@article{259945cb050648dd87e1689507cb9b25,
title = "Heme oxygenase-1 inhibition potentiates the effects of nab-paclitaxel-gemcitabine and modulates the tumor microenvironment in pancreatic ductal adenocarcinoma",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Tumor hypoxia plays an active role in promoting tumor progression, malignancy, and resistance to therapy in PDAC. We present evidence that nab-paclitaxel–gemcitabine (NPG) and/or a hypoxic tumor microenvironment (TME) up-regulate heme oxygenase-1 (HO-1), providing a survival advantage for tumors. Using PDAC cells in vitro and a PDAC mouse model, we found that NPG chemotherapy up-regulated expression of HO-1 in PDAC cells and increased its nuclear translocation. Inhibition of HO-1 with ZnPP and SnPP sensitized PDAC cells to NPG-induced cytotoxicity (p < 0.05) and increased apoptosis (p < 0.05). Additionally, HO-1 expression was increased in gemcitabineresistant PDAC cells (p < 0.05), and HO-1 inhibition increased GEM-resistant PDAC sensitivity to NPG (p < 0.05). NPG combined with HO-1 inhibitor inhibited tumor size in an orthotopic model. In parallel, HO-1 inhibition abrogated the influx of macrophages and FoxP3+ cells, while increasing the proportion of CD8+ infiltration in the pancreatic tumors. These effects were mediated primarily by reducing expression of the immunosuppressive cytokine IL-10.",
keywords = "Chemotherapy, Heme oxygenase-1, Immune cells, PDAC",
author = "Ahmad, {Iman M.} and Dafferner, {Alicia J.} and O{\textquoteright}connell, {Kelly A.} and Kamiya Mehla and Britigan, {Bradley E.} and Hollingsworth, {Michael A.} and Abdalla, {Maher Y.}",
note = "Funding Information: Acknowledgments: The University of Nebraska DNA Sequencing Core receives partial support from the National Institute for General Medical Science (NIGMS) INBRE—P20GM103427-19 grant, the COBRE—1P30GM110768, and The Fred & Pamela Buffett Cancer Center Support Grant—P30 CA036727. This publication{\textquoteright}s contents are the sole responsibility of the authors and do not necessarily represent the official views of the NIH or NIGMS. We would like to thank Celgene for providing the nab-paclitaxel (Abraxane) that was used in our study. Funding Information: The University of Nebraska DNA Sequencing Core receives partial support from the National Institute for General Medical Science (NIGMS) INBRE?P20GM103427-19 grant, the COBRE?1P30GM110768, and The Fred & Pamela Buffett Cancer Center Support Grant?P30 CA036727. This publication?s contents are the sole responsibility of the authors and do not necessarily represent the official views of the NIH or NIGMS. We would like to thank Celgene for providing the nab-paclitaxel (Abraxane) that was used in our study. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2021",
month = may,
day = "1",
doi = "10.3390/cancers13092264",
language = "English (US)",
volume = "13",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "9",
}