| Abstract: |
Purpose: Multidrug resistance (MDR) continues to be a major obstacle for successful anticancer therapy. One of the principal factors implicated in MDR is the over expression of P-glycoprotein (Pgp), the product of the MDR1 gene. Methods: Here we explore the possibility of using the transcription inhibitor tetra-O-methyl nordihydroguaiaretic acid (M4N) to inhibit Sp1-regulated MDR1 gene expression and restore doxorubicin and paclitaxel sensitivity to multidrug resistant human cancer cells in vitro and in vivo. Results: We found that M4N acted synergistically with doxorubicin and paclitaxel in inhibiting the growth of the cells in culture allowing significant dose reductions of both drugs. We observed no such synergism when M4N was used in combination with cisplatin, another chemotherapeutic agent, but not a Pgp substrate, as analyzed by the combination index and isobologram methods. Analysis of MDR1 mRNA and Pgp levels revealed that at sublethal doses, M4N inhibited MDR1 gene expression in the multidrug resistant NCI/ADR-RES cells and reversed the MDR phenotype as measured by Rhodamine-123 retention. In addition, M4N was found to inhibit doxorubicin-induced MDR1 gene expression in drug sensitive MCF-7 breast cancer cells. Conclusions: M4N and maltose-tri-O-methyl nordihydroguaiaretic acid (maltose-M3N), a water-soluble derivative of NDGA, were also able to reverse the MDR phenotype of the tumor cells in a xenograft model system and combination therapy with M4N or maltose-M3N and paclitaxel was effective at inhibiting growth of these tumors in nude mice. © Springer-Verlag 2006. |
| Keywords: |
cancer chemotherapy; controlled study; unclassified drug; human cell; cisplatin; doxorubicin; drug dose reduction; drug efficacy; drug potentiation; nonhuman; paclitaxel; antineoplastic agent; mouse; phenotype; animals; mice; cancer prevention; breast cancer; gene expression; cell growth; antineoplastic combined chemotherapy protocols; animal experiment; animal model; antineoplastic agents, phytogenic; genetic transcription; tumor xenograft; dose-response relationship, drug; drug resistance, neoplasm; xenograft model antitumor assays; cell line, tumor; breast neoplasms; gene expression regulation; cancer inhibition; blotting, western; xenograft; cell culture; nude mouse; mice, nude; messenger rna; reverse transcriptase polymerase chain reaction; rna, messenger; cancer cell; transcription factor sp1; water; drug sensitivity; multidrug resistance; drug use; lethality; p-glycoprotein; drug resistance, multiple; drug solubility; glycoprotein p; rna analysis; exploratory research; nordihydroguaiaretic acid; monosaccharides; m4n; maltose-m3n; maltose tri o methylnordihydroguaiaretic acid; tetra o methylnordihydroguaiaretic acid
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