Heme Oxygenase-1 Inhibition Potentiates the Effects of Nab-Paclitaxel-Gemcitabine and Modulates the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma

Iman M. Ahmad; Alicia J. Dafferner; Kelly A. O’Connell; Kamiya Mehla; Bradley E. Britigan; Michael A. Hollingsworth; Maher Y. Abdalla

doi:10.3390/cancers13092264

Cancers (May 2021)

Heme Oxygenase-1 Inhibition Potentiates the Effects of Nab-Paclitaxel-Gemcitabine and Modulates the Tumor Microenvironment in Pancreatic Ductal Adenocarcinoma

Iman M. Ahmad,
Alicia J. Dafferner,
Kelly A. O’Connell,
Kamiya Mehla,
Bradley E. Britigan,
Michael A. Hollingsworth,
Maher Y. Abdalla

Affiliations

Iman M. Ahmad: College of Allied Health Professions, University of Nebraska Medical Center, Omaha, NE 68198, USA
Alicia J. Dafferner: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
Kelly A. O’Connell: Fred & Pamela Buffett Cancer Center, The Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198, USA
Kamiya Mehla: Fred & Pamela Buffett Cancer Center, The Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198, USA
Bradley E. Britigan: Veterans Affairs Medical Center-Nebraska Western Iowa, Department of Internal Medicine and Research Service, Omaha, NE 68105, USA
Michael A. Hollingsworth: Fred & Pamela Buffett Cancer Center, The Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198, USA
Maher Y. Abdalla: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA

DOI: https://doi.org/10.3390/cancers13092264
Journal volume & issue: Vol. 13, no. 9
p. 2264

Abstract

Read online

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 p p 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.

Published in Cancers

ISSN: 2072-6694 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.mdpi.com/journal/cancers/

About the journal

Abstract

Keywords