Inhibition of mammalian target of rapamycin signaling potentiates the effects of all-trans retinoic acid to induce growth arrest and differentiation of human acute myelogenous leukemia cells.
Our study explored the drug interaction of all-trans retinoic acid (ATRA) and RAD001 (everolimus), the inhibitor of mammalian target of rapamycin complex 1 (mTORC1), in acute myelogenous leukemia (AML) NB4 and HL60 cells. RAD001 (10 nM) significantly enhanced the ATRA-induced growth arrest and differentiation of these cells, as measured by colony-forming assay and cell cycle analysis, and expression of CD11b cell surface antigen and nitroblue tetrazolium reduction, respectively. ATRA (0.1-1 microM) upregulated levels of RTP801, a negative regulator of mTORC1, and inhibited mTORC1 signaling as assessed by measurement of the levels of p-p70S6K and p-4E-BP1 in HL60 and NB4 cells. ATRA (0.1-1 microM) in combination with RAD001 (10 nM) strikingly downregulated the levels of p-70S6K and p-4E-BP1 without affecting the total amount of these proteins. Notably, RAD001 (10 nM) significantly augmented ATRA-induced expression of CCAAT/enhancer-binding protein epsilon (C/EBPepsilon) and p27(kip1) and downregulated levels of c-Myc in these cells. Furthermore, RAD001 (5 mg/kg) enhanced the ability of ATRA (10 mg/kg) to inhibit the proliferation of HL60 cells growing as tumor xenografts in immune-deficient nude mice. Taken together, concomitant blockade of the RA and mTORC1 signaling may be a promising treatment strategy for individuals with AML.
Nishioka
Chie
C
Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
Ikezoe
Takayuki
T
Yang
Jing
J
Gery
Sigal
S
Koeffler
H Phillip
HP
Yokoyama
Akihito
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins; D039481:CD11b Antigen / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation; D004357:Drug Synergism; D000068338:Everolimus; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D009580:Nitroblue Tetrazolium / Q000378:metabolism; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D022762:CCAAT-Enhancer-Binding Proteins; D039481:CD11b Antigen; C469991:DDIT4 protein, human; C509295:ITGAM protein, human; C489427:MYC protein, human; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; C070790:CEBPE protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27; D009580:Nitroblue Tetrazolium; D014212:Tretinoin; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus