PMID- 33303632
OWN - NLM
STAT- MEDLINE
DCOM- 20210830
LR  - 20231111
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 296
DP  - 2021 Jan-Jun
TI  - A cell competition-based small molecule screen identifies a novel compound that 
      induces dual c-Myc depletion and p53 activation.
PG  - 100179
LID - S0021-9258(20)00175-1 [pii]
LID - 10.1074/jbc.RA120.015285 [doi]
LID - 100179
AB  - Breakpoint Cluster Region-Abelson kinase (BCR-Abl) is a driver oncogene that 
      causes chronic myeloid leukemia and a subset of acute lymphoid leukemias. 
      Although tyrosine kinase inhibitors provide an effective treatment for these 
      diseases, they generally do not kill leukemic stem cells (LSCs), the 
      cancer-initiating cells that compete with normal hematopoietic stem cells for the 
      bone marrow niche. New strategies to target cancers driven by BCR-Abl are 
      therefore urgently needed. We performed a small molecule screen based on 
      competition between isogenic untransformed cells and BCR-Abl-transformed cells 
      and identified several compounds that selectively impair the fitness of 
      BCR-Abl-transformed cells. Interestingly, systems-level analysis of one of these 
      novel compounds, DJ34, revealed that it induced depletion of c-Myc and activation 
      of p53. DJ34-mediated c-Myc depletion occurred in a wide range of tumor cell 
      types, including lymphoma, lung, glioblastoma, breast cancer, and several forms 
      of leukemia, with primary LSCs being particularly sensitive to DJ34. Further 
      analyses revealed that DJ34 interferes with c-Myc synthesis at the level of 
      transcription, and we provide data showing that DJ34 is a DNA intercalator and 
      topoisomerase II inhibitor. Physiologically, DJ34 induced apoptosis, cell cycle 
      arrest, and cell differentiation. Taken together, we have identified a novel 
      compound that dually targets c-Myc and p53 in a wide variety of cancers, and with 
      particularly strong activity against LSCs.
CI  - Copyright (c) 2020 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Tadele, Dagim Shiferaw
AU  - Tadele DS
AD  - Department of Molecular Cell Biology, Institute for Cancer Research, The 
      Norwegian Radium Hospital, Oslo, Norway.
FAU - Robertson, Joseph
AU  - Robertson J
AD  - Department of Molecular Cell Biology, Institute for Cancer Research, The 
      Norwegian Radium Hospital, Oslo, Norway.
FAU - Crispin, Richard
AU  - Crispin R
AD  - Department of Molecular Cell Biology, Institute for Cancer Research, The 
      Norwegian Radium Hospital, Oslo, Norway.
FAU - Herrera, Maria C
AU  - Herrera MC
AD  - Section for Biochemistry and Molecular Biology, Faculty of Mathematics and 
      Natural Sciences, University of Oslo, Oslo, Norway.
FAU - Chlubnova, Marketa
AU  - Chlubnova M
AD  - Department of Molecular Cell Biology, Institute for Cancer Research, The 
      Norwegian Radium Hospital, Oslo, Norway.
FAU - Piechaczyk, Laure
AU  - Piechaczyk L
AD  - Department of Molecular Cell Biology, Institute for Cancer Research, The 
      Norwegian Radium Hospital, Oslo, Norway.
FAU - Ayuda-Duran, Pilar
AU  - Ayuda-Duran P
AD  - Department of Molecular Cell Biology, Institute for Cancer Research, The 
      Norwegian Radium Hospital, Oslo, Norway.
FAU - Singh, Sachin Kumar
AU  - Singh SK
AD  - Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium 
      Hospital, Oslo, Norway.
FAU - Gedde-Dahl, Tobias
AU  - Gedde-Dahl T
AD  - Department of Hematology, Oslo University Hospital, Oslo, Norway.
FAU - Floisand, Yngvar
AU  - Floisand Y
AD  - Department of Hematology, Oslo University Hospital, Oslo, Norway.
FAU - Skavland, Jorn
AU  - Skavland J
AD  - Precision Oncology Research Group, Department of Clinical Science, University of 
      Bergen, Bergen, Norway.
FAU - Wesche, Jorgen
AU  - Wesche J
AD  - Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium 
      Hospital, Oslo, Norway.
FAU - Gjertsen, Bjorn-Tore
AU  - Gjertsen BT
AD  - Precision Oncology Research Group, Department of Clinical Science, University of 
      Bergen, Bergen, Norway.
FAU - Enserink, Jorrit M
AU  - Enserink JM
AD  - Department of Molecular Cell Biology, Institute for Cancer Research, The 
      Norwegian Radium Hospital, Oslo, Norway. Electronic address: 
      jorrit.enserink@ibv.uio.no.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201217
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Antineoplastic Agents)
RN  - 0 (MYC protein, human)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (Small Molecule Libraries)
RN  - 0 (Tumor Suppressor Protein p53)
SB  - IM
MH  - Antineoplastic Agents/chemistry/*pharmacology
MH  - Cell Competition/*drug effects
MH  - Cell Line, Tumor
MH  - Drug Screening Assays, Antitumor/*methods
MH  - Humans
MH  - Neoplasms/drug therapy/metabolism
MH  - Proto-Oncogene Proteins c-myc/*metabolism
MH  - Small Molecule Libraries/chemistry/*pharmacology
MH  - Tumor Suppressor Protein p53/*metabolism
PMC - PMC7948465
OTO - NOTNLM
OT  - Abl
OT  - anticancer drug
OT  - c-Myc
OT  - drug screening
OT  - leukemia
OT  - mRNA
OT  - p53
OT  - phosphoproteomics
OT  - tyrosine kinase
COIS- Conflict of interest J. M. E. has received research funding from ARIAD 
      pharmaceuticals (now part of Takeda Oncology). The other authors do not declare 
      conflict of interest.
EDAT- 2020/12/12 06:00
MHDA- 2021/08/31 06:00
PMCR- 2020/12/17
CRDT- 2020/12/11 05:50
PHST- 2020/07/18 00:00 [received]
PHST- 2020/11/26 00:00 [revised]
PHST- 2020/12/10 00:00 [accepted]
PHST- 2020/12/12 06:00 [pubmed]
PHST- 2021/08/31 06:00 [medline]
PHST- 2020/12/11 05:50 [entrez]
PHST- 2020/12/17 00:00 [pmc-release]
AID - S0021-9258(20)00175-1 [pii]
AID - 100179 [pii]
AID - 10.1074/jbc.RA120.015285 [doi]
PST - ppublish
SO  - J Biol Chem. 2021 Jan-Jun;296:100179. doi: 10.1074/jbc.RA120.015285. Epub 2020 
      Dec 17.