Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common malignant tumour worldwide and is responsible for every fourth death of tumour patients [1]. e number of new cases is rising rapidly worldwide, especially in western industrialized countries
We developed a highly competitive Cytochrome P450 2E1 (CYP2E1) inhibitor 12-imidazolyl1-dodecanol (I-ol) (Table S1) and have already demonstrated proof-of-concept that it can successfully be used to treat alcoholic steatohepatitis (ASH) (Figure S1) and nonalcoholic steatohepatitis (NASH) (Figure S2). e findings of this study indicate that I-ol is effective against hepatocarcinogenesis, and our findings imply that I-ol could be potentially used to treat fatty liver disease (FLD)
I-ol showed a strong concentration-dependent antiproliferative effect between concentrations ranging from 3 μM to 200 μM. is effect occurred in HepG2 cells (Figure 1(a)) after only a 2hour incubation, in a very highly significant manner. e initial fluorescence values of HepG2 cells treated with 100 μM I-ol did not increase over the entire experimental period
Summary
Hepatocellular carcinoma (HCC) is the fifth most common malignant tumour worldwide and is responsible for every fourth death of tumour patients [1]. e number of new cases is rising rapidly worldwide, especially in western industrialized countries. There are no drugs that, alone or in combination with other chemotherapeutic agents, can lead to an outstanding overall survival rate. A general trend exists in that new antitumour drugs are increasingly replacing traditional chemotherapeutic agents, such as cisplatin, doxorubicin, 5-fluorouracil, and its prodrug capecitabine. Sorafenib as a targeted chemotherapeutic for treating HCC prolongs survival time by an average of only three months [2]. Lenvatinib is noninferior to sorafenib [3] and was approved as a first-line treatment by the US Food and Drug Administration and European Commission. Due to the low level of innovation in the development of new drugs, other therapeutic approaches are being pursued in parallel, which rely on classic chemotherapeutic agents. Capecitabine is a representative of the concept of metronomic chemotherapy, according to which the therapeutic agent is administered continuously but in a reduced dose [8, 9]
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