Amino acids are essential components in various biochemical pathways. The deprivation of certain amino acids is an antimetabolite strategy for the treatment of amino acid-dependent cancers which exploits the compromised metabolism of malignant cells. This review summarizes recent progress in the relationship between amino acids metabolism and cancer therapy, with a particular focus on L-asparagine, L-methionine, L-arginine and L-lysine degrading enzymes and their formulations, which have been successfully used in the treatment of several types of cancer.
Purpose-Transformed cells are vulnerable to depletion of certain amino acids. Lysine oxidase (LO) catalyzes the oxidative deamination of lysine, resulting in lysine depletion and hydrogen peroxide production. Although LO has broad antitumor activity in preclinical models, the cytotoxic mechanisms of LO are poorly understood.Methods-Triple (ER/PR/HER2)-negative breast cancer (TNBC) cells were treated with control media, lysine-free media or control media supplemented with LO and examined for cell viability, caspase activation, induction of reactive oxygen species (ROS) and antioxidant signaling. To determine the role of nuclear factor erythroid 2-related factor 2 (NRF2) and thioredoxin reductatase-1 (TXNRD1) in LO-induced cell death, NRF2 and TXNRD1 were individually silenced by RNAi. Additionally, the pan-TXNRD inhibitor auranofin was used in combination with LO.Results-LO activates caspase-independent cell death that is suppressed by necroptosis and ferroptosis inhibitors, which are inactive against lysine depletion, pointing to fundamental Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1
Prostate
cancer is the second most common type of cancer among
men. Its main method of treatment is chemotherapy, which has a wide
range of side effects. One of the solutions to this challenge is targeted
delivery to prostate cancer cells. Here we synthesized a novel small-molecule
PSMA-targeted conjugate based on the monomethyl auristatin E. Its
structure and conformational properties were investigated by NMR spectroscopy.
Cytotoxicity, intracellular reactive oxygen species induction, and
stability under liver microsomes and P450-cytochrome species were
investigated for this conjugate. The conjugate demonstrated 77–85%
tumor growth inhibition levels on 22Rv1 (PSMA (+)) xenografts, compared
with a 37% inhibition level on PC-3 (PSMA (−)) xenografts,
in a single dose of 0.3 mg/kg and a sufficiently high therapeutic
index of 21. Acute, chronic, and subchronic toxicities and pharmacokinetics
have shown that the synthesized conjugate is a promising potential
agent for the chemotherapy of prostate cancer.
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