Polymerized human hemoglobin increases the effectiveness of cisplatin-based chemotherapy in non-small cell lung cancer.

Carlos Munoz,Donald A Belcher,Alexander T Williams,Pedro Cabrales,Andre F Palmer,Alfredo Lucas

doi:10.18632/oncotarget.27776

Carlos Munoz, Donald A Belcher + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.27776

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Abstract

Cisplatin is a promising therapeutic for the treatment of non-small cell lung cancer (NSCLC). Unfortunately, a significant portion of NSCLC patients relapse due to cisplatin chemoresistance. This chemoresistance is thought to be primarily associated with hypoxia in the tumor microenvironment. Administration of hemoglobin (Hb)-based oxygen (O2) carriers (HBOCs) is a promising strategy to alleviate hypoxia in the tumor, which may make cisplatin more effective. In this study, we administered a high O2 affinity, relaxed state (R-state) polymerized hemoglobin (PolyHb) to three different NSCLC cell lines cultured in vitro and implanted in vivo into healthy mice. The R-state PolyHb administered in this study is unable to deliver O2 unless under severe hypoxia which significantly limits its oxygenation potential. In vitro sensitivity studies indicate that the administration of PolyHb increases the effectiveness of cisplatin under hypoxic conditions. Additional animal studies revealed that co-administration of PolyHb with cisplatin attenuated tumor growth without alleviating hypoxia. Analysis of reactive O2 species production in the presence of hypoxic culture indicates that exogenous ROS production by oxidized PolyHb may the mechanism of chemosensitization. This ROS mechanism, coupled with oxygenation, may be a potential chemosensitizing strategy for use in NSCLC treatment.

Highlights

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer death and constitutes ~80 to 85% of all types of lung cancers [1]
Analysis of the chromatogram obtained with SEC-HPLC revealed the complete removal of extremely low molecular weight (MW) polymerized hemoglobin (PolyHb) and unpolymerized Hb (128 kDa, 64 kDa) in the transfused sample
For H549 cells, the IC50 for cisplatin, cisplatin with PolyHb at 0.1 g/dL, and cisplatin with PolyHb at 0.2 g/dL were 5.27 μM, 2.47 μM, and 1.31 μM, respectively. These results indicate that the largest decrease in cell viability during hypoxia, for the three studied cell types, was produced from treatment with cisplatin and PolyHb at a 0.2 g/dL concentration

Summary

Introduction

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer death and constitutes ~80 to 85% of all types of lung cancers [1]. 40% of all newly diagnosed NSCLCs are in stage IV, for which cytotoxic combination chemotherapy is the first line of defense [2]. In many combination chemotherapy regimens for NSCLC, cisplatin is used in combination with etoposide [3]. Through large multicenter clinical trials, cisplatin-based combination therapy results in a moderate survival advantage for treating metastatic NSCLC [4, 5]. A significant fraction of patient relapses occur due to cisplatin chemoresistance.

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