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

// James DuHadaway 1 and George C. Prendergast 1,2 1 Lankenau Institute for Medical Research, Wynnewood, PA, USA 2 Sidney Kimmel Cancer Center and Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelpia, PA, USA Correspondence to: George C. Prendergast, email: // Keywords : cancer metabolism, tumor microenvironment, thiol homeostasis, pentose phosphate cycle, chemotherapy Received : October 02, 2015 Accepted : January 23, 2016 Published : January 28, 2016 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.