Methionine-stress: A pleiotropic approach in enhancing the efficacy of chemotherapy

• Published in: Cancer letters Vol. 233; no. 2; pp. 195 - 207
• Main Author: Kokkinakis, Demetrius M.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 28.02.2006; Elsevier Limited
• Subjects: Animals; Antineoplastic Agents, Alkylating - therapeutic use; Apoptosis; Brain tumors; Carbon-Sulfur Lyases - metabolism; Carmustine; CDK1; Cell cycle; Cell cycle check points; Chemotherapy; Deoxyribonucleic acid; Dihydrofolate reductase; DNA; DNA methylation; Enzymes; Gene expression; Homocysteine; Humans; Kinases; Metabolism; Metabolites; Methioninase; Methionine; Methionine - deficiency; Methionine-stress; Mitosis; Mutation; Neoplasms - drug therapy; Neoplasms - metabolism; O-Methylguanine-DNA Methyltransferase - metabolism; p21; p27; p53; Protein synthesis; Proteins; Signal Transduction; Temozolomide; Transcription factors; Tumors; Methionine-stress; Mitosis; Brain tumors; Carmustine; Methionine; Methioninase; p21; p53; p27; Cell cycle check points; CDK1; Temozolomide; Homocysteine
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2005.02.034

Malignant cells fail to utilize homocysteine (HCYS) in place of methionine (MET) and they are dependent on exogenous MET for growth. In animals, reduction of plasma MET to <5 μM can be induced by combined dietary restriction of MET and administration of l-methionine-α-deamino-γ-lyase (methioninase). This treatment, termed as MET-stress, inhibits the growth of brain tumor xenografts in athymic mice and enhances the efficacy of DNA alkylating chemotherapeutic agents. The response of tumors to MET-stress depends on their mutational status, however, it always involves inhibition of CDK1 and in most cases the upregulation of p21, p27, GADDs and 14-3-3σ in response to upregulation of TGF-β, IRF-1, TNF-α, Rb and/or MDA-7 and the downregulation of PI3K, RAS and NF-κB. Although inhibition of the cell cycle and mitosis is not necessarily dependent on the tumor's p53 status, the expression of p21, GADD45 and apoptosis related genes (BAX, BCL-2) are regulated by wt-p53, in addition to their regulation by TGF-β or MDA-7 in mutated p53 tumors. Mutational variability determines the mode of death (mitotic catastrophe versus apoptosis) in tumor cells subjected to MET-stress. The increase of the efficacy of alkylating agents is related to marked inhibition of O 6-methylguanine-DNA methyltransferase (MGMT) expression, the induction of cell cycle check points and the inhibition of pro-survival pathways by MET-stress.