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Reversal of multidrug resistance by two nordihydroguaiaretic acid derivatives, M4N and maltose-M3N, and their use in combination with doxorubicin or paclitaxel.
Cancer Chemother Pharmacol. 2006 Nov; 58(5):640-53.CC

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.

Authors+Show Affiliations

Department of Biology, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16544145

Citation

Chang, Chih-Chuan, et al. "Reversal of Multidrug Resistance By Two Nordihydroguaiaretic Acid Derivatives, M4N and maltose-M3N, and Their Use in Combination With Doxorubicin or Paclitaxel." Cancer Chemotherapy and Pharmacology, vol. 58, no. 5, 2006, pp. 640-53.
Chang CC, Liang YC, Klutz A, et al. Reversal of multidrug resistance by two nordihydroguaiaretic acid derivatives, M4N and maltose-M3N, and their use in combination with doxorubicin or paclitaxel. Cancer Chemother Pharmacol. 2006;58(5):640-53.
Chang, C. C., Liang, Y. C., Klutz, A., Hsu, C. I., Lin, C. F., Mold, D. E., Chou, T. C., Lee, Y. C., & Huang, R. C. (2006). Reversal of multidrug resistance by two nordihydroguaiaretic acid derivatives, M4N and maltose-M3N, and their use in combination with doxorubicin or paclitaxel. Cancer Chemotherapy and Pharmacology, 58(5), 640-53.
Chang CC, et al. Reversal of Multidrug Resistance By Two Nordihydroguaiaretic Acid Derivatives, M4N and maltose-M3N, and Their Use in Combination With Doxorubicin or Paclitaxel. Cancer Chemother Pharmacol. 2006;58(5):640-53. PubMed PMID: 16544145.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reversal of multidrug resistance by two nordihydroguaiaretic acid derivatives, M4N and maltose-M3N, and their use in combination with doxorubicin or paclitaxel. AU - Chang,Chih-Chuan, AU - Liang,Yu-Chuan, AU - Klutz,Athena, AU - Hsu,Chuan-I, AU - Lin,Chien-Fu, AU - Mold,David E, AU - Chou,Ting-Chao, AU - Lee,Yuan Chuan, AU - Huang,Ru Chih C, Y1 - 2006/03/17/ PY - 2005/10/24/received PY - 2006/02/11/accepted PY - 2006/3/18/pubmed PY - 2006/10/17/medline PY - 2006/3/18/entrez SP - 640 EP - 53 JF - Cancer chemotherapy and pharmacology JO - Cancer Chemother Pharmacol VL - 58 IS - 5 N2 - 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. SN - 0344-5704 UR - https://www.unboundmedicine.com/medline/citation/16544145/Reversal_of_multidrug_resistance_by_two_nordihydroguaiaretic_acid_derivatives_M4N_and_maltose_M3N_and_their_use_in_combination_with_doxorubicin_or_paclitaxel_ L2 - https://dx.doi.org/10.1007/s00280-006-0214-9 DB - PRIME DP - Unbound Medicine ER -