ApoE-modified liposomes mediate the antitumour effect of survivin promoter-driven HSVtk in hepatocellular carcinoma

Cytochrome P450 2E1 (CYP2E1) is a key target protein in the development of alcoholic and nonalcoholic fatty liver disease (FLD). The pathophysiological correlate is the massive production of reactive oxygen species. The role of CYP2E1 in the development of hepatocellular carcinoma (HCC), the final complication of FLD, remains controversial. Specifically, CYP2E1 has not yet been defined as a molecular target for HCC therapy. In addition, a CYP2E1-specific drug has not been developed. We have already shown that our newly developed CYP2E1 inhibitor 12-imidazolyl-1-dodecanol (I-ol) was therapeutically effective against alcoholic and nonalcoholic steatohepatitis. In this study, we investigated the effect of I-ol on HCC tumorigenesis and whether I-ol could serve as a possible treatment option for terminal-stage FLD. I-ol exerted a very highly significant antitumour effect against hepatocellular HepG2 cells. Cell viability was reduced in a dose-dependent manner, with only the highest doses causing a cytotoxic effect associated with caspase 3/7 activation. Comparable results were obtained for the model colorectal adenocarcinoma cell line, DLD-1, whose tumorigenesis is also associated with CYP2E1. Transcriptome analyses showed a clear effect of I-ol on apoptosis and cell-cycle regulation, with the increased expression of p27Kip1 being particularly noticeable. These observations were confirmed at the protein level for HepG2 and DLD-1 cells grafted on a chorioallantoic membrane. Cell-cycle analysis showed a complete loss of proliferating cells with a simultaneous increase in S-phase arrest beginning at a threshold dose of 30 μM. I-ol also reduced xenograft tumour growth in nude mice. This antitumour effect was not associated with tumour cachexia. I-ol was not toxic to healthy tissues or organs. This study demonstrates for the first time the therapeutic effect of the specific CYP2E1 inhibitor I-ol on the tumorigenesis of HCC. Our findings imply that I-ol can potentially be applied therapeutically on patients at the final stage of FLD.

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Enhanced antitumour effect for hepatocellular carcinoma in the advanced stage using a cyclodextrin-sorafenib-chaperoned inclusion complex

Biomaterials Science ◽

10.1039/c9bm01190k ◽

2019 ◽

Vol 7 (11) ◽

pp. 4758-4768

Author(s):

Chiuyen Phan ◽

Ziyang Zheng ◽

Jianwei Wang ◽

Qiwen Wang ◽

Xiurong Hu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Inclusion Complex ◽

Inclusion Complexes ◽

Nude Mice ◽

Advanced Stage ◽

Antitumour Effect ◽

Advanced Hcc ◽

Tumor Bearing

We have proposed and classified the HCC tumor of HCC tumor-bearing BALB/c nude mice to four stages. Cyclodextrin-sorafenib-chaperoned inclusion complexes were prepared and applied to treat advanced HCC tumor-bearing mice.

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Antitumour effect of intratumoral injection of human recombinant interleukin-2 in patients with hepatocellular carcinoma: a preliminary report

European Journal of Cancer and Clinical Oncology ◽

10.1016/0277-5379(90)90048-x ◽

1990 ◽

Vol 26 (10) ◽

pp. 1045-1048 ◽

Cited By ~ 16

Author(s):

Mutsunori Shirai ◽

Seishiro Watanabe ◽

Mikio Nishioka

Keyword(s):

Hepatocellular Carcinoma ◽

Preliminary Report ◽

Interleukin 2 ◽

Intratumoral Injection ◽

Antitumour Effect ◽

Recombinant Interleukin 2

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Upregulation of the ErbB family by EZH2 in hepatocellular carcinoma confers resistance to FGFR inhibitor

10.21203/rs.3.rs-520044/v1 ◽

2021 ◽

Author(s):

Aldo Prawira ◽

Thi Bich Uyen Le ◽

Rebecca Zhi Wen Ho ◽

Hung Huynh

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Investigation ◽

Treatment Options ◽

Acquired Resistance ◽

Feedback Mechanism ◽

Term Treatment ◽

Gene Overexpression ◽

Antitumour Effect ◽

Erbb Family ◽

Long Term Treatment

Abstract Purpose Hepatocellular carcinoma (HCC), the most common manifestation of liver cancer, is one of the leading causes of cancer-related mortality worldwide with limited treatment options. Infigratinib, a pan-FGFR inhibitor, has shown a potent antitumour effect in HCC. However, drug resistance is often observed in long term treatment. In this study, we examined the potential feedback mechanism(s) leading to infigratinib and explored a combination therapy to overcome resistance in HCC. Methods Patient-derived xenograft (PDX) tumours were subcutaneously implanted into SCID mice and were subsequently treated with infigratinib. Tumour growth was monitored over time, and tumour samples were subjected to immunohistochemistry and Western blotting. For drug combination studies, mice were treated with infigratinib and/or varlitinib. Gene overexpression and knockdown studies were conducted to investigate the relationship between EZH2 and ErbB activity in infigratinib resistance. Results Infigratinib-resistant tumours exhibited higher levels of p-ErbB2 and p-ErbB3, concomitant with an increase in EZH2 expression. Gene overexpression and knockdown studies revealed that EZH2 directly regulates the levels of p-ErbB2 and p-ErbB3 in acquired resistance to infigratinib. The addition of varlitinib effectively overcame infigratinib resistance and prolonged the antitumour response, with minimal toxicity. Conclusion The upregulation of the ErbB family by EZH2 appears to contribute to infigratinib resistance. The combination of infigratinib and varlitinib showed a potent antitumour effect and did not result in additional toxicity, warranting further clinical investigation.

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Upregulation of the ErbB family by EZH2 in hepatocellular carcinoma confers resistance to FGFR inhibitor

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-021-03703-6 ◽

2021 ◽

Author(s):

Aldo Prawira ◽

Thi Bich Uyen Le ◽

Rebecca Zhi Wen Ho ◽

Hung Huynh

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Investigation ◽

Treatment Options ◽

Acquired Resistance ◽

Feedback Mechanism ◽

Term Treatment ◽

Gene Overexpression ◽

Antitumour Effect ◽

Erbb Family ◽

Long Term Treatment

Abstract Purpose Hepatocellular carcinoma (HCC), the most common manifestation of liver cancer, is one of the leading causes of cancer-related mortality worldwide with limited treatment options. Infigratinib, a pan-FGFR inhibitor, has shown a potent antitumour effect in HCC. However, drug resistance is often observed in long-term treatment. In this study, we examined the potential feedback mechanism(s) leading to infigratinib and explored a combination therapy to overcome resistance in HCC. Methods Patient-derived xenograft (PDX) tumours were subcutaneously implanted into SCID mice and were subsequently treated with infigratinib. Tumour growth was monitored over time, and tumour samples were subjected to immunohistochemistry and Western blotting. For drug combination studies, mice were treated with infigratinib and/or varlitinib. Gene overexpression and knockdown studies were conducted to investigate the relationship between EZH2 and ErbB activity in infigratinib resistance. Results Infigratinib-resistant tumours exhibited higher levels of p-ErbB2 and p-ErbB3, concomitant with an increase in EZH2 expression. Gene overexpression and knockdown studies revealed that EZH2 directly regulates the levels of p-ErbB2 and p-ErbB3 in acquired resistance to infigratinib. The addition of varlitinib effectively overcame infigratinib resistance and prolonged the antitumour response, with minimal toxicity. Conclusion The upregulation of the ErbB family by EZH2 appears to contribute to infigratinib resistance. The combination of infigratinib and varlitinib showed a potent antitumour effect and did not result in additional toxicity, warranting further clinical investigation.

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