Mechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-01-21 Epub Date: 2024-12-26 DOI:10.1016/j.xcrm.2024.101881

Ganji Purnachandra Nagaraju, Madhu Sudhana Saddala, Jeremy B Foote, Ateeq M Khaliq, Ashiq Masood, Yuvasri Golivi, Dhana Sekhar Reddy Bandi, Sujith Sarvesh, Sudhir Putty Reddy, Jeffrey Switchenko, Julienne L Carstens, Mehmet Akce, Cameron Herting, Olatunji B Alese, Karina J Yoon, Upender Manne, Manoj K Bhasin, Gregory B Lesinski, Vikas P Sukhatme, Bassel F El-Rayes

{"title":"Mechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine.","authors":"Ganji Purnachandra Nagaraju, Madhu Sudhana Saddala, Jeremy B Foote, Ateeq M Khaliq, Ashiq Masood, Yuvasri Golivi, Dhana Sekhar Reddy Bandi, Sujith Sarvesh, Sudhir Putty Reddy, Jeffrey Switchenko, Julienne L Carstens, Mehmet Akce, Cameron Herting, Olatunji B Alese, Karina J Yoon, Upender Manne, Manoj K Bhasin, Gregory B Lesinski, Vikas P Sukhatme, Bassel F El-Rayes","doi":"10.1016/j.xcrm.2024.101881","DOIUrl":null,"url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) has a minimal (<15%) 5-year existence, in part due to resistance to chemoradiotherapy. Previous research reveals the impact of paricalcitol (P) and hydroxychloroquine (H) on altering the lysosomal fusion, decreasing stromal burden, and triggering PDAC to chemotherapies. This investigation aims to elucidate the molecular properties of the H and P combination and their potential in sensitizing PDAC to gemcitabine (G). PH potentiates the effects of G in in vitro, orthotopic mouse models, and a patient-derived xenograft model of PDAC. Proteomic and single-cell RNA sequencing (RNA-seq) analyses reveal that GPH treatment upregulates autophagy and endoplasmic reticulum (ER) stress-related transcripts. GPH treatment decreases the number of Ki67, fibroblast-associated protein (FAP), and alpha-smooth muscle actin (SMA)-expressing fibroblasts with a decrease in autophagy-related transcripts. The GPH treatment increases M1 polarization and CD4+ and CD8+ T cells and reduces CD4+ and CD8+ regulatory T cells (Tregs). These effects of GPH were confirmed in paired biopsies obtained from patients treated in a clinical trial (NCT04524702).","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101881"},"PeriodicalIF":11.7000,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Reports Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.xcrm.2024.101881","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/26 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a minimal (<15%) 5-year existence, in part due to resistance to chemoradiotherapy. Previous research reveals the impact of paricalcitol (P) and hydroxychloroquine (H) on altering the lysosomal fusion, decreasing stromal burden, and triggering PDAC to chemotherapies. This investigation aims to elucidate the molecular properties of the H and P combination and their potential in sensitizing PDAC to gemcitabine (G). PH potentiates the effects of G in in vitro, orthotopic mouse models, and a patient-derived xenograft model of PDAC. Proteomic and single-cell RNA sequencing (RNA-seq) analyses reveal that GPH treatment upregulates autophagy and endoplasmic reticulum (ER) stress-related transcripts. GPH treatment decreases the number of Ki67, fibroblast-associated protein (FAP), and alpha-smooth muscle actin (SMA)-expressing fibroblasts with a decrease in autophagy-related transcripts. The GPH treatment increases M1 polarization and CD4⁺ and CD8⁺ T cells and reduces CD4⁺ and CD8⁺ regulatory T cells (Tregs). These effects of GPH were confirmed in paired biopsies obtained from patients treated in a clinical trial (NCT04524702).

查看原文本刊更多论文

盐酸白藜芦醇联合羟氯喹提高胰腺导管腺癌化疗疗效的机制。

胰腺导管腺癌（Pancreatic ductal adencarcinoma， PDAC）有少量（+和CD8+） T细胞，CD4+和CD8+调节性T细胞（Tregs）减少。在一项临床试验（NCT04524702）中，从接受治疗的患者中获得的配对活检证实了GPH的这些作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.