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. 2017 Jul 28;8(49):85311-85325.
doi: 10.18632/oncotarget.19672. eCollection 2017 Oct 17.

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

Xiang Qi  1 , Bing L Wong  2 , Sze Hang Lau  2 , Kevin Tak-Pan Ng  1 , Sui Yi Kwok  2 , Chris Kin-Wai Sun  2 , Fei Chuen Tzang  2 , Yan Shao  1 , Chang Xian Li  1 , Wei Geng  1 , Chang Chun Ling  1 , Yuen Yuen Ma  1 , Xiao Bing Liu  1 , Hui Liu  1 , Jiang Liu  1 , Wai Ho Yeung  1 , Chung Mau Lo  1   3 , Kwan Man  1   3
Affiliations

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

Xiang Qi et al. Oncotarget. .

Abstract

Background and objective: 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.

Methods: 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.

Results: 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.

Conclusion: YQ23 treatment may be a potential therapeutic strategy to sensitize chemotherapy in HCC.

Keywords: Cisplatin; HCC; chemoresistance; hemoglobin-based oxygen carrier; intravital imaging.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST The YQ23 product is provided by New β Innovation Limited.

Figures

Figure 1
Figure 1. Oxygen carrier YQ23 significantly sensitized Cisplatin treatment by MTT assay in vitro
(A) YQ23 administration significantly suppressed the proliferation of HCC cells under Cisplatin treatment in a dose dependent manner. (B) YQ23 could most significantly sensitize Cisplatin treatment at lower dosage of Cisplatin at day 7.
Figure 2
Figure 2. Oxygen carrier YQ23 significantly suppressed the colony formation of HCC cells under Cisplatin in a dose dependent manner
(A) Images of colony formation for 3 weeks. (B) Quantification and statistical analysis for colony formation.
Figure 3
Figure 3. Oxygen carrier YQ23 significantly sensitized Cisplatin treatment in vivo
(A) YQ23 administration kinetically sensitized Cisplatin based chemotherapy in orthotopic xenograft liver cancer model. (B) The tumor volume was significantly lower by YQ23 treatment combined with Cisplatin therapy when the nude mice were sacrificed.
Figure 4
Figure 4. Oxygen carrier YQ23 combined with Cisplatin treatment induced more necrosis and apoptosis in tumor tissues
(A) More necrotic areas were observed in combined treatment group by H&E staining (400×). (B) More apoptotic cells were induced by combined treatment examined by TUNEL assay (400×).
Figure 5
Figure 5. Down-regulation of dihydrofolate reductase (DHFR) may be one of the reasons for YQ23 sensitizing Cisplatin based chemotherapy
(A) RT2 Profiler PCR array showed that 4 down-regulated genes (DHFR, SULT1E1, RARB and CYP3A4) and 2 up-regulated genes (CYP1A1 and CYP1A2) were identified in HCC cells after YQ23 treatment. (B) Only DHFR was significantly down-regulated upon YQ23 treatment combined with Cisplatin in orthotopic xenograft liver cancer model. *P<0.05.
Figure 6
Figure 6. Real-time intravital imaging (Confocal) showed that YQ23 accumulated in the tumor tissue in ectopic xenograft liver cancer model using dorsal window chamber
(A) Establishment of nude mice ectopic xenograft liver cancer model with dorsal window chamber. (B) YQ23 could be accumulated at different layers of the tumor tissues as early as 1 day after systemic administration. (C) YQ23 could be maintained in the tumor tissues as long as 3 days after administration.
Figure 7
Figure 7. Examination of YQ distribution in the whole body and tumor cells
(A) The IVIS spectrum examination showed that YQ23 distributed mainly at liver and bladder within first 36 hours after injection and gradually excreted through bladder afterwards. (B) YQ23 could be accumulated intracellularly in HCC cells as early as 1 day after administration.
See this image and copyright information in PMC

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