Abstract
BackgroundThe dose-dependent toxicities of doxorubicin (DOX) limit its clinical applications, particularly in drug-resistant cancers, such as liver cancer. In this study, we investigated the role of quercetin on the antitumor effects of DOX on liver cancer cells and its ability to provide protection against DOX-mediated liver damage in mice.Methodology and ResultsThe MTT and Annexin V/PI staining assay demonstrated that quercetin selectively sensitized DOX-induced cytotoxicity against liver cancer cells while protecting normal liver cells. The increase in DOX-mediated apoptosis in hepatoma cells by quercetin was p53-dependent and occurred by downregulating Bcl-xl expression. Z-VAD-fmk (caspase inhibitor), pifithrin-α (p53 inhibitor), or overexpressed Bcl-xl decreased the effects of quercetin on DOX-mediated apoptosis. The combined treatment of quercetin and DOX significantly reduced the growth of liver cancer xenografts in mice. Moreover, quercetin decreased the serum levels of alanine aminotransferase and aspartate aminotransferase that were increased in DOX-treated mice. Quercetin also reversed the DOX-induced pathological changes in mice livers.Conclusion and SignificanceThese results indicate that quercetin potentiated the antitumor effects of DOX on liver cancer cells while protecting normal liver cells. Therefore, the development of quercetin may be beneficial in a combined treatment with DOX for increased therapeutic efficacy against liver cancer.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common types of liver cancer and the fourth leading cause of cancer deaths worldwide [1]
Cultures were exposed to quercetin at doses of 0 mM to 150 mM to determine the effects of quercetin on liver cancer cells and normal cells
Annexin V/propidium iodide (PI) staining was performed to investigate whether or not DOX-induced cell death in hepatoma cells occurs through apoptosis
Summary
Hepatocellular carcinoma (HCC) is one of the most common types of liver cancer and the fourth leading cause of cancer deaths worldwide [1]. Chemotherapy remains the viable option for the treatment of inoperable HCC patients. Doxorubicin (DOX) has become a routinely and widely used agent in HCC treatment. Studies have shown that some cancer cells, including hepatoma, are resistant to the apoptotic effects of DOX [3]. DOX-based chemotherapy is associated with severe side effects to nontumorous tissues, such as the heart, liver, and kidney, greatly limiting its clinical applications [4,5]. Improved therapeutic regimens that potentiate DOX effects, which allow dose reduction and protection of nontumorous tissues, are needed to improve the treatment of liver cancer patients. The dose-dependent toxicities of doxorubicin (DOX) limit its clinical applications, in drug-resistant cancers, such as liver cancer. We investigated the role of quercetin on the antitumor effects of DOX on liver cancer cells and its ability to provide protection against DOX-mediated liver damage in mice
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