Curcumol enhances the sensitivity of doxorubicin in triple-negative breast cancer via regulating the miR-181b-2-3p-ABCC3 axis
| Autor: | Cun Zhang, Jianguo Lu, Yuan Gao, Cheng Zeng, Xiaoju Li, Lijuan Sun, Xuanxuan Zhou, Siwang Wang, Qian Yang, Jiani Yuan, Jintao Gu, Jun Han, Dong Fan, Ying Xu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cell Survival medicine.medical_treatment Mice Nude Triple Negative Breast Neoplasms Kaplan-Meier Estimate Biochemistry 03 medical and health sciences 0302 clinical medicine In vivo Cell Line Tumor medicine Animals Humans Doxorubicin Sensitization Triple-negative breast cancer Adjuvants Pharmaceutic Pharmacology Chemotherapy Antibiotics Antineoplastic Dose-Response Relationship Drug Chemistry Xenograft Model Antitumor Assays In vitro Gene Expression Regulation Neoplastic MicroRNAs 030104 developmental biology medicine.anatomical_structure Drug Resistance Neoplasm Apoptosis 030220 oncology & carcinogenesis Cancer cell Cancer research Multidrug Resistance-Associated Proteins Sesquiterpenes Signal Transduction medicine.drug |
| Zdroj: | Biochemical Pharmacology. 174:113795 |
| ISSN: | 0006-2952 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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