尽管癌症治疗取得了进展，但由于缺乏有效的治疗方法，胰腺导管腺癌（PDAC）仍然具有高度致命性。我们之前的研究表明，木犀草素 (Lut) 是一种黄酮类化合物，可抑制胰腺癌的发生，并减少 PDAC 中二氢嘧啶脱氢酶 (DPYD) 的表达，DPYD 是一种降解嘧啶如 5-氟尿嘧啶 (5-FU) 的酶。在本研究中，我们研究了 DPYD 的作用，并评估了 5-FU 与 Lut 组合在 PDAC 中的治疗潜力。过表达 DPYD 的 PDAC 细胞显示出增殖和侵袭性增加，增加了对 5-FU 的耐药性。与对照异种移植肿瘤相比，DPYD 过表达 PDAC 细胞的异种移植肿瘤也表现出增强的生长和侵袭。对 DPYD 过表达的 PDAC 异种移植肿瘤的 RNA-seq 分析揭示了与金属肽酶活性相关的基因 MMP9 和 MEP1A 的上调。此外，PDAC 中 MEP1A 的过度表达与侵袭相关。接下来，我们研究了 DPYD 抑制剂 Lut 和 5-FU 对 DPYD 过表达异种移植肿瘤和 Pdx1-Cre 的 PDAC 的联合影响； LSL-KrasG12D/； Trp53flox/flox(KPPC) 小鼠。单独施用 5-FU 和 Lut 均未显示出显着的抑制作用；然而，5-FU 和 Lut 的联合给药在异种移植肿瘤和 KPPC 模型中均表现出显着的肿瘤抑制作用。我们已经阐明，DPYD 表达有助于 PDAC 的增殖、侵袭性和 5-FU 耐药性。 Lut 和 5-FU 的联合疗法具有增强对抗 PDAC 疗效的潜力。© 2024 作者。约翰·威利出版的癌症医学

Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5-fluorouracil (5-FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5-FU with Lut in PDACs.PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5-FU. The xenograft tumors of DPYD-overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA-seq analysis of the DPYD-overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity-MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5-FU on DPYD-overexpressing xenograft tumors and PDAC of Pdx1-Cre; LSL-KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5-FU nor Lut showed significant inhibitory effects; however, the combined administration of 5-FU and Lut exhibited a significant tumor-suppressive effect in both the xenograft tumors and KPPC models.We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5-FU resistance, in PDACs. The combination therapy of Lut and 5-FU holds the potential for enhanced efficacy against PDACs.© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.