title: Methionine-stress: a pleiotropic approach in enhancing the efficacy of chemotherapy.
abstract: 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 microM can be induced by combined dietary restriction of MET and administration of L-methionine-alpha-deamino-gamma-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 14-3-3sigma in response to upregulation of TGF-beta, IRF-1, TNF-alpha, Rb and/or MDA-7 and the downregulation of PI3K, RAS and NF-kappaB. 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-beta 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 O6-methylguanine-DNA methyltransferase (MGMT) expression, the induction of cell cycle check points and the inhibition of pro-survival pathways by MET-stress.
authors.affiliation: Department of Pathology and the Cancer Institute, Hillman Cancer Center, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. kokkinakisdm@upmc.edu
authors.forename: Demetrius M
authors.initials: DM
authors.lastname: Kokkinakis
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D013437:Carbon-Sulfur Lyases / Q000378:metabolism; D006801:Humans; D008715:Methionine / Q000172:deficiency*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018906:Antineoplastic Agents, Alkylating; D008715:Methionine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase