Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Efficacy of dual inhibition of glycolysis and glutaminolysis for therapy of renal lesions in Tsc2+/− Mice1

Jones, Ashley T., Narov, Kalin, Yang, Jian, Sampson, Julian R. and Shen, Ming Hong 2019. Efficacy of dual inhibition of glycolysis and glutaminolysis for therapy of renal lesions in Tsc2+/− Mice1. NEOPLASIA 21 (2) , pp. 230-238. 10.1016/j.neo.2018.12.003

[img]
Preview
PDF - Published Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.

Download (3MB) | Preview

Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Elsevier
ISSN: 1522-8002
Date of First Compliant Deposit: 10 January 2019
Date of Acceptance: 13 December 2018
Last Modified: 21 Aug 2019 02:14
URI: http://orca.cf.ac.uk/id/eprint/118284

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics