叶绿素与吉西他滨通过诱导杯突酶对胰腺癌产生协同抗肿瘤作用

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jiaqiang Ren, Tong Su, Jiachun Ding, Fan Chen, Jiantao Mo, Jie Li, Zheng Wang, Liang Han, Zheng Wu, Shuai Wu
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引用次数: 0

摘要

胰腺癌(PC)由于多种原因具有高致死率,其对吉西他滨(GEM)等常规化疗的有限反应是不可忽视的。因此,本研究引入叶绿素(CHL)作为提高GEM治疗效果的有效候选药物。我们的研究结果表明,CHL和GEM联合使用可靶向PC中的多种致癌过程,包括抑制细胞增殖、侵袭和迁移,以及诱导细胞凋亡,具有显著的协同抗肿瘤作用。进一步的机制研究表明,CHL通过一个多方面的过程诱导PC细胞铜变性,包括消耗细胞内谷胱甘肽(GSH),增加活性氧(ROS)水平,随后上调HSP70蛋白以应对氧化应激升高。此外,CHL释放游离Cu2+,与铁氧还蛋白1 (FDX1)蛋白结合,最终导致二氢脂酰胺s -乙酰转移酶(DLAT)蛋白寡聚化,从而放大PC细胞内的铜毒性。此外,体内实验表明,CHL和GEM联合使用可有效抑制皮下移植肿瘤的生长,同时保持良好的生物安全性。综上所述,我们的研究发现CHL通过诱导铜体增生而有效增强GEM在PC中的抗肿瘤作用,从而为PC患者提供了一种新的治疗途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Chlorophyllin exerts synergistic anti-tumor effect with gemcitabine in pancreatic cancer by inducing cuproptosis.

Pancreatic cancer (PC) has high lethality due to multiple reasons, and its limited response to conventional chemotherapy like gemcitabine (GEM) is a non-negligible one. Therefore, our study introduces Chlorophyllin (CHL) as an effective therapeutic candidate to enhance the therapeutic efficacy of GEM. Our results demonstrate that the combination of CHL and GEM exhibits a significant synergistic anti-tumor effect by targeting multiple oncogenic processes in PC, including inhibiting cell proliferation, invasion, and migration, as well as inducing cell apoptosis. Further investigations of mechanism have revealed that CHL induces cuproptosis in PC cells through a multifaceted process, involving depleting cellular intracellular glutathione (GSH), increasing reactive oxygen species (ROS) levels, and subsequently upregulating the HSP70 protein in response to heightened oxidative stress. Additionally, CHL releases free Cu2+, binds to the Ferredoxin 1 (FDX1) protein, and ultimately leads to the oligomerization of Dihydrolipoamide S-Acetyltransferase (DLAT) proteins to amplify the copper toxicity within PC cells. Moreover, in vivo experiments have demonstrated that the combination of CHL and GEM effectively inhibits the growth of subcutaneously transplanted tumors while maintaining a favorable biosafety profile. In conclusion, our study identifies CHL as a potent enhancer of GEM's anti-tumor effects in PC through the induction of cuproptosis, thus providing a novel therapeutic avenue for patients with PC.

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来源期刊
Molecular Medicine
Molecular Medicine 医学-生化与分子生物学
CiteScore
8.60
自引率
0.00%
发文量
137
审稿时长
1 months
期刊介绍: Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.
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