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Antimetabolite TTL-315 selectively kills glucose-deprived cancer cells and enhances responses to cytotoxic chemotherapy in preclinical models of cancer.

ABSTRACT: Maintaining thiol homeostasis is an imperative for cancer cell survival in the nutrient-deprived microenvironment of solid tumors. Despite this metabolic vulnerability, a selective approach has yet to be developed to disrupt thiol homeostasis in solid tumors for therapeutic purposes. In this study, we report the identification of 2-mercaptopropionyl glycine disulfide (TTL-315) as a novel antimetabolite that blocks cell survival in a manner conditional on glucose deprivation. In the presence of glucose, TTL-315 lacks cytotoxic effects in normal cells where it is detoxified by reduction to 2-mercaptopropionyl glycine, a compound with known clinical pharmacologic and safety profiles. In several rodent models of aggressive breast, lung and skin cancers, TTL-315 blocked tumor growth and cooperated with the DNA damaging drug cisplatin to trigger tumor regression. Our results offer preclinical proof of concept for TTL-315 as a novel antimetabolite to help selectively eradicate solid tumors by exploiting the glucose-deprived conditions of the tumor microenvironment.

SUBMITTER: DuHadaway J

PROVIDER: S-EPMC4884924 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Antimetabolite TTL-315 selectively kills glucose-deprived cancer cells and enhances responses to cytotoxic chemotherapy in preclinical models of cancer.

DuHadaway James J Prendergast George C GC

Oncotarget 20160201 7

Maintaining thiol homeostasis is an imperative for cancer cell survival in the nutrient-deprived microenvironment of solid tumors. Despite this metabolic vulnerability, a selective approach has yet to be developed to disrupt thiol homeostasis in solid tumors for therapeutic purposes. In this study, we report the identification of 2-mercaptopropionyl glycine disulfide (TTL-315) as a novel antimetabolite that blocks cell survival in a manner conditional on glucose deprivation. In the presence of g ...[more]

PMID: 26840263

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Project description:Malignant pleural mesothelioma is an aggressive cancer with poor prognosis. Here we have investigated in vitro efficacy of BAMLET and BLAGLET complexes (anti-cancer complexes consisting of oleic acid and bovine α-lactalbumin or β-lactoglobulin respectively) in killing mesothelioma cells, determined BAMLET and BLAGLET structures, and investigated possible biological mechanisms. We performed cell viability assays on 16 mesothelioma cell lines. BAMLET and BLAGLET having increasing oleic acid content inhibited human and rat mesothelioma cell line proliferation at decreasing doses. Most of the non-cancer primary human fibroblasts were more resistant to BAMLET than were human mesothelioma cells. BAMLET showed similar cytotoxicity to cisplatin-resistant, pemetrexed-resistant, vinorelbine-resistant, and parental rat mesothelioma cells, indicating the BAMLET anti-cancer mechanism may be different to drugs currently used to treat mesothelioma. Cisplatin, pemetrexed, gemcitabine, vinorelbine, and BAMLET, did not demonstrate a therapeutic window for mesothelioma compared with immortalised non-cancer mesothelial cells. We demonstrated by quantitative PCR that ATP synthase is downregulated in mesothelioma cells in response to regular dosing with BAMLET. We sought structural insight for BAMLET and BLAGLET activity by performing small angle X-ray scattering, circular dichroism, and scanning electron microscopy. Our results indicate the structural mechanism by which BAMLET and BLAGLET achieve increased cytotoxicity by holding increasing amounts of oleic acid in an active cytotoxic state encapsulated in increasingly unfolded protein. Our structural studies revealed similarity in the molecular structure of the protein components of these two complexes and in their encapsulation of the fatty acid, and differences in the microscopic structure and structural stability. BAMLET forms rounded aggregates and BLAGLET forms long fibre-like aggregates whose aggregation is more stable than that of BAMLET due to intermolecular disulphide bonds. The results reported here indicate that BAMLET and BLAGLET may be effective second-line treatment options for mesothelioma.

Dataset Information

Antimetabolite TTL-315 selectively kills glucose-deprived cancer cells and enhances responses to cytotoxic chemotherapy in preclinical models of cancer.

Publications

Antimetabolite TTL-315 selectively kills glucose-deprived cancer cells and enhances responses to cytotoxic chemotherapy in preclinical models of cancer.

Similar Datasets

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