Demethylzeylasteral (ZST93) inhibits cell growth and enhances cell chemosensitivity to gemcitabine in human pancreatic cancer cells via apoptotic and autophagic pathways
Demethylzeylasteral (ZST93) inhibits cell growth and enhances cell chemosensitivity to gemcitabine in human pancreatic cancer cells via apoptotic and autophagic pathways
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Demethylzeylasteral (ZST93) 通过细胞凋亡和自噬途径抑制人胰腺癌细胞的细胞生长并增强细胞对吉西他滨的化学敏感性。
DOI：
10.1002/ijc.31211
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发表时间：
2018-05-01
影响因子：
6.4
通讯作者：
Yang, Yinmo
中科院分区：
文献类型：
--
作者：
Wang, Feng;Tian, Xiaodong;Yang, Yinmo
由于胰腺癌的侵袭性生长、早期转移和对常规放化疗的抵抗，其患者的总体5年生存率仍低于8%。因此，开发新的有效的治疗药物以改善其预后至关重要。ZST 93是从雷公藤属植物根的木质部中提取的一种新的三萜类单体。我们的研究旨在评估ZST 93对人胰腺癌细胞增殖的影响及其在吉西他滨化疗敏感性中的作用。在各种人胰腺癌细胞系中评价ZST 93对癌细胞增殖、细胞周期分布、凋亡和自噬的作用，并且在异种移植小鼠模型中鉴定ZST 93单独和与吉西他滨组合的抗肿瘤作用。结果表明，ZST 93可通过调控Cyclin D1和Cyclin A2的表达，抑制胰腺癌细胞的增殖，使细胞周期阻滞于G 0/G1期。此外，ZST 93通过两种不同的机制杀死胰腺癌细胞：在低浓度下诱导自噬性细胞死亡和在高浓度下诱导凋亡性细胞死亡。此外，ZST 93可以通过调节自噬和凋亡之间的串扰来增强胰腺癌细胞在体外和体内对吉西他滨的化疗敏感性。ZST 93是一种潜在的治疗药物，可用于开发人类胰腺癌的新治疗策略。胰腺癌是一种侵袭性疾病，以早期转移、放化疗抵抗和低生存率为特征。此外，对现有化疗剂的反应率很差，需要开发新的疗法。在这项研究中，demethylzeylasteral（ZST 93），从植物雷公藤中分离的化合物，研究其对人胰腺癌细胞系和小鼠异种移植瘤的影响。在体外和体内，ZST 93抑制癌细胞增殖并增加对吉西他滨的敏感性。人胰腺癌细胞中增强的吉西他滨化疗敏感性与过度ZST 93诱导的自噬或凋亡细胞死亡相关。
The overall 5-year survival rate of patients with human pancreatic cancer remains less than 8% because of its aggressive growth, early metastasis and resistance to conventional chemoradiotherapy. It is essential to develop innovative and effective therapeutic agents to improve its prognosis. Demethylzeylasteral (ZST93) is a novel triterpenoid monomer extracted from the xylem of Tripterygium roots. Our study aimed to assess the effects of ZST93 on cell proliferation and its role in the chemosensitivity to gemcitabine in human pancreatic cancer cells. The effects of ZST93 on cancer cell proliferation, cell cycle distribution, apoptosis and autophagy were evaluated in various human pancreatic cancer cell lines, and the antitumor effects of ZST93 alone and in combination with gemcitabine were identified in a xenograft mouse model. The results showed that ZST93 could inhibit the proliferation of pancreatic cancer cells and arrest cell cycle at G0/G1 phase by regulating the expression of Cyclin D1 and Cyclin A2. Moreover, ZST93 killed pancreatic cancer cells through two different mechanisms: inducing autophagic cell death at low concentrations and apoptotic cell death at high concentrations. Furthermore, ZST93 could enhance the chemosensitivity of pancreatic cancer cells to gemcitabine both in vitro and in vivo through modulation of the cross talk between autophagy and apoptosis. ZST93 is a potential therapeutic agent for developing novel therapeutic strategies in human pancreatic cancer.What's new?Pancreatic cancer is an aggressive disease, marked by early metastasis, resistance to chemoradiotherapy, and low survival rates. Moreover, response rates to existing chemotherapeutic agents are poor, necessitating the development of new therapies. In this study, demethylzeylasteral (ZST93), a compound isolated from the plant Tripterygium wilfordii, was investigated for its effects on human pancreatic cancer cell lines and xenograft tumors in mice. Both in vitro and in vivo, ZST93 inhibited cancer cell proliferation and increased sensitivity to gemcitabine. Enhanced gemcitabine chemosensitivity in human pancreatic cancer cells was associated with excessive ZST93-induced autophagic or apoptotic cell death.