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

Cancer Letters
Demetrius M Kokkinakis

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 alkylati...Continue Reading

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Citations

Jun 23, 2009·Annals of the New York Academy of Sciences·James M MullinMary Carmen Valenzano
Dec 18, 2008·International Journal of Cancer. Journal International Du Cancer·Jian Hu, Nai-Kong V Cheung
Mar 6, 2012·Biochemical and Biophysical Research Communications·Hao DingJi-xiang Zhang
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Nov 1, 2016·Applied Biochemistry and Biotechnology·Ashraf S A El-SayedSadik Esener
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Mar 23, 2021·Biochimica Et Biophysica Acta. Proteins and Proteomics·Timothy C FooKallidaikurichi V Venkatachalam

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