Jiaqiang Ren, Tong Su, Jiachun Ding, Fan Chen, Jiantao Mo, Jie Li, Zheng Wang, Liang Han, Zheng Wu, Shuai Wu
{"title":"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","authors":"Jiaqiang Ren, Tong Su, Jiachun Ding, Fan Chen, Jiantao Mo, Jie Li, Zheng Wang, Liang Han, Zheng Wu, Shuai Wu","doi":"10.1186/s10020-025-01180-y","DOIUrl":null,"url":null,"abstract":"<p><p>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 Cu<sup>2+</sup>, 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.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"126"},"PeriodicalIF":6.0000,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969790/pdf/","citationCount":"0","resultStr":"{\"title\":\"Chlorophyllin exerts synergistic anti-tumor effect with gemcitabine in pancreatic cancer by inducing cuproptosis.\",\"authors\":\"Jiaqiang Ren, Tong Su, Jiachun Ding, Fan Chen, Jiantao Mo, Jie Li, Zheng Wang, Liang Han, Zheng Wu, Shuai Wu\",\"doi\":\"10.1186/s10020-025-01180-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 Cu<sup>2+</sup>, 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.</p>\",\"PeriodicalId\":18813,\"journal\":{\"name\":\"Molecular Medicine\",\"volume\":\"31 1\",\"pages\":\"126\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2025-04-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969790/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s10020-025-01180-y\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s10020-025-01180-y","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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.
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.