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NADPH/quinone oxidoreductase is a priority target of glioblastoma chemotherapy
T Okamura1, K Kurisu, W Yamamoto
1Department of Neurosurgery, Hiroshima University School of Medicine, Hiroshima, Japan.
Abstract:
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.
Insights
NQO may be a priority target for glioblastoma chemotherapy. Analyzing gene expression of NQO1, tubulin, MGMT, MDR1, and GSTpi can help identify effective drugs against glioblastomas.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Glioblastoma exhibits resistance to chemotherapy.
- Understanding glioblastoma's unique biologic nature is crucial for effective drug targeting.
- Drug resistance mechanisms vary across cancer types, necessitating cell-specific strategies.
Purpose of the Study:
- To identify chemotherapy targets specific to glioblastoma cells.
- To compare glioblastoma's drug resistance profile with other cancer types.
- To find drugs with favorable responses against glioblastoma.
Main Methods:
- Gene expression analysis of 12 drug-related properties in 13 human cancer cell lines (including 3 glioblastoma lines).
- Biochemical quantitative assays were performed.
- Comparative analysis of drug sensitivity and resistance markers.
Main Results:
- Glioblastoma cells overexpressed MDR1, MRP, MGMT, and GSTpi but had low Topoisomerase I (Topo I) and comparable alpha/beta-tubulin expression.
- NADPH/quinone oxidoreductase gene (NQO1) was upregulated, and its enzyme NQO activated Mitomycin C (MMC).
- MMC demonstrated higher activity than Topo I inhibitors and docetaxel (TXT) in glioblastoma cells, while MGMT, GSTpi, and MDR1 mediated resistance to other drugs.
Conclusions:
- NADPH/quinone oxidoreductase (NQO) is a potential priority target for glioblastoma chemotherapy.
- Expression analysis of NQO1, alpha/beta-tubulin, MGMT, MDR1, and GSTpi can guide the selection of active drugs for glioblastomas.
- Tailoring chemotherapy based on glioblastoma's specific biochemical properties enhances drug efficacy.