title: Granulocyte colony-stimulating factor potentiates differentiation induction             by all-trans retinoic acid and arsenic trioxide and enhances arsenic uptake in             the acute promyelocytic leukemia cell line HT93A.
abstract: The effects of arsenic trioxide (ATO), all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF), alone or in combination, were investigated by focusing on differentiation, growth inhibition and arsenic uptake in the acute promyelocytic leukemia (APL) cell line HT93A. ATO induced differentiation at low concentrations (0.125 µM) and apoptosis at high concentrations (1-2 µM). Furthermore, ATRA induced greater differentiation than ATO. No synergistic effect of ATRA and ATO was found on differentiation. G-CSF promoted differentiation-inducing activities of both ATO and ATRA. The combination of ATRA and G-CSF showed maximum differentiation and ATO addition was not beneficial. Addition of 1 µM ATRA and/or 50 ng/ml G-CSF to ATO did not affect apoptosis compared to ATO treatment alone. ATRA induced expression of aquaporin-9 (AQP9), a transmembrane transporter recognized as a major pathway of arsenic uptake, in a time- and dose-dependent manner. However, treatment with 1 µM ATRA decreased arsenic uptake by 43.7% compared to control subject. Although G-CSF addition did not enhance AQP9 expression in the cells, the reduced arsenic uptake was recovered to the same level as that in controls. ATRA decreased cell viability and addition of 50 ng/ml G-CSF to ATRA significantly increased the number of viable cells compared with that in ATRA alone treated cells. G-CSF not only promotes differentiation-inducing activities of both ATRA and ATO, but also makes APL cells vulnerable to increased arsenic uptake. These observations provide new insights into combination therapy using these three agents for the treatment of APL.
authors.affiliation: Department of Hematology and Rheumatology, Itabashi Hospital,                     Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Iriyama
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hatta
authors.forename: Akira
authors.initials: A
authors.lastname: Horikoshi
authors.forename: Yuta
authors.initials: Y
authors.lastname: Yoshino
authors.forename: Hiroo
authors.initials: H
authors.lastname: Toyoda
authors.forename: Shin
authors.initials: S
authors.lastname: Aizawa
authors.forename: Jin
authors.initials: J
authors.lastname: Takeuchi
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D020346:Aquaporins / Q000096:biosynthesis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D014408:Biomarkers, Tumor; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016256:Lewis X Antigen / Q000378:metabolism; D010087:Oxides / Q000378:metabolism / Q000494:pharmacology*; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: C109669:AQP9 protein, human; D018952:Antigens, CD34; D020346:Aquaporins; D001152:Arsenicals; D014408:Biomarkers, Tumor; D039481:CD11b Antigen; D016256:Lewis X Antigen; D010087:Oxides; D016179:Granulocyte Colony-Stimulating Factor; D014212:Tretinoin; D000077237:Arsenic Trioxide