A novel DDIT3 activator dehydroevodiamine effectively inhibits tumor growth and tumor cell stemness in pancreatic cancer,Phytomedicine

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A novel DDIT3 activator dehydroevodiamine effectively inhibits tumor growth and tumor cell stemness in pancreatic cancer
Phytomedicine ( IF 6.7 ) Pub Date : 2024-01-19 , DOI: 10.1016/j.phymed.2024.155377
Su-Li Zhu ₁ , Ming Qi ₂ , Mei-Ting Chen ₃ , Jia-Peng Lin ₂ , Hai-Fu Huang ₄ , Li-Juan Deng ₅ , Xing-Wang Zhou ₁

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The existence of pancreatic cancer stem cells (PCSCs) results in limited survival benefits from current treatment options. There is a scarcity of effective agents for treating pancreatic cancer patients. Dehydroevodiamine (DeHE), a quinazoline alkaloid isolated from the traditional Chinese herb , exhibited potent inhibition of pancreatic ductal adenocarcinoma (PDAC) cell proliferation and tumor growth both . The cytotoxic effect of DeHE on PDAC cells was assessed using CCK-8 and colony formation assays. The antitumor efficacy of DeHE were appraised in human PANC-1 xenograft mouse model. Sphere formation assay and flow cytometry were employed to quantify the tumor stemness. RNA‐Seq analysis, drug affinity responsive target stability assay (DARTS), and RNA interference transfection were conducted to elucidate potential signaling pathways. Western blotting and immunohistochemistry were utilized to assess protein expression levels. DeHE effectively inhibited PDAC cell proliferation and tumor growth , and exhibited a better safety profile compared to the clinical drug gemcitabine (GEM). DeHE inhibited PCSCs, as evidenced by its suppression of self-renewal capabilities of PCSCs, reduced the proportion of ALDH cells and downregulated stemness-associated proteins (Nanog, Sox-2, and Oct-4) both and . Furthermore, there is potential involvement of DDIT3 and its downstream DDIT3/TRIB3/AKT/mTOR pathway in the suppression of stemness characteristics within DeHE-treated PDAC cells. Additionally, results from the DARTS assay indicated that DeHE interacts with DDIT3, safeguarding it against degradation mediated by pronase. Notably, the inhibitory capabilities of DeHE on PDAC cell proliferation and tumor stemness were partially restored by siDDIT3 or the AKT activator SC-79. In summary, our study has identified DeHE, a novel antitumor natural product, as an activator of DDIT3 with the ability to suppress the AKT/mTOR pathway. This pathway is intricately linked to tumor cell proliferation and stemness characteristics in PDAC. These findings suggest that DeHE holds potential as a promising candidate for the development of innovative anticancer therapeutics.

中文翻译：

新型 DDIT3 激活剂脱氢吴茱萸碱可有效抑制胰腺癌中的肿瘤生长和肿瘤细胞干细胞

胰腺癌干细胞（PCSC）的存在导致当前治疗方案的生存获益有限。缺乏治疗胰腺癌患者的有效药物。脱氢吴茱萸碱 (DeHE) 是一种从传统中草药中分离出来的喹唑啉生物碱，对胰腺导管腺癌 (PDAC) 细胞增殖和肿瘤生长具有有效抑制作用。使用 CCK-8 和集落形成测定评估 DeHE 对 PDAC 细胞的细胞毒性作用。 DeHE 的抗肿瘤功效在人 PANC-1 异种移植小鼠模型中进行了评估。采用球体形成测定和流式细胞术来量化肿瘤干性。进行RNA测序分析、药物亲和力响应靶稳定性测定（DARTS）和RNA干扰转染来阐明潜在的信号通路。利用蛋白质印迹和免疫组织化学来评估蛋白质表达水平。 DeHE有效抑制PDAC细胞增殖和肿瘤生长，并且与临床药物吉西他滨（GEM）相比表现出更好的安全性。 DeHE 抑制 PCSC，其对 PCSC 自我更新能力的抑制证明了这一点，降低了 ALDH 细胞的比例并下调了干性相关蛋白（Nanog、Sox-2 和 Oct-4）。此外，DDIT3 及其下游 DDIT3/TRIB3/AKT/mTOR 通路可能参与 DeHE 处理的 PDAC 细胞干性特征的抑制。此外，DARTS 测定的结果表明 DeHE 与 DDIT3 相互作用，保护其免受链霉蛋白酶介导的降解。值得注意的是，SiDDIT3 或 AKT 激活剂 SC-79 部分恢复了 DeHE 对 PDAC 细胞增殖和肿瘤干性的抑制能力。总之，我们的研究确定了 DeHE（一种新型抗肿瘤天然产物）作为 DDIT3 的激活剂，具有抑制 AKT/mTOR 通路的能力。该通路与 PDAC 中的肿瘤细胞增殖和干性特征密切相关。这些发现表明 DeHE 具有作为开发创新抗癌疗法的有希望的候选者的潜力。

更新日期：2024-01-19

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