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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

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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.

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Acknowledgements

This study is supported by grant P690-C25-2407 from Erimos Pharmaceuticals LLC to RCH. The authors would like to thank Theresa Landewe, Mingyu Xi, Chui Cheng and Amy Dinitz for their assistance. YC Liang is a visiting predoctoral fellow from Tunghai University, Taiwan, supported by the National Science Council, Taiwan, R.O.C. CIL and CFL are visiting predoctoral students from National Tsing Hua University, Taiwan.

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Authors and Affiliations

  1. Department of Biology, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD, 21218, USA

    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

  2. Preclinical Pharmacology Core Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021, USA

    Ting-Chao Chou

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  1. Chih-Chuan Chang
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Correspondence to Ru Chih C. Huang.

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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 58, 640–653 (2006). https://doi.org/10.1007/s00280-006-0214-9

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