Human pancreatic tumor cells such as PANC‐1 are known for their ability to tolerate nutrient starvation and thrive under the hypovascular tumor microenvironment, a phenomenon termed as ‘austerity’. A search of agents that preferentially inhibit the cancer cell viability under the starvation condition without toxicity in the nutrient‐rich condition is a promising approach in anticancer drug discovery. In this study, a triterpene lactone, 3β‐hydroxy‐13,28‐epoxyurs‐11‐en‐28‐one (ursenolide), isolated from a Callistemon citrinus extract has shown strong preferential cytotoxicity against PANC‐1 cells under nutrient starvation with PC50 value of 0.4 μm. Ursenolide‐induced rounding of PANC‐1 cell morphology followed by rupture of the cell membrane leading to cell death. In a real‐time cell migration study, ursenolide was found to inhibit PANC‐1 cell migration significantly. Mechanistically, it inhibited GRP78 and GRP94 under the starvation condition suggesting inhibition of unfolded protein response (UPR), an adaptive process of cell survival during starvation. It also inhibited the phosphorylation of the key survival protein Akt and mTOR. Overall results suggested that ursenolide is a potential anticancer agent against pancreatic cancer.

中文翻译：

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Callistemon citrinus 中的三萜内酯通过抑制未折叠蛋白反应来抑制 PANC-1 人胰腺癌细胞的活力

人类胰腺肿瘤细胞（如 PANC-1）以其耐受营养缺乏的能力而闻名，并在低血管肿瘤微环境下茁壮成长，这种现象被称为“紧缩”。寻找在饥饿条件下优先抑制癌细胞活力而在营养丰富的条件下没有毒性的药剂是抗癌药物发现的一种有前途的方法。在这项研究中，从柑橘属植物提取物中分离出的三萜内酯 3β-羟基-13,28-epoxyurs-11-en-28-one（熊果内酯）在 PC50 营养饥饿条件下对 PANC-1 细胞显示出强烈的优先细胞毒性0.4 μm 的值。熊内酯诱导的 PANC-1 细胞形态变圆，随后细胞膜破裂导致细胞死亡。在实时细胞迁移研究中，发现熊果内酯显着抑制 PANC-1 细胞迁移。从机制上讲，它在饥饿条件下抑制 GRP78 和 GRP94，表明抑制未折叠蛋白反应 (UPR)，这是饥饿期间细胞存活的适应性过程。它还抑制了关键存活蛋白 Akt 和 mTOR 的磷酸化。总体结果表明，熊果内酯是一种潜在的胰腺癌抗癌剂。