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

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

doi:10.3390/cancers13092264

Iman M Ahmad, Kelly A O'Connell + Show 5 more

Open Access

https://doi.org/10.3390/cancers13092264

Copy DOI

Journal: Cancers	Publication Date: May 8, 2021
Citations: 14	License type: CC BY 4.0

Affiliation: University of Nebraska Medical Center

Abstract

Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies. Chemotherapy has had limited success in extending the life span of patients with advanced PDAC. Thus, new treatment approaches are needed. Heme oxygenase-1 (HO-1) is a key enzyme for the protection of cells against oxidative stress. Interestingly, HO-1 is overexpressed in several cancers, including PDAC. In the present study, our findings demonstrate the novel role of HO-1 in vivo in PDAC progression and in sensitizing tumor cells to cytotoxic chemotherapy by modulating the tumor microenvironment (TME).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 gemcitabine-resistant 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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is among the most common and lethal cancers, with more than 60,430 new cases annually [1] and a 5-year overall survival of around 10% [1]
We extend our studies to test the effect of heme oxygenase-1 (HO-1) inhibition in combination with NPG on PDAC cells and the tumor microenvironment (TME)
Our results show that NPG treatment increased HO-1 expression in PDAC cells through the activation of mitogen-activated protein kinase (MAPK)-p38 signaling pathway

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is among the most common and lethal cancers, with more than 60,430 new cases annually [1] and a 5-year overall survival of around 10% [1]. PDAC is projected to be the second leading cause of cancer-related death in the United States by 2030 [2]. PDAC, less than 20% of patients with pancreatic cancer are surgically treated at the time of 4.0/). Conventional chemotherapy and radiotherapy are commonly employed as first-line treatment in patients with non-resectable or borderline-resectable tumors [5]. Hypoxia plays an active role in promoting tumor growth, progression, metastasis, and resistance to chemotherapy and radiation therapy [8,9]. In PDAC, HIF-1α is overexpressed in pancreatic tumor cells and is associated with cell proliferation [10,11]

Methods

Discussion

Conclusion