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The drug resistance suppression induced by curcuminoids in colon cancer SW-480 cells is mediated by reactive oxygen species-induced disruption of the microRNA-27a-ZBTB10-Sp axis

Authors

  • Giuliana D. Noratto,

    Corresponding author
    • School of Food Science, Washington State University, WA, USA
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  • Indira Jutooru,

    1. Department of Veterinary Physiology and Pharmacology, College Station, TX, USA
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  • Stephen Safe,

    1. Department of Veterinary Physiology and Pharmacology, College Station, TX, USA
    2. Center for Environmental and Genetic Medicine, Texas A&M Health Science Center, Houston, TX, USA
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  • Gabriela Angel-Morales,

    1. Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA
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  • Susanne U. Mertens-Talcott

    Corresponding author
    1. Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA
    2. Institute for Obesity Research and Program Evaluation, Texas A&M University, College Station, TX, USA
    • School of Food Science, Washington State University, WA, USA
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Correspondence: Dr. Giuliana Noratto, School of Food Science, Washington State University, FSHN Bldg. 106, Pullman, WA 99164, USA

E-mail: giuliana.noratto@wsu.edu

Fax: +1-509-335-4815

Additional corresponding author: Dr. Susanne U. Mertens-Talcott,

E-mail: smtalcott@tamu.edu

Abstract

Scope

Mechanisms involving the curcuminoids effects in decreasing the prooncogenic specificity protein (Sp) transcription factors, and Sp-regulated genes in SW-480 colon cancer cells and how the multidrug resistance protein (MDR1) inhibition is mediated by Sp suppression.

Methods and results

HT-29 and SW-480 colon cancer and normal CCD-18Co colon fibroblast cells were treated with curcuminoids previously analyzed by HPLC. Gene and protein expression regulation were assessed by RT-PCR, transfections with expression constructs, and Western blots. Curcuminoids (2.5–10 μg/mL) suppressed preferentially the growth of SW-480 and HT-29 compared to CCD-18Co cells and enhanced the anticancer activity of the chemotherapeutic drug 5-fluorouracil due to the suppression of MDR1. Additionally, Sp1, Sp3, and Sp4 and Sp-regulated genes were downregulated by curcuminoids in SW-480 and this was accompanied by suppression of microRNA-27a (miR-27a) and induction of ZBTB10, an mRNA target of miR-27a and a transcriptional repressor of Sp expression. This mechanism was mediated by the induction of ROS. RNA-interference and transfection with ZBTB10-expression plasmid demonstrated that MDR1 was regulated by Sp1 and Sp3 and the disruption of the miR-27a-ZBTB10-Sp axis.

Conclusion

Colon cancer treatment with curcuminoids will enhance the therapeutic effects of drugs in patients who have developed drug resistance.

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