School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, PR China.
Institute of Pharmaceutical Sciences, University of Veterinary & Animal Sciences, Lahore, Pakistan.
J Pharm Pharmacol. 2023 Oct 5;75(10):1294-1309. doi: 10.1093/jpp/rgad055.
Pancreatic cancer (PC) is a very lethal malignancy with a scarcity of treatment options. Although erlotinib- and gemcitabine-based treatments have been approved for PC, their effectiveness is limited. The present study is aimed at exploring the molecular and epigenetic mechanisms of anticancer activities of homoharringtonine (HHT) and its interaction with erlotinib to develop a potential therapeutic strategy for PC.
The RT-qPCR, western blotting, immunofluorescence and expression-vectors and oligonucleotide transfection were employed to determine the expression characteristics of onco-factors. Anticancer activities were determined by MTT, colony forming, and flowcytometric analysis. Dual luciferase assay was conducted to confirm putative target of miR-130b-3p. In-vivo experiments were followed by immunohistochemical assay.
The EphB4/JAK2/STAT3 pathway drives the growth and proliferation of PC through induction of prosurvival factors and cell cycle mediators. HHT directly and epigenetically via miR-130b-3p targets EphB4, leading to downregulation of JAK2/STAT3 pathway. The inactivation of STAT3 results in diminution of antiapoptotic factors and cell cycle mediators. HHT also enhances the anticancer activity of erlotinib.
HHT demonstrates potential anticancer activities in PC by downregulating EphB4/JAK2/STAT3 signalling. HHT also produces synergistic effects with erlotinib.
胰腺癌（PC）是一种非常致命的恶性肿瘤，治疗选择有限。尽管厄洛替尼和吉西他滨为基础的治疗已被批准用于 PC，但它们的疗效有限。本研究旨在探讨高三尖杉酯碱（HHT）的抗癌活性及其与厄洛替尼相互作用的分子和表观遗传机制，为 PC 开发潜在的治疗策略。
采用 RT-qPCR、western blot、免疫荧光和表达载体及寡核苷酸转染技术，确定癌基因因子的表达特征。采用 MTT、集落形成和流式细胞术分析测定抗癌活性。双荧光素酶报告实验证实miR-130b-3p 的潜在靶标。进行体内实验后，采用免疫组织化学法进行检测。
EphB4/JAK2/STAT3 通路通过诱导生存因子和细胞周期调节剂驱动 PC 的生长和增殖。HHT 通过 miR-130b-3p 直接和表观遗传靶向 EphB4，导致 JAK2/STAT3 通路下调。STAT3 的失活导致抗凋亡因子和细胞周期调节剂减少。HHT 还增强了厄洛替尼的抗癌活性。
HHT 通过下调 EphB4/JAK2/STAT3 信号通路在 PC 中表现出潜在的抗癌活性。HHT 还与厄洛替尼产生协同作用。
