title: Src family kinase inhibitor PP2 enhances differentiation of acute promyelocytic leukemia cell line induced by combination of all-trans-retinoic acid and arsenic trioxide.
abstract: An all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) combination yields high-quality remission and survival in newly-diagnosed acute promyelocytic leukemia (APL). For subsequent similar data, NCCN guidelines indicate that ATRA plus ATO is one of the recommended regimens for the treatment of patients with APL. We demonstrated SFK (Src family kinase) inhibitor PP2-enhanced APL cell differentiation when combined with either ATRA or ATO with difference in activation of RA-induced genes. In this study, we investigated whether SFK inhibitor PP2 could enhance the differentiation of NB4 APL cells when combined with ATRA and ATO and the changes in the expression of intercellular adhesion molecule-1 (ICAM-1) derived from the retinoic acid receptor (RAR) target gene. Treatment of NB4 cells with 1 μM of ATRA, 0.5 μM of ATO, or 10 μM of PP2 for 72 h induced expression of CD11b-positive cells by 13.01%, 11.53% or 13.28%, respectively. However, the combination of ATRA and ATO and the combination of three agents (ATRA, ATO, and PP2) led to a significantly higher expression of CD11b-positive cells (30.96% and 63.17%, respectively). The synergistic effect of the combination of three agents was more significant than the combination of ATRA and ATO. These results were confirmed with NBT staining. These effects were not related to apoptosis. Annexin-V-fluorescein staining revealed that a combination of ATRA and ATO and combination of the three agents did not induce apoptosis in NB4 cells. The expression of ICAM-1 markedly increased in cells treated with the combination of the three agents. These findings suggest that the SFK inhibitor can enhance differentiation of APL cells combined with ATRA and ATO. FDA approved SFK inhibitors, such as dasatinib and bosutinib, may be beneficial for the treatment of APL with a combination of ATRA and ATO.
authors: Division of Hematology-Oncology, Department of Internal Medicine, and Institute for Clinical Molecular Biology Research, Soonchunhang University College of Medicine, Soonchunhang University Seoul Hospital, Seoul, Republic of Korea.
authors: Yun Seok
authors: YS
authors: Jung
authors: Division of Hematology-Oncology, Department of Internal Medicine, and Institute for Clinical Molecular Biology Research, Soonchunhang University College of Medicine, Soonchunhang University Seoul Hospital, Seoul, Republic of Korea.
authors: Hee-Jeong
authors: HJ
authors: Cheong
authors: Division of Hematology-Oncology, Department of Internal Medicine, and Institute for Clinical Molecular Biology Research, Soonchunhang University College of Medicine, Soonchunhang University Seoul Hospital, Seoul, Republic of Korea.
authors: Sook-Ja
authors: SJ
authors: Kim
authors: Division of Hematology-Oncology, Department of Internal Medicine, and Institute for Clinical Molecular Biology Research, Soonchunhang University College of Medicine, Soonchunhang University Seoul Hospital, Seoul, Republic of Korea.
authors: Kyoung Ha
authors: KH
authors: Kim
authors: Division of Hematology-Oncology, Department of Internal Medicine, and Institute for Clinical Molecular Biology Research, Soonchunhang University College of Medicine, Soonchunhang University Seoul Hospital, Seoul, Republic of Korea.
authors: Namsu
authors: N
authors: Lee
authors: Division of Hematology-Oncology, Department of Internal Medicine, and Institute for Clinical Molecular Biology Research, Soonchunhang University College of Medicine, Soonchunhang University Seoul Hospital, Seoul, Republic of Korea.
authors: Hee Sook
authors: HS
authors: Park
authors: Division of Hematology-Oncology, Department of Internal Medicine, and Institute for Clinical Molecular Biology Research, Soonchunhang University College of Medicine, Soonchunhang University Seoul Hospital, Seoul, Republic of Korea. Electronic address: jhwon@schmc.ac.kr.
authors: Jong-Ho
authors: JH
authors: Won
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism / Q000473:pathology*; D010087:Oxides / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C412373:AG 1879; D001152:Arsenicals; D039481:CD11b Antigen; C509295:ITGAM protein, human; D010087:Oxides; D011743:Pyrimidines; D014212:Tretinoin; D000077237:Arsenic Trioxide
keywords: Acute promyelocytic leukemia; All-trans retinoic acid; Arsenic trioxide; Differentiation; Src kinase