Expression of human glutathione S-transferases in Saccharomyces cerevisiae confers resistance to the anticancer drugs adriamycin and chlorambucil

TY - JOUR

T1 - Expression of human glutathione S-transferases in Saccharomyces cerevisiae confers resistance to the anticancer drugs adriamycin and chlorambucil

AU - Black, S M

AU - Beggs, J D

AU - Hayes, J D

AU - Bartoszek, A

AU - Muramatsu, M

AU - Sakai, M

AU - Wolf, C R

PY - 1990/6/1

Y1 - 1990/6/1

N2 - Adaptation and resistance to chemicals in the environment is a critical part of the evolutionary process. As a result, a wide variety of defence systems that protect cells against chemical insult have evolved. Such chemical resistance mechanisms appear to play a central role in determining the sensitivity of human tumours to treatment with chemotherapeutic drugs. The glutathione S-transferases (GST) are important detoxification enzymes whose over-expression has been associated with drug-resistance. In order to evaluate this possibility we have expressed the human Alpha-class and Pi-class GST cDNAs that encode GST B1B1 and GST pi in the yeast Saccharomyces cerevisiae. The expression of GST B1B1 or GST pi resulted in a marked reduction in the cytotoxic effects of chlorambucil, a bifunctional alkylating agent, and an anthracycline, adriamycin. These data provide direct evidence that the over-expression of GST in cells can confer resistance to anticancer drugs.

AB - Adaptation and resistance to chemicals in the environment is a critical part of the evolutionary process. As a result, a wide variety of defence systems that protect cells against chemical insult have evolved. Such chemical resistance mechanisms appear to play a central role in determining the sensitivity of human tumours to treatment with chemotherapeutic drugs. The glutathione S-transferases (GST) are important detoxification enzymes whose over-expression has been associated with drug-resistance. In order to evaluate this possibility we have expressed the human Alpha-class and Pi-class GST cDNAs that encode GST B1B1 and GST pi in the yeast Saccharomyces cerevisiae. The expression of GST B1B1 or GST pi resulted in a marked reduction in the cytotoxic effects of chlorambucil, a bifunctional alkylating agent, and an anthracycline, adriamycin. These data provide direct evidence that the over-expression of GST in cells can confer resistance to anticancer drugs.

KW - Alkylating Agents/pharmacology

KW - Chlorambucil/pharmacology

KW - DNA, Fungal/biosynthesis

KW - DNA, Recombinant/biosynthesis

KW - Doxorubicin/pharmacology

KW - Drug Resistance, Microbial

KW - Escherichia coli/genetics

KW - Gene Expression

KW - Glutathione Transferase/biosynthesis

KW - Microbial Sensitivity Tests

KW - Saccharomyces cerevisiae/drug effects

U2 - 10.1042/bj2680309

DO - 10.1042/bj2680309

M3 - Article

C2 - 2194447

SN - 0264-6021

VL - 268

SP - 309

EP - 315

JO - Biochemical Journal

JF - Biochemical Journal

IS - 2

ER -