NADPH/quinone oxidoreductase is a priority target of glioblastoma chemotherapy.
We attempted to determine a target of chemotherapy specific to glioblastoma cells to ensure a favorable response to anticancer drugs, through comparison in biologic nature related to drug resistance with other types of cancer cells. Using 13 human cancer cell lines including 3 glioblastoma lines, gene expression analysis and biochemical quantitative assay were performed for a total of 12 properties, which have been linked to drug action. Although most of genes related to drug resistance, such as MDR1, MRP, MGMT and GSTpi, were overexpressed in T98G, U-373MG, and U-251MG glioblastoma cells, Topo I (topoisomerase I) expression was relatively low and alpha- and beta-TUB (tubulin) expression was comparable to other types of 10 cell lines. The glioblastoma cell lines also showed an increased expression of NADPH/quinone oxidoreductase gene (NQO1), but the respective enzyme NQO activated MMC. Among the drugs targeting such properties, MMC was more active than Topo I inhibitors and docetaxel (TXT) due to the lack of other sensitivity (resistance) determinants. Differing from MMC, MGMT was shown to participate in the resistance of Topo I inhibitors (CPT-11, SN-38 and DX-8951f), while GSTpi and MDR1 were involved in docetaxel (TXT) resistance. MMC was also more active than ACNU and CDDP in the three glioblastoma cells. NQO may be a priority target of glioblastoma chemotherapy suitable for biochemical nature of the cells, and expression analysis of NQO1, alpha-TUB, beta-TUB, MGMT, MDR1 and GSTpi may help to seek a truly active drug against glioblastomas.
Okamura
T
T
Department of Neurosurgery, Hiroshima University School of Medicine, Hiroshima, Japan.
Kurisu
K
K
Yamamoto
W
W
Takano
H
H
Nishiyama
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology; D004264:DNA Topoisomerases, Type I / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016685:Mitomycin / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000187:drug effects / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism*; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D014404:Tubulin; D016685:Mitomycin; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase; D004264:DNA Topoisomerases, Type I; D005978:Glutathione