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:
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Authors | Chih-Chuan Chang, Yu-Chuan Liang, Athena Klutz, Chuan-I Hsu, Chien-Fu Lin, David E Mold, Ting-Chao Chou, Yuan Chuan Lee, Ru Chih C Huang |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 58
Issue 5
Pg. 640-53
(Nov 2006)
ISSN: 0344-5704 [Print] Germany |
PMID | 16544145
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Antineoplastic Agents, Phytogenic
- Monosaccharides
- RNA, Messenger
- maltose-tri-O-methyl nordihydroguaiaretic acid
- Masoprocol
- Doxorubicin
- Paclitaxel
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(antagonists & inhibitors, genetics, metabolism)
- Animals
- Antineoplastic Agents, Phytogenic
(pharmacology)
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Blotting, Western
- Breast Neoplasms
(genetics, metabolism, pathology)
- Cell Line, Tumor
- Dose-Response Relationship, Drug
- Doxorubicin
(administration & dosage, pharmacology)
- Drug Resistance, Multiple
(drug effects, genetics)
- Drug Resistance, Neoplasm
(drug effects, genetics)
- Female
- Gene Expression
(drug effects)
- Humans
- Masoprocol
(administration & dosage, analogs & derivatives, pharmacology)
- Mice
- Mice, Nude
- Monosaccharides
(administration & dosage, pharmacology)
- Paclitaxel
(administration & dosage, pharmacology)
- RNA, Messenger
(genetics, metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Xenograft Model Antitumor Assays
(methods)
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