1. Academic Validation
  2. Curcumol enhances the sensitivity of doxorubicin in triple-negative breast cancer via regulating the miR-181b-2-3p-ABCC3 axis

Curcumol enhances the sensitivity of doxorubicin in triple-negative breast cancer via regulating the miR-181b-2-3p-ABCC3 axis

  • Biochem Pharmacol. 2020 Apr;174:113795. doi: 10.1016/j.bcp.2020.113795.
Cheng Zeng 1 Dong Fan 2 Ying Xu 3 Xiaoju Li 3 Jiani Yuan 1 Qian Yang 1 Xuanxuan Zhou 1 Jianguo Lu 2 Cun Zhang 3 Jun Han 3 Jintao Gu 3 Yuan Gao 4 Lijuan Sun 5 Siwang Wang 6
Affiliations

Affiliations

  • 1 Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University, Xi'an 710032, China.
  • 2 Department of General Surgery, Tangdu Hospital, Air Force Medical University, Xi'an 710038, China.
  • 3 State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Air Force Medical University, Xi'an 710032, China.
  • 4 State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Air Force Medical University, Xi'an 710032, China. Electronic address: gaoyuan321@fmmu.edu.cn.
  • 5 Eye Institute of Chinese PLA and Department of Ophthalmology, Xijing Hospital, Air Force Medical University, Xi'an 710032, China. Electronic address: sunlijuan777@126.com.
  • 6 Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, Air Force Medical University, Xi'an 710032, China. Electronic address: wangsiw@fmmu.edu.cn.
Abstract

Chemoresistance is a major cause of recurrence and poor prognosis in triple-negative breast Cancer (TNBC) patients. The essential oil of Rhizoma Curcumae has been recently reported to enhance the chemosensitivity of Cancer cells. However, few reports have systematically illuminated the mechanism. Curcumol is the major component of the essential oil of Rhizoma Curcumae. Therefore, we wondered whether curcumol combined with chemotherapy could increase the Anticancer effects. In the present study, we evaluated the Anticancer effects of doxorubicin and curcumol alone or in combination by a series of growth proliferation and Apoptosis assays in TNBC cells. Our results showed that curcumol enhanced the sensitivity of MDA-MB-231 cells to doxorubicin in vitro and in vivo. Through miRNA-seq, we found that miR-181b-2-3p was involved in the curcumol-mediated promotion of doxorubicin-sensitivity in both parental and doxorubicin-resistant MDA-MB-231 (MDA-MB-231/ADR) cells. Further study showed that miR-181b-2-3p suppressed ABCC3 expression by targeting its 3'UTR. More importantly, we identified that overexpression of miR-181b-2-3p sensitized MDA-MB-231/ADR cells to doxorubicin by inhibiting the drug efflux transporter ABCC3. Furthermore, we found that NFAT1 could be activated by curcumol. In addition, ChIP assay results revealed that NFAT1 could directly bind to the promoter region of miR-181b-2-3p. Finally, using PDX models, we identified that curcumol could enhance sensitivity to doxorubicin to suppress tumor growth by the miR-181b-2-3p-ABCC3 axis in vivo. Taken together, our study provides novel mechanistic evidence for curcumol-mediated sensitization to doxorubicin in TNBC, and it highlights the potential therapeutic usefulness of curcumol as an adjunct drug in TNBC patients with doxorubicin-resistance.

Keywords

ABCC3; Curcumol; Doxorubicin-resistance; TNBC; miRNA.

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