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Cancer Lett. 2006 Feb 28;233(2):195-207.

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

Author information

1
Department of Pathology and the Cancer Institute, Hillman Cancer Center, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. kokkinakisdm@upmc.edu

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.

PMID:
16520149
DOI:
10.1016/j.canlet.2005.02.034
[Indexed for MEDLINE]

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