title: Synergism between the mTOR inhibitor rapamycin and FAK down-regulation in the treatment of acute lymphoblastic leukemia.
abstract: BACKGROUND
  Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells in both children and adults. Although improvements in contemporary therapy and development of new treatment strategies have led to dramatic increases in the cure rate in children with ALL, the relapse rate remains high and the prognosis of relapsed childhood ALL is poor. Molecularly targeted therapies have emerged as the leading treatments in cancer therapy. Multi-cytotoxic drug regimens have achieved success, yet many studies addressing targeted therapies have focused on only one single agent. In this study, we attempted to investigate whether the effect of the mammalian target of rapamycin (mTOR) inhibitor rapamycin is synergistic with the effect of focal adhesion kinase (FAK) down-regulation in the treatment of ALL.
  
  
  METHODS
  The effect of rapamycin combined with FAK down-regulation on cell proliferation, the cell cycle, and apoptosis was investigated in the human precursor B acute lymphoblastic leukemia cells REH and on survival time and leukemia progression in a non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse model.
  
  
  RESULTS
  When combined with FAK down-regulation, rapamycin-induced suppression of cell proliferation, G0/G1 cell cycle arrest, and apoptosis were significantly enhanced. In addition, REH cell-injected NOD/SCID mice treated with rapamycin and a short-hairpin RNA (shRNA) to down-regulate FAK had significantly longer survival times and slower leukemia progression compared with mice injected with REH-empty vector cells and treated with rapamycin. Moreover, the B-cell CLL/lymphoma-2 (BCL-2) gene family was shown to be involved in the enhancement, by combined treatment, of REH cell apoptosis.
  
  
  CONCLUSIONS
  FAK down-regulation enhanced the in vitro and in vivo inhibitory effects of rapamycin on REH cell growth, indicating that the simultaneous targeting of mTOR- and FAK-related pathways might offer a novel and powerful strategy for treating ALL.
authors.affiliation: Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, West Yan Jiang Road, Guangzhou, Guangdong, 510120, China. scorpiospj@163.com.
authors.forename: Pei-Jie
authors.initials: PJ
authors.lastname: Shi
authors.affiliation: Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, West Yan Jiang Road, Guangzhou, Guangdong, 510120, China. xulvhong@126.com.
authors.forename: Lu-Hong
authors.initials: LH
authors.lastname: Xu
authors.affiliation: Department of Life Science, Sun Yat-sen University, No. 135, West Xin Gang Road, Guangzhou, Guangdong, 510275, China. xiaoyu85321@126.com.
authors.forename: Kang-Yu
authors.initials: KY
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, West Yan Jiang Road, Guangzhou, Guangdong, 510120, China. wengwenjunlin@126.com.
authors.forename: Wen-jun
authors.initials: WJ
authors.lastname: Weng
authors.affiliation: Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, West Yan Jiang Road, Guangzhou, Guangdong, 510120, China. jpfang2005@163.com.
authors.forename: Jian-Pei
authors.initials: JP
authors.lastname: Fang
mesh_terms: D000293:Adolescent; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C546842:MTOR protein, human; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus