PMID- 26175935
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20150715
LR  - 20211110
IS  - 2156-6976 (Print)
IS  - 2156-6976 (Electronic)
IS  - 2156-6976 (Linking)
VI  - 5
IP  - 5
DP  - 2015
TI  - Effects of topoisomerase inhibitors that induce DNA damage response on glucose 
      metabolism and PI3K/Akt/mTOR signaling in multiple myeloma cells.
PG  - 1649-64
AB  - Hallmarks of cancer cells comprise altered glucose metabolism (aerobic 
      glycolysis) and differences in DNA damage response (DDR). Glucose transporters 
      (GLUT), glycolytic enzymes such as hexokinase (HK) and metabolic pathways (e.g. 
      PI3K/Akt/mTor) have been shown to be upregulated in multiple myeloma and other 
      cancer cell lines. Here we have investigated the effects of clinically used 
      inhibitors of topoisomerases, of DDR and of the PI3K/Akt/mTor pathway on glucose 
      metabolism and on cell survival in multiple myeloma cells. The effects of DNA 
      damaging topoisomerase inhibitors (doxorubicin, etoposide, topotecan), non-DNA 
      damaging agents (bortezomib, vincristine) as well as of molecular inhibitors of 
      DNA damage related kinases PIKKs (KU55933 [ATM], NU7026 [DNA-PKCs]) and 
      PI3K/Akt/mTor signaling (BEZ235 [PI3K/mTor], MK-2206 [Akt]) were analyzed 24 
      hours after treatment of OPM-2 multiple myeloma cells. For this purpose we 
      monitored [18F]-FDG uptake, cell viability using an ATP assay and expression of 
      GLUT-1, hexokinase II (HKII), cleaved caspase-3 and cleaved PARP via 
      Western-blotting. All topoisomerase inhibitors used could upregulate expression 
      of GLUT-1 and HKII in OPM-2 cells, resulting in elevated [18F]-FDG uptake and 
      promotion of cell survival. In contrast, bortezomib and vincristine induced a 
      decline in [18F]-FDG uptake combined with early induction of apoptosis. 
      Combination treatment with topoisomerase inhibitors and molecular inhibitors of 
      PIKK and PI3K could reverse elevated [18F]-FDG uptake, as observed after 
      application of topoisomerase inhibitors only, and aggravate induction of 
      apoptosis. Thus, elevated glucose consumption in OPM-2 cells can be reversed by 
      targeting both DDR and PI3K/Akt/mTOR signaling, thus providing a promising 
      strategy in the treatment of cancer.
FAU - Demel, Hans-Richard
AU  - Demel HR
AD  - Department of Nuclear Medicine, Technische Universitat Munchen Munich, Germany.
FAU - Feuerecker, Benedikt
AU  - Feuerecker B
AD  - Department of Nuclear Medicine, Technische Universitat Munchen Munich, Germany.
FAU - Piontek, Guido
AU  - Piontek G
AD  - Department of Otolaryngology-Head and Neck Surgery, Technische Universitat 
      Munchen Munich, Germany.
FAU - Seidl, Christof
AU  - Seidl C
AD  - Department of Nuclear Medicine, Technische Universitat Munchen Munich, Germany ; 
      Department of Obstetrics and Gynecology, Technische Universitat Munchen Munich, 
      Germany.
FAU - Blechert, Birgit
AU  - Blechert B
AD  - Department of Nuclear Medicine, Technische Universitat Munchen Munich, Germany.
FAU - Pickhard, Anja
AU  - Pickhard A
AD  - Department of Otolaryngology-Head and Neck Surgery, Technische Universitat 
      Munchen Munich, Germany.
FAU - Essler, Markus
AU  - Essler M
AD  - Department of Nuclear Medicine, Technische Universitat Munchen Munich, Germany ; 
      Department of Nuclear Medicine, Universitat sklinikum Bonn Bonn, Germany.
LA  - eng
PT  - Journal Article
DEP - 20150415
PL  - United States
TA  - Am J Cancer Res
JT  - American journal of cancer research
JID - 101549944
PMC - PMC4497433
OTO - NOTNLM
OT  - DNA damage response
OT  - Glucose metabolism
OT  - PI3K/Akt/mTor pathway
OT  - apoptosis
OT  - cancer treatment
OT  - cell survival
OT  - topoisomerase inhibitors
EDAT- 2015/07/16 06:00
MHDA- 2015/07/16 06:01
PMCR- 2015/04/15
CRDT- 2015/07/16 06:00
PHST- 2015/02/13 00:00 [received]
PHST- 2015/04/12 00:00 [accepted]
PHST- 2015/07/16 06:00 [entrez]
PHST- 2015/07/16 06:00 [pubmed]
PHST- 2015/07/16 06:01 [medline]
PHST- 2015/04/15 00:00 [pmc-release]
PST - epublish
SO  - Am J Cancer Res. 2015 Apr 15;5(5):1649-64. eCollection 2015.