Aronia Berry Extract Modulates MYD88/NF-kB/P-Glycoprotein Axis to Overcome Gemcitabine Resistance in Pancreatic Cancer

Pharmaceuticals Pub Date : 2024-07-09 DOI:10.3390/ph17070911
Yuan Li, Caiming Xu, Haiyong Han, Silvia Pascual-Sabater, C. Fillat, A. Goel
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor survival rates, primarily due to the limited effectiveness of gemcitabine (Gem)-based chemotherapy, as well as the acquisition of chemotherapeutic resistance. Aronia berry extracts (ABEs), abundant in phenolic constituents, have been recently recognized for their anticancer properties as well as their encouraging potential to help overcome chemoresistance in various cancers. In the present study, we explored ABE’s potential to overcome Gem resistance in PDAC and identify specific growth regulatory pathways responsible for its anticancer activity. Through a series of in vitro experiments in gemcitabine-resistant (Gem-R) cells, we elucidated the synergistic interactions between Gem and ABE treatments. Using advanced transcriptomic analysis and network pharmacology, we revealed key molecular pathways linked to chemoresistance and potential therapeutic targets of ABE in Gem-R PDAC cells. Subsequently, the findings from cell culture studies were validated in patient-derived 3D tumor organoids (PDOs). The combination treatment of ABE and Gem demonstrated significant synergism and anticancer effects on cell viability, proliferation, migration, and invasion in Gem-R cells. Transcriptomic analysis revealed a correlation between the NF-Κb signaling pathway and Gem-R (p < 0.05), exhibiting a marked upregulation of MYD88. Additionally, MYD88 exhibited a significant correlation with the overall survival rates in patients with PDAC patients in the TCGA cohort (HR = 1.58, p < 0.05). The MYD88/NF-Κb pathway contributes to chemoresistance by potentially upregulating efflux transporters like P-glycoprotein (P-gp). Our findings revealed that the combined treatment with ABE suppressed the NF-Κb pathway by targeting MYD88 and reducing P-gp expression to overcome Gem resistance. Lastly, the combination therapy proved highly effective in PDOs in reducing both their number and size (p < 0.05). Our study offers previously unrecognized insights into the ability of ABE to overcome Gem resistance in PDAC cells through its targeting of the MYD88/NF-κb/P-gp axis, hence providing a safe and cost-effective adjunctive therapeutic strategy to improve treatment outcomes in PDAC.
欧龙眼浆果提取物调节 MYD88/NF-kB/P 糖蛋白轴,克服胰腺癌患者对吉西他滨的耐药性
胰腺导管腺癌(PDAC)是一种致死率很高的疾病,存活率很低,主要原因是以吉西他滨(Gem)为基础的化疗效果有限,而且会产生化疗耐药性。阿罗尼亚浆果提取物(ABE)含有丰富的酚类成分,其抗癌特性以及帮助克服各种癌症的化疗耐药性的潜力最近已得到认可。在本研究中,我们探索了 ABE 克服 PDAC 中 Gem 抗性的潜力,并确定了其抗癌活性的特定生长调节途径。通过在吉西他滨耐药(Gem-R)细胞中进行一系列体外实验,我们阐明了 Gem 和 ABE 治疗之间的协同作用。利用先进的转录组学分析和网络药理学,我们揭示了 Gem-R PDAC 细胞中与化疗耐药性相关的关键分子通路以及 ABE 的潜在治疗靶点。随后,细胞培养研究的结果在患者衍生的三维肿瘤器官组织(PDOs)中得到了验证。ABE 和 Gem 的联合治疗对 Gem-R 细胞的细胞活力、增殖、迁移和侵袭具有显著的协同和抗癌作用。转录组分析表明,NF-Κb 信号通路与 Gem-R 之间存在相关性(p < 0.05),显示出 MYD88 的明显上调。此外,MYD88与TCGA队列中PDAC患者的总生存率有显著相关性(HR = 1.58,p < 0.05)。MYD88/NF-Κb通路可能通过上调P-糖蛋白(P-gp)等外流转运体而导致化疗耐药性。我们的研究结果表明,ABE联合疗法通过靶向MYD88和减少P-gp表达,抑制了NF-Κb通路,从而克服了Gem耐药性。最后,联合疗法对减少 PDOs 的数量和大小非常有效(p < 0.05)。我们的研究提供了以前未曾认识到的ABE通过靶向MYD88/NF-κb/P-gp轴克服PDAC细胞Gem耐药性的能力,从而提供了一种安全、经济有效的辅助治疗策略,改善了PDAC的治疗效果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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