Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Department of Pharmacy, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, 230001, China.
Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, 230032, China.
Phytomedicine. 2023 Oct;119:155004. doi: 10.1016/j.phymed.2023.155004. Epub 2023 Aug 3.
As a malignant digestive system tumor, pancreatic cancer has a high mortality rate. Xanthatin is a sesquiterpene lactone monomer compound purified from the traditional Chinese herb Xanthium strumarium L. It has been reported that Xanthatin exhibits inhibitory effects on various cancer cells in retinoblastoma, glioma, hepatoma, colon cancer, lung cancer, as well as breast cancer. However, in pancreatic cancer cells, only one report exists on the suppression of Prostaglandin E2 synthesis and the induction of caspase 3/7 activation in Xanthatin-treated MIA PaCa-2 cells, while systematic in vitro and in vivo investigations and related mechanisms have yet to be explored.
This research aims to explore the in vitro and in vivo effects of Xanthatin on pancreatic cancer and its molecular mechanisms.
The anticancer effects and mechanisms of Xanthatin on pancreatic cancer cells were assessed through employing cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay, carboxyfluorescein diacetate succinimidyl ester (CFDA SE) cell proliferation assay, colony formation assay, wound healing assay, transwell assay, Annexin V-FITC/propidium iodide (PI) dual staining, Hoechst nuclear staining, Western blot analysis, phosphoproteomics, and reactive oxygen species (ROS) measurement. The in vivo anticancer effects of Xanthatin on pancreatic cancer cells were studied using a nude mouse model.
The present study showed that Xanthatin can prevent the proliferation and metastasis of pancreatic cancer cells and trigger the exposure of phosphatidylserine (PS), chromatin condensation, and caspase activation, thereby inducing apoptosis. Phosphoproteomic analysis indicated that Xanthatin inhibits the phosphorylation of the proliferation-associated protein RBL1, and oxidative stress can lead to RBL1 dephosphorylation. Further investigation revealed that Xanthatin significantly upregulates ROS levels in pancreatic cancer cells, and the antioxidant N-acetylcysteine (NAC) can reverse Xanthatin-induced cell proliferation inhibition and apoptosis. In addition, Xanthatin can suppress pancreatic cancer cell growth in a xenograft nude mouse model with low toxicity to the mice.
Xanthatin may inhibit the proliferation of pancreatic cancer cells and trigger apoptosis through the ROS/RBL1 signaling pathway.
胰腺癌是一种恶性消化系统肿瘤，死亡率较高。Xanthatin 是从传统中药苍耳中提取的一种倍半萜内酯单体化合物。已有报道称，Xanthatin 对视网膜母细胞瘤、神经胶质瘤、肝癌、结肠癌、肺癌和乳腺癌等多种癌细胞具有抑制作用。然而，在胰腺癌细胞中，仅有一份关于 Xanthatin 抑制前列腺素 E2 合成和诱导 Xanthatin 处理的 MIA PaCa-2 细胞中 caspase 3/7 激活的报告，而系统的体外和体内研究及相关机制尚未得到探索。
本研究旨在探讨 Xanthatin 对胰腺癌的体外和体内作用及其分子机制。
通过使用细胞计数试剂盒-8（CCK-8）测定法、乳酸脱氢酶（LDH）测定法、羧基荧光素二乙酸琥珀酰亚胺酯（CFDA SE）细胞增殖测定法、集落形成测定法、划痕愈合测定法、Transwell 测定法、Annexin V-FITC/碘化丙啶（PI）双重染色法、Hoechst 核染色法、Western blot 分析、磷酸化蛋白质组学和活性氧（ROS）测量来评估 Xanthatin 对胰腺癌细胞的抗癌作用和机制。使用裸鼠模型研究了 Xanthatin 对胰腺癌细胞的体内抗癌作用。
本研究表明，Xanthatin 可阻止胰腺癌细胞的增殖和转移，并引发磷脂酰丝氨酸（PS）暴露、染色质浓缩和半胱天冬酶激活，从而诱导细胞凋亡。磷酸化蛋白质组学分析表明，Xanthatin 抑制与增殖相关的蛋白 RBL1 的磷酸化，氧化应激可导致 RBL1 去磷酸化。进一步的研究表明，Xanthatin 可显著增加胰腺癌细胞中的 ROS 水平，抗氧化剂 N-乙酰半胱氨酸（NAC）可逆转 Xanthatin 诱导的细胞增殖抑制和细胞凋亡。此外，Xanthatin 可抑制裸鼠异种移植模型中胰腺癌细胞的生长，且对小鼠的毒性较低。
Xanthatin 可能通过 ROS/RBL1 信号通路抑制胰腺癌细胞的增殖并触发细胞凋亡。
