Effect of a single nucleotide polymorphism in the murine double minute 2 promoter (SNP309) on the sensitivity to topoisomerase II-targeting drugs.
A single nucleotide polymorphism (SNP) SNP309 (T-->G) in the murine double minute 2 (MDM2) promoter creates a high-affinity Sp1 binding site and increases the expression of MDM2 mRNA and protein. Approximately 40% of the populations harbor at least one variant allele and 12% to 17% are homozygous G/G at codon 309. This MDM2 SNP increases susceptibility to cancer and decreases the response of cancer cells to certain forms of treatment, such as radiation therapy and DNA-damaging drugs. Topoisomerase II (TopoII)-targeting agents are commonly used chemotherapeutic drugs with a broad spectrum of activity. However, resistance to TopoII poisons limits their effectiveness. We show that MDM2 SNP309 rendered a panel of cancer cell lines that are homozygous for SNP309 selectively resistant (approximately 10-fold) to certain TopoII-targeting chemotherapeutic drugs (etoposide, mitoxantrone, amsacrine, and ellipticine). The mechanism underlying this observation was Mdm2-mediated down-regulation of TopoII; on drug exposure, MDM2 bound to TopoII and resulted in decreased cellular enzyme content. Knockdown of MDM2 by RNA interference stabilized TopoIIalpha and decreased resistance to TopoII-targeting drugs. Thus, MDM2 SNP309 (T-->G) may represent a relatively common, previously unappreciated determinant of drug sensitivity. Given the frequency of SNP309 in the general population (40% in heterozygous T/G and 12% in homozygous G/G condition), our observation may have important implications for the individualization of cancer chemotherapy.
Nayak
Mamatha S
MS
Department of Pharmacology, The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.
Yang
Jin-Ming
JM
Hait
William N
WN
D000677:Amsacrine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000187:drug effects / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004611:Ellipticines / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D018613:Microscopy, Confocal; D008942:Mitoxantrone / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D004611:Ellipticines; D000677:Amsacrine; C034192:ellipticine; D005047:Etoposide; D008942:Mitoxantrone; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D004250:DNA Topoisomerases, Type II