Peters GJ

References (2)

Title : Multifactorial resistance to aminopeptidase inhibitor prodrug CHR2863 in myeloid leukemia cells: down-regulation of carboxylesterase 1, drug sequestration in lipid droplets and pro-survival activation ERK\/Akt\/mTOR - Verbrugge_2016_Oncotarget_7_5240
Author(s) : Verbrugge SE , Al M , Assaraf YG , Kammerer S , Chandrupatla DM , Honeywell R , Musters RP , Giovannetti E , O'Toole T , Scheffer GL , Krige D , de Gruijl TD , Niessen HW , Lems WF , Kramer PA , Scheper RJ , Cloos J , Ossenkoppele GJ , Peters GJ , Jansen G
Ref : Oncotarget , 7 :5240 , 2016
Abstract : Aminopeptidase inhibitors are receiving attention as combination chemotherapeutic agents for the treatment of refractory acute myeloid leukemia. However, the factors determining therapeutic efficacy remain elusive. Here we identified the molecular basis of acquired resistance to CHR2863, an orally available hydrophobic aminopeptidase inhibitor prodrug with an esterase-sensitive motif, in myeloid leukemia cells. CHR2863 enters cells by diffusion and is retained therein upon esterase activity-mediated conversion to its hydrophilic active metabolite drug CHR6768, thereby exerting amino acid depletion. Carboxylesterases (CES) serve as candidate prodrug activating enzymes given CES1 expression in acute myeloid leukemia specimens. We established two novel myeloid leukemia sublines U937/CHR2863(200) and U937/CHR2863(5uM), with low (14-fold) and high level (270-fold) CHR2863 resistance. The latter drug resistant cells displayed: (i) complete loss of CES1-mediated drug activation associated with down-regulation of CES1 mRNA and protein, (ii) marked retention/sequestration of the prodrug, (iii) a substantial increase in intracellular lipid droplets, and (iv) a dominant activation of the pro-survival Akt/mTOR pathway. Remarkably, the latter feature coincided with a gain of sensitivity to the mTOR inhibitor rapamycin. These finding delineate the molecular basis of CHR2863 resistance and offer a novel modality to overcome this drug resistance in myeloid leukemia cells.
ESTHER : Verbrugge_2016_Oncotarget_7_5240
PubMedSearch : Verbrugge_2016_Oncotarget_7_5240
PubMedID: 26496029

Title : Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences - Strausberg_2002_Proc.Natl.Acad.Sci.U.S.A_99_16899
Author(s) : Strausberg RL , Feingold EA , Grouse LH , Derge JG , Klausner RD , Collins FS , Wagner L , Shenmen CM , Schuler GD , Altschul SF , Zeeberg B , Buetow KH , Schaefer CF , Bhat NK , Hopkins RF , Jordan H , Moore T , Max SI , Wang J , Hsieh F , Diatchenko L , Marusina K , Farmer AA , Rubin GM , Hong L , Stapleton M , Soares MB , Bonaldo MF , Casavant TL , Scheetz TE , Brownstein MJ , Usdin TB , Toshiyuki S , Carninci P , Prange C , Raha SS , Loquellano NA , Peters GJ , Abramson RD , Mullahy SJ , Bosak SA , McEwan PJ , McKernan KJ , Malek JA , Gunaratne PH , Richards S , Worley KC , Hale S , Garcia AM , Gay LJ , Hulyk SW , Villalon DK , Muzny DM , Sodergren EJ , Lu X , Gibbs RA , Fahey J , Helton E , Ketteman M , Madan A , Rodrigues S , Sanchez A , Whiting M , Young AC , Shevchenko Y , Bouffard GG , Blakesley RW , Touchman JW , Green ED , Dickson MC , Rodriguez AC , Grimwood J , Schmutz J , Myers RM , Butterfield YS , Krzywinski MI , Skalska U , Smailus DE , Schnerch A , Schein JE , Jones SJ , Marra MA
Ref : Proc Natl Acad Sci U S A , 99 :16899 , 2002
Abstract : The National Institutes of Health Mammalian Gene Collection (MGC) Program is a multiinstitutional effort to identify and sequence a cDNA clone containing a complete ORF for each human and mouse gene. ESTs were generated from libraries enriched for full-length cDNAs and analyzed to identify candidate full-ORF clones, which then were sequenced to high accuracy. The MGC has currently sequenced and verified the full ORF for a nonredundant set of >9,000 human and >6,000 mouse genes. Candidate full-ORF clones for an additional 7,800 human and 3,500 mouse genes also have been identified. All MGC sequences and clones are available without restriction through public databases and clone distribution networks (see http:mgc.nci.nih.gov).
ESTHER : Strausberg_2002_Proc.Natl.Acad.Sci.U.S.A_99_16899
PubMedSearch : Strausberg_2002_Proc.Natl.Acad.Sci.U.S.A_99_16899
PubMedID: 12477932
Gene_locus related to this paper: bovin-q3zcj6 , danre-OVCA2 , danre-q4qrh4 , danre-q4v960 , danre-q32ls6 , danre-q503e2 , ratno-CPVL , ratno-q3mhs0 , ratno-q4qr68 , ratno-q5fvr5 , ratno-q32q55 , xenla-a2bd54 , xenla-q2tap9 , xenla-q3kq37 , xenla-q3kq76 , xenla-q4klb6 , xenla-q32n48 , xenla-q32ns5 , xenla-q52l41 , xentr-q4va73 , danre-a7mbu9