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

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 (O 2 ) 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 O 2 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 O 2 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 O 2 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.

Biocompatibility of the oxygen carrier polymerized human hemoglobin towards HepG2/C3A cells

“…3 B); however, the mechanistic connection between PolyHb and arginase II is unclear at this time. Since arginase II is a mitochondrial enzyme (as opposed to arginase I, which is cytosolic), a potential route for further investigation may involve increased oxygen delivery to the cells in the presence of the oxygen carrier [ 52 , 53 ].…”

Hemoglobin/Red Blood Cell Distribution Width Ratio in Peripheral Blood Is Positively Associated with Prognosis of Patients with Primary Hepatocellular Carcinoma

“…Our study found that HRR is inversely correlated with CNLC staging, suggesting that HRR may affect patient outcomes by promoting tumor progression, but its specific mechanism is not well understood. Anemia is a common symptom in patients with malignant tumors, which can be caused by a variety of factors such as tumor rupture, bleeding, and treatment adverse effects [ 39 ]. Anemia occurs with increased neovascularization and elevated levels of tumor invasion metastasis, which may be one of the potential mechanisms by which HRR promotes tumor progression in HCC.…”

Extracellular Hemoglobin: Modulation of Cellular Functions and Pathophysiological Effects

“…The aforementioned data indicate a very complex role of endogenous accumulation of extracellular hemoglobin as well as exogenous hemoglobin treatments. Namely, recently Lucas et al [ 118 ] showed that co-administration of polymerized hemoglobin with cisplatin in an animal model attenuated tumor growth without alleviating hypoxia [ 118 ], where most probably the exogenous ROS production by oxidized polymerized hemoglobin is the mechanism of chemo-sensitization [ 118 ].…”