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A hemoglobin-based oxygen carrier sensitized Cisplatin based chemotherapy in hepatocellular carcinoma.

ABSTRACT: Our previous study showed that liver graft injury not only promotes tumor recurrence, but also induces chemoresistance in recurrent HCC after liver transplantation. Recently, we found that the hemoglobin-based oxygen carrier"YQ23" significantly ameliorates hepatic IR injury and prevent tumor recurrence. Here, we intended to explore the novel therapeutic strategy using oxygen carrier "YQ23"to sensitize chemotherapy in HCC.To investigate the role of YQ23 combined with Cisplatin, the proliferation of HCC cells was examined under combined treatment by MTT and colony formation. To explore the effect of YQ23 on sensitization of Cisplatin based chemotherapy, the orthotopic liver cancer model was established. To characterize the delivery of YQ23 in tumor tissue, the intravital imaging system was applied for longitudinal observation in ectopic liver cancer model. The distribution of YQ23 was examined by IVIS spectrum.YQ23 significantly suppressed the proliferation of HCC cells under Cisplatin treatment in a dose and time dependent manner. Moreover, YQ23 administration significantly sensitized Cisplatin based chemotherapy in orthotopic liver cancer model. Down-regulation of DHFR may be one of the reasons for YQ23 sensitizing Cisplatin based chemotherapy. Real-time intravital imaging showed that YQ23 accumulated in the tumor tissue and maintained as long as 3 days in ectopic liver cancer model. The IVIS spectrum examination showed that YQ23 distributed mainly at liver and bladder within the first 36 hours after administration in orthotopic liver cancer model.YQ23 treatment may be a potential therapeutic strategy to sensitize chemotherapy in HCC.

SUBMITTER: Qi X

PROVIDER: S-EPMC5689611 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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A hemoglobin-based oxygen carrier sensitized Cisplatin based chemotherapy in hepatocellular carcinoma.

Qi Xiang X Wong Bing L BL Lau Sze Hang SH Ng Kevin Tak-Pan KT Kwok Sui Yi SY Kin-Wai Sun Chris C Tzang Fei Chuen FC Shao Yan Y Li Chang Xian CX Geng Wei W Ling Chang Chun CC Ma Yuen Yuen YY Liu Xiao Bing XB Liu Hui H Liu Jiang J Yeung Wai Ho WH Lo Chung Mau CM Man Kwan K

Oncotarget 20170728 49

<h4>Background and objective</h4>Our previous study showed that liver graft injury not only promotes tumor recurrence, but also induces chemoresistance in recurrent HCC after liver transplantation. Recently, we found that the hemoglobin-based oxygen carrier"YQ23" significantly ameliorates hepatic IR injury and prevent tumor recurrence. Here, we intended to explore the novel therapeutic strategy using oxygen carrier "YQ23"to sensitize chemotherapy in HCC.<h4>Methods</h4>To investigate the role of ...[more]

PMID: 29156721

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Project description:Hemoglobin (Hb) based oxygen carriers (HBOCs) are designed to minimize the toxicity of extracellular Hb, while preserving its high oxygen-carrying capacity for oxygen delivery to cells. Polymerized human Hb (PolyHb) is a novel type of nanosized HBOC synthesized via glutaraldehyde-mediated crosslinking of free Hb, and which preserves the predominant quaternary state during the crosslinking reaction (low oxygen affinity tense (T) quaternary state PolyHb is synthesized at 0% Hb oxygen saturation, and high oxygen affinity relaxed (R) quaternary state PolyHb is synthesized at 100% Hb oxygen saturation). Major potential applications for PolyHbs, and HBOCs in general, include oxygenation of bioreactor systems containing large liver cell masses, and ex-vivo perfusion preservation of explanted liver grafts. The toxicity of these compounds toward liver cells must be evaluated before testing their use in these complex systems for oxygen delivery. Herein, we characterized the effect of PolyHbs on the hepatoma cell line HepG2/C3A, used as a model hepatocyte and as a cell line used in some investigational bioartificial liver support devices. HepG2/C3A cells were incubated in cell culture media containing PolyHbs or unmodified Hb at concentrations up to 50 mg/mL and for up to 6 days. PolyHbs were well tolerated at a dose of 10 mg/mL, with no significant decrease in cell viability; however, proliferation was inhibited as much as 10-fold after 6 days of exposure at 50 mg/mL. Secretion of albumin, and urea, as well as glucose and ammonia removal were measured in presence of 10 mg/mL of PolyHbs or unmodified Hb. In addition, methoxy- and ethoxy-resorufin deacetylase (MROD and EROD) activities, which reflect cytochrome P450 metabolism, were measured. R-state PolyHb displayed improved or intact activity in 3 out of 7 functions compared to unmodified Hb. T-state PolyHb displayed improved or intact activity in 4 out of 7 functions compared to unmodified Hb. Thus, PolyHbs, both in the R-state and T-state, are safer to use at a concentration of 10 mg/mL as compared to unmodified Hb in static culture liver-related applications.

Dataset Information

A hemoglobin-based oxygen carrier sensitized Cisplatin based chemotherapy in hepatocellular carcinoma.

Publications

A hemoglobin-based oxygen carrier sensitized Cisplatin based chemotherapy in hepatocellular carcinoma.

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