PMID- 30622053
OWN - NLM
STAT- MEDLINE
DCOM- 20190211
LR  - 20211204
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 21
IP  - 2
DP  - 2019 Feb
TI  - Efficacy of Dual Inhibition of Glycolysis and Glutaminolysis for Therapy of Renal 
      Lesions in Tsc2(+/-) Mice.
PG  - 230-238
LID - S1476-5586(18)30575-X [pii]
LID - 10.1016/j.neo.2018.12.003 [doi]
AB  - Tuberous sclerosis is caused by mutations in the TSC1 or TSC2 gene and 
      characterized by development of tumors in multiple organs including the kidneys. 
      TSC-associated tumors exhibit somatic loss of the second allele of the TSC genes, 
      leading to aberrant activation of the mechanistic target of rapamycin (mTOR) 
      signaling pathway. Activation of mTOR complex 1 (mTORC1) causes addiction to 
      glucose and glutamine in Tsc1(-/-)or Tsc2(-/-) mouse embryonic fibroblasts 
      (MEFs). Blocking of glutamine anaplerosis in combination with glycolytic 
      inhibition causes significant cell death in Tsc2(-/-) but not Tsc2(+/+) MEFs. In 
      this study, we tested efficacy of dual inhibition of glycolysis with 3-BrPA and 
      glutaminolysis with CB-839 for renal tumors in Tsc2(+/-) mice. Following 2 months 
      of treatment of Tsc2(+/-) mice from the age of 12 months, combination of 3-BrPA 
      and CB-839 significantly reduced overall size and cellular areas of all renal 
      lesions (cystic/papillary adenomas and solid carcinomas), but neither alone did. 
      Combination of 3-BrPA and CB-839 inhibited mTORC1 and the proliferation of tumor 
      cells but did not increase apoptosis. However, combination of 3-BrPA and CB-839 
      was not as efficacious as rapamycin alone or rapamycin in combination with either 
      3-BrPA or CB-839 for renal lesions of Tsc2(+/-) mice. Consistently, rapamycin 
      alone or rapamycin in combination with either 3-BrPA or CB-839 had stronger 
      inhibitory effects on mTORC1 and proliferation of tumor cells than combination of 
      3-BrPA and CB-839. We conclude that combination of 3-BRPA and CB-839 may not 
      offer a better therapeutic strategy than rapamycin for TSC-associated tumors.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Jones, Ashley T
AU  - Jones AT
AD  - Institute of Medical Genetics, Division of Cancer and Genetics, School of 
      Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
FAU - Narov, Kalin
AU  - Narov K
AD  - Institute of Medical Genetics, Division of Cancer and Genetics, School of 
      Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
FAU - Yang, Jian
AU  - Yang J
AD  - Institute of Medical Genetics, Division of Cancer and Genetics, School of 
      Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
FAU - Sampson, Julian R
AU  - Sampson JR
AD  - Institute of Medical Genetics, Division of Cancer and Genetics, School of 
      Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
FAU - Shen, Ming Hong
AU  - Shen MH
AD  - Institute of Medical Genetics, Division of Cancer and Genetics, School of 
      Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. Electronic 
      address: shenmh@cf.ac.uk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190108
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (3-bromo-2-oxopropionic acid)
RN  - 0 (Benzeneacetamides)
RN  - 0 (CB-839)
RN  - 0 (Pyruvates)
RN  - 0 (Thiadiazoles)
RN  - 0 (Tsc2 protein, mouse)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Benzeneacetamides/pharmacology
MH  - Cell Proliferation/drug effects
MH  - Disease Models, Animal
MH  - Genotype
MH  - Glucose/*metabolism
MH  - Glutamic Acid/*metabolism
MH  - Glycolysis/drug effects
MH  - Immunohistochemistry
MH  - Kidney Diseases/drug therapy/*genetics/*metabolism/pathology
MH  - Kidney Neoplasms/genetics/metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Pyruvates/pharmacology
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Thiadiazoles/pharmacology
MH  - Tuberous Sclerosis Complex 2 Protein/genetics/metabolism
PMC - PMC6324218
EDAT- 2019/01/10 06:00
MHDA- 2019/02/12 06:00
PMCR- 2019/01/08
CRDT- 2019/01/10 06:00
PHST- 2018/10/25 00:00 [received]
PHST- 2018/12/12 00:00 [revised]
PHST- 2018/12/13 00:00 [accepted]
PHST- 2019/01/10 06:00 [pubmed]
PHST- 2019/02/12 06:00 [medline]
PHST- 2019/01/10 06:00 [entrez]
PHST- 2019/01/08 00:00 [pmc-release]
AID - S1476-5586(18)30575-X [pii]
AID - 10.1016/j.neo.2018.12.003 [doi]
PST - ppublish
SO  - Neoplasia. 2019 Feb;21(2):230-238. doi: 10.1016/j.neo.2018.12.003. Epub 2019 Jan 
      8.