Caffeic acid, a dietary polyphenol, pre-sensitizes pancreatic ductal adenocarcinoma to chemotherapeutic drug

Resistance to chemotherapeutics is an eminent cause that leads to search for options that help in diminution of pancreatic ductal adenocarcinoma (PDAC) by overcoming resistance issues. Caffeic acid (CFA), a polyphenol occurring in many dietary foods, is known to show antidiabetic and anticancer properties potential. To unveil the effect of CFA on PDAC, we carried out this research in PDAC cells, following which we checked the combination effect of CFA and chemotherapeutics and pre-sensitization effects of CFA. Multitudinous web-based approaches were applied for identifying CFA targets in PDAC and then getting their interconnections. Subsequently, we manifested CFA effects by <i>in-vitro</i> analysis showing IC₅₀ concentrations of 37.37 and 15.06 µM on Panc-1 and Mia-PaCa-2, respectively. The combination index of CFA with different drugs was explored which showed the antagonistic effects of combination treatment leading to further investigation of the pre-sensitizing effects. CFA pre-sensitization reduced IC₅₀ concentration of doxorubicin in both PDAC cell lines which also triggered ROS generation determined by 2′,7′-dichlorofluorescin diacetate assay. The differential gene expression analysis after CFA treatment showed discrete genes affected in both cells, i.e. N-Cad and Cas9 in Panc-1 and Pi3K/AkT/mTOR along with p53 in Mia-PaCa-2. Collectively, this study investigated the role of CFA as PDAC therapeutics and explored the mechanism in mitigating resistance of PDAC by sensitizing to chemotherapeutics.

化疗耐药是促使研究者探索通过克服耐药难题以改善胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）治疗策略的关键诱因。咖啡酸（Caffeic acid, CFA）是一种广泛存在于多种膳食食物中的多酚类物质，被证实具备潜在的抗糖尿病与抗肿瘤活性。为揭示咖啡酸对胰腺导管腺癌的作用效果，本研究以胰腺导管腺癌细胞为模型展开实验，先后考察了咖啡酸与化疗药物的联合用药效应，以及咖啡酸的肿瘤细胞预致敏作用。本研究采用多种网络生物学分析方法，筛选出咖啡酸在胰腺导管腺癌细胞中的作用靶点，并解析其相互作用调控网络。随后通过体外（in vitro）实验验证了咖啡酸的抗肿瘤效果：在Panc-1与Mia-PaCa-2两种胰腺导管腺癌细胞系中，咖啡酸的半最大效应浓度（IC₅₀）分别为37.37 μM与15.06 μM。本研究进一步考察了咖啡酸与多种化疗药物的联合指数，结果显示二者联合用药呈现拮抗效应，因此转而深入探究咖啡酸的预致敏作用。咖啡酸预致敏处理可降低两种胰腺导管腺癌细胞系对阿霉素的IC₅₀值，同时还可通过2′,7′-二氯荧光素二乙酸酯（DCFH-DA）实验检测到活性氧（Reactive Oxygen Species, ROS）生成量的升高。咖啡酸处理后的差异基因表达分析显示，两种细胞系受调控的基因存在显著差异：Panc-1细胞系中受影响的基因为N-Cad与Cas9，而Mia-PaCa-2细胞系中则为PI3K/AKT/mTOR信号通路相关基因及p53基因。综上，本研究探究了咖啡酸作为胰腺导管腺癌治疗候选药物的潜力，并阐明了其通过致敏胰腺导管腺癌细胞以增强化疗敏感性、逆转耐药的分子机制。