title: Antileukaemia effect of rapamycin alone or in combination with daunorubicin on Ph+ acute lymphoblastic leukaemia cell line.
abstract: The translocation (9;22) (q34;q11), known as the Philadelphia (Ph) chromosome and bcr-abl fusion gene, is the common cytogenetic abnormality and an unfavourable prognosis in adult acute lymphoblastic leukaemia (ALL). Although chemotherapeutic treatment produced high rates of complete response in approximately 70%-80% of newly diagnosed Ph+ ALL, the onset of resistance and clinical relapse is rapid. Therefore, the efficacy of treatment in Ph+ ALL is still to be determined. In this study, we aimed to assess the antileukemic activity of rapamycin (RAPA) (Sigma-Aldrich Corporation, MO, USA), a mammalian target of rapamycin inhibitor, alone and in combination with daunorubicin (DNR) (Pharmacia & Upjohn Company, Germany) in a Ph+ acute lymphoblastic cell line SUP-B15 and a primary Ph+ ALL sample in vitro. Here, we demonstrated that 50 nmol/L of RAPA significantly intensified the inhibition induced by DNR on both Ph+ ALL cell line and a primary Ph+ ALL sample. Notably, we reported that the consequence of DNR treatment induced the over expression of the components of mammalian target of rapamycin signalling pathway, whereas RAPA effectively eliminated this deleterious side effect of DNR, which might enhance DNR's ability to kill drug-resistant cancer. The synergistic effect was also associated with the increase in autophagy, blockage of cell cycle progression in the G1 phase. Altogether, our results suggest that DNR in combination with RAPA is more effective in the treatment of Ph+ ALL compared with DNR alone.
authors: Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China.
authors: Xi
authors: X
authors: Yang
authors: Juan
authors: J
authors: Lin
authors: Yuping
authors: Y
authors: Gong
authors: Hongbing
authors: H
authors: Ma
authors: Xiao
authors: X
authors: Shuai
authors: Ruiqing
authors: R
authors: Zhou
authors: Yong
authors: Y
authors: Guo
authors: Qingqing
authors: Q
authors: Shan
authors: Guangcui
authors: G
authors: He
mesh_terms: D000328:Adult; D001343:Autophagy / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D003630:Daunorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D020014:K562 Cells / Q000187:drug effects; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology; D010588:Phagosomes / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000032:analysis / Q000502:physiology; D014410:Tumor Stem Cell Assay
chemical_list: D009363:Neoplasm Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D003630:Daunorubicin