Minnelide, a prodrug, inhibits cervical cancer growth by blocking HPV-induced changes in p53 and pRb.
Minnelide, a prodrug, inhibits cervical cancer growth by blocking HPV-induced changes in p53 and pRb.
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发表时间：
2021
影响因子：
5.3
通讯作者：
V. Ramakrishnan;C. de Haydu;P. Wilkinson;Urvashi Hooda;Bhuwan Giri;J. Oleas;Veronica Rive;Sabita Roy;V. Dudeja;Brian Slomovitch;A. Saluja;S. Ramakrishnan
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作者：
V. Ramakrishnan;C. de Haydu;P. Wilkinson;Urvashi Hooda;Bhuwan Giri;J. Oleas;Veronica Rive;Sabita Roy;V. Dudeja;Brian Slomovitch;A. Saluja;S. Ramakrishnan
HPV引起的宫颈癌是世界范围内最常见的妇科恶性肿瘤之一。在本研究中，我们确定了Minnelide的功效，Minnelide是一种前药，可在体内转化为其活性形式（雷公藤内酯醇）对抗宫颈癌细胞。我们的研究表明，雷公藤甲素抑制HPV-16和HPV-18阳性细胞在纳摩尔浓度。雷公藤内酯醇处理的肿瘤细胞不能以浓度依赖的方式在3-D培养中生长。雷公藤内酯醇显著降低E6和E7转录水平。进一步的研究表明，接触雷公藤甲素增加了p53和pRb的水平。雷公藤内酯醇可诱导宫颈癌细胞Caspase-3/7活化和凋亡。随后，我们评估了Minnelide在宫颈癌异种移植模型中的疗效。Minnelide在非常低的剂量下有效地抑制了所有三种测试动物模型中已建立的宫颈癌的生长。此外，Minnelide治疗更有效时，与铂为基础的化疗。这些研究表明，Minnelide可用于抑制宫颈癌的生长。
HPV-induced cervical cancer is one of the prevalent gynecological cancers world-wide. In the present study, we determined the efficacy of Minnelide, a prodrug which is converted to its active form (Triptolide) in vivo against cervical cancer cells. Our studies show that Triptolide inhibited HPV-16 and HPV-18 positive cells at nanomolar concentrations. Tumor cells treated with Triptolide failed to grow in 3-D cultures in a concentration-dependent manner. Triptolide markedly reduced E6 and E7 transcript levels. Further studies revealed that exposure to Triptolide increased the levels of p53 and pRb. As a consequence, Caspase-3/7 activation and apoptosis was induced in cervical cancer cells by Triptolide. Subsequently, we evaluated the efficacy of Minnelide in xenotransplantation models of cervical cancer. Minnelide at very low doses effectively inhibited the growth of established cervical cancers in all the three animal models tested. Furthermore, Minnelide treatment was more effective when combined with platinum-based chemotherapy. These studies show that Minnelide can be used to inhibit the growth of cervical cancer.