Inhibition of tachykinin NK1receptor using aprepitant induces apoptotic cell death and G1 arrest through Akt/p53 axis in pre-B acute lymphoblastic leukemia cells.
Increasing number of genetic and cancer biology studies indicated a prominent role for tachykinin NK1receptor (NK1R) in cancer cell growth and survival. Considering the fact that neoplastic lymphoid precursors in acute lymphoblastic leukemia (ALL) carry a three- to four-fold NK1R expression as compared to normal lymphocytes, using NK1R antagonist seems to be noteworthy in the treatment of ALL patients. In this study, we found that inhibition of NK1R with aprepitant, a selective high-affinity antagonist of the human NK1R, exerts cytotoxic and anti-proliferative effects against pre-B ALL-derived Nalm-6 cells either as single drug or in combination with doxorubicin. Our data showed that treatment of the cells with the inhibitor resulted in apoptotic cell death, at least partly, through abrogation of PI3K/Akt pathway, as revealed by the reduction of phospho/total Akt ratio. In agreement with the inhibitory effect on Akt, we also found that aprepitant increased the expression level of p21 and p27, which in turn leads to the induction of G1 cell cycle arrest. Overall, this study recommends mechanistic pathways by which inhibition of NK1R can augment apoptotic cell death through a plausible p53-dependent pathway rather than NF-κB-depended mechanism in pre-B ALL cells; however, further studies are needed to better characterize the application of NK1R inhibition in clinical cancer treatment.
Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran; Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Samaneh
S
Bayati
Department of Hematology and Blood banking, Faculty of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Davood
D
Bashash
Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran. Electronic address: sh.ahmadian@ut.ac.ir.
Shahin
S
Ahmadian
Department of Hematology and Blood banking, Faculty of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Ava
A
Safaroghli-Azar
Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Kamran
K
Alimoghaddam
Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Ardeshir
A
Ghavamzadeh
Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: shghaffari200@yahoo.com.
Seyed H
SH
Ghaffari
D017209:Apoptosis / Q000187:drug effects*; D000077608:Aprepitant; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009025:Morpholines / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D009025:Morpholines; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D018039:Receptors, Tachykinin; D016159:Tumor Suppressor Protein p53; D000077608:Aprepitant; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3
Acute lymphoblastic leukemia; Aprepitant; Nalm-6 cells; P53; Tachykinin NK(1) receptor