Arsenic trioxide plus cisplatin/interferon α-2b/doxorubicin/capecitabine combination chemotherapy for unresectable hepatocellular carcinoma

Abstract

The failure of existing treatments for liver cancer has recently been attributed to the existence of cancer stem cells, which are difficult to kill using current drugs due to their chemoresistant properties as well as their ability to stimulate neoangiogenesis. The aim of the current study was to evaluate in vitro the antitumor efficacy of arsenic trioxide in combination with conventional chemotherapy, as proposed by the concept of "differentiation therapy" in anticancer research. Cancer stem cells showed enhanced chemoresistance to cancer drugs (carboplatin and doxorubicin) and had the ability to exclude rhodamine 123 dye, proving the existence of the multidrug resistance efflux pump. Arsenic trioxide was added prior to a tyrosine kinase inhibitor or to a slightly modified PIAF regimen with capecitabine replacing 5-fluorouracil. We also compared both cancer and normal stem cell lines with the hepG2 non-stem liver cancer cell line to investigate the differences between differentiated and more anaplastic cells. Molecular characterization (immunocytochemistry and RT-PCR analysis) of all the cell lines was carried out. Initially, the cells had a high proliferative potential, even when cultured in a medium supplemented with cytostatics, eliminated rhodamine 123 immediately in culture and also formed spheroids in suspension. The molecular characterization showed the expression of albumin, α1-antitrypsin, α-fetoprotein, citokeratin-18, telomerase, CD90 and CD133. Low concentrations of arsenic trioxide lead to morphologic differentiation and differentiation-associated cytochemical features, like increased sensitivity to cytostatic drugs. Our study suggests that arsenic trioxide sensitizes liver stem-like cancer cells to conventional chemotherapy. Still, further studies on animal models will be needed before we implement this idea in human clinical trials.