoxifen or antiangiogenic therapeutics, including Ginsenoside Rg3, bevacizumab, Apatinib, and Endostar, antagonized the proangiogenic effect of cantharidin or its derivatives. These regimens presented remarkable additive antitumor effects in vivo. Although cantharidin presents antitumor effects in vitro and has been applied in clinical practice, we revealed an unfavorable proangiogenic side effect. We recommend that the clinical application of cantharidin should be performed on the premise of antivascularization therapy.
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