Arsenic trioxide and breast cancer: analysis of the apoptotic, differentiative and immunomodulatory effects.
Arsenic trioxide (As2O3) is used clinically to treat acute promyelocytic leukemia and has activity in vitro against several solid tumour cell lines, where induction of differentiation and apoptosis are the prime effects. To investigate the potential therapeutic application of As2O3 to breast cancer, we analysed the effects of As2O3 on the growth of four human breast cancer cell lines: MCF7, MDA-MB-231, T-47D and BT-20. Cells were cultured in 0.5, 2 and 5 microM AS2O3, a range of pharmacologically achievable concentrations of AS2O3. At > or = 2 microM, AS2O3 rapidly induced cell death by apoptosis in MCF7 and MDA-MB-231 while T-47D and BT-20 were partially resistant. At 0.5 microM, As2O3 was subapoptotic but induced features of differentiation consisting in upregulation of ICAM-1 (CD54), a marker of mammary epithelial differentiation, and cell cultures appeared morphologically more organized. Furthermore, we demonstrate by standard cytotoxicity assays that As2O3 treatment can augment breast cancer cell lysis by lymphokine-activated killer cells and demonstrate an important role of the ICAM-1/LFA-1 interaction in this process. This additional activity of As2O3 could translate into improved antitumour immunosurveillance in vivo. In conclusion, As2O3 induced varying degrees of differentiation, apoptosis and lysis in these model cell lines, and may be a promising adjuvant to current treatments of breast cancer by virtue of its triple apoptotic, differentiative and immunomodulatory effects.
Baj
Germano
G
Laboratories of Gynecologic Oncology, University of Eastern Piedmont A. Avogadro, Novara, Italy.
Arnulfo
Alberto
A
Deaglio
Silvia
S
Mallone
Roberto
R
Vigone
Alessandro
A
De Cesaris
Maria Grazia
MG
Surico
Nicola
N
Malavasi
Fabio
F
Ferrero
Enza
E
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D019254:Genes, bcl-2 / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015979:Killer Cells, Lymphokine-Activated / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D001152:Arsenicals; D016169:Lymphocyte Function-Associated Antigen-1; D010087:Oxides; D013438:Sulfhydryl Compounds; D018799:Intercellular Adhesion Molecule-1; D005978:Glutathione; D000077237:Arsenic Trioxide