期刊
NEOPLASIA
卷 21, 期 2, 页码 230-238出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neo.2018.12.003
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资金
- Wales Gene Park
- Tuberous Sclerosis Association
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.
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