Methionine-stress: a pleiotropic approach in enhancing the efficacy of chemotherapy.
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.
Kokkinakis
Demetrius M
DM
Department of Pathology and the Cancer Institute, Hillman Cancer Center, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. kokkinakisdm@upmc.edu
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
D018906:Antineoplastic Agents, Alkylating; D008715:Methionine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase