Search

Extensive studies in prostate cancer and other malignancies have revealed that L-methionine (L-Met) and its metabolites play a critical role in tumorigenesis. Preclinical and clinical studies have demonstrated that systemic restriction of serum L-Met, either via partial dietary restriction or with bacterial L-Met-degrading enzymes exerts potent antitumor effects. However, administration of bacterial L-Met-degrading enzymes has not proven practical for human therapy because of problems with immunogenicity. As the human genome does not encode L-Met-degrading enzymes, we engineered the human cystathionine-γ-lyase (hMGL-4.0) to catalyze the selective degradation of L-Met. At therapeutically relevant dosing, hMGL-4.0 reduces serum L-Met levels to >75% for >72 h and significantly inhibits the growth of multiple prostate cancer allografts/xenografts without weight loss or toxicity. We demonstrate that in vitro, hMGL-4.0 causes tumor cell death, associated with increased reactive oxygen species, S-adenosyl-methionine depletion, global hypomethylation, induction of autophagy, and robust poly(ADP-ribose) polymerase (PARP) cleavage indicative of DNA damage and apoptosis. [ABSTRACT FROM AUTHOR]