title: Arsenic trioxide plus cisplatin/interferon α-2b/doxorubicin/capecitabine combination chemotherapy for unresectable hepatocellular carcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Cancer Immunology, Ion Chiricuta Oncology Institute, Cluj Napoca, Romania. ciprian.tomuleasa@gmail.com
authors: Ciprian
authors: C
authors: Tomuleasa
authors: Olga
authors: O
authors: Soritau
authors: Eva
authors: E
authors: Fischer-Fodor
authors: Teodora
authors: T
authors: Pop
authors: Sergiu
authors: S
authors: Susman
authors: Ofelia
authors: O
authors: Mosteanu
authors: Bobe
authors: B
authors: Petrushev
authors: Mihaela
authors: M
authors: Aldea
authors: Monica
authors: M
authors: Acalovschi
authors: Alexanru
authors: A
authors: Irimie
authors: Gabriel
authors: G
authors: Kacso
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D000069287:Capecitabine; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005456:Fluorescent Dyes / Q000737:chemistry; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000494:pharmacology; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000494:pharmacology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D010087:Oxides / Q000494:pharmacology; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D020112:Rhodamine 123 / Q000737:chemistry; D018800:Thy-1 Antigens / Q000276:immunology / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D001152:Arsenicals; D005456:Fluorescent Dyes; D006023:Glycoproteins; D016898:Interferon-alpha; D010087:Oxides; C000606023:PROM1 protein, human; D010455:Peptides; D018800:Thy-1 Antigens; D003841:Deoxycytidine; D020112:Rhodamine 123; D000069287:Capecitabine; D004317:Doxorubicin; D002945:Cisplatin; D000077237:Arsenic Trioxide; D005472:Fluorouracil