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

Autor:	Nagaraju GP; Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA., Saddala MS; Bioinformatics, Genomics and Proteomics, University of California, Irvine, Irvine, CA 92697, USA., Foote JB; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA., Khaliq AM; Indiana University School of Medicine, Indianapolis, IN 46202, USA., Masood A; Indiana University School of Medicine, Indianapolis, IN 46202, USA., Golivi Y; Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA., Bandi DSR; Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA., Sarvesh S; Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA., Reddy SP; Department of Protein Sciences & Mass Spectrometry, Translational Medicine, Bristol Myers Squibb, Princeton, NJ 08543, USA., Switchenko J; Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA 30322, USA., Carstens JL; Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA., Akce M; Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA., Herting C; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA., Alese OB; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA., Yoon KJ; Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35233, USA., Manne U; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA., Bhasin MK; Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Pediatrics, Emory University, Atlanta, GA 30322, USA., Lesinski GB; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA., Sukhatme VP; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA; Department of Medicine, Emory University, Atlanta, GA 30322, USA., El-Rayes BF; Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL 35233, USA. Electronic address: belrayes@uabmc.edu.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 Dec 17, pp. 101881. Date of Electronic Publication: 2024 Dec 17.
DOI:	10.1016/j.xcrm.2024.101881
Abstrakt:	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). Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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