title: 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.
authors: Lankenau Institute for Medical Research, Wynnewood, PA, USA.
authors: James
authors: J
authors: DuHadaway
authors: Lankenau Institute for Medical Research, Wynnewood, PA, USA.|Sidney Kimmel Cancer Center and Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelpia, PA, USA.
authors: George C
authors: GC
authors: Prendergast
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000963:Antimetabolites; D000970:Antineoplastic Agents; D004151:Dipeptides; C000613031:TTL-315; D005947:Glucose; D002945:Cisplatin
keywords: cancer metabolism; chemotherapy; pentose phosphate cycle; thiol homeostasis; tumor microenvironment