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Acquired tamoxifen resistance is surmounted by GW8510 through ribonucleotide reductase M2 downregulation-mediated autophagy induction.
Metadata
Journalbiochemical and biophysical research communications2.985Date
2020 Jun 03
4 months ago
Type
Journal Article
Volume
2020-Jul-30 / 528 : 554-560
Author
Li ZN 1, Shu Y 2, Chen CG 3, Li XQ 4, Li MY 3, Zhao XH 5, Wang S 6, Li J 7
Affiliation
  • 2. Center of Medical Experiment, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China.
  • 3. Department of Pulmonary Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China.
  • 4. Department of Medical Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China.
  • 5. Department of Pathology, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China.
  • 6. Department of Breast Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, Jiangsu, China. Electronic address: [email protected]
  • 7. Department of Pulmonary Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China. Electronic address: [email protected]
Doi
PMIDMESH
Abstract
Tamoxifen resistance is a major roadblock in the treatment of patients with breast cancer. Ribonucleotide reductase M2 (RRM2) was found to be involved in acquired resistance of breast cancer cells (BCCs) to tamoxifen. Here, we used GW8510, which has been identified as a potential RRM2 inhibitor, to evaluate the effect of RRM2 inhibition on reversing resistance of BCCs to tamoxifen and investigate its mechanisms. We showed that RRM2 overexpression played a key role in the development of acquired tamoxifen resistance in BCCs through downregulation of autophagy level. Combination treatment with tamoxifen and GW8510 significantly inhibited survival of the tamoxifen-resistant BCCs through induction of autophagic cell death compared to either of the two drugs. Furthermore, combination of tamoxifen and GW8510 resulted in marked growth inhibition of tamoxifen-resistant BBC xenograft tumor in vivo compared to tamoxifen or GW8510 alone. In conclusion, tamoxifen in combination with GW8510 can overcome acquired tamoxifen resistance in BCCs and may be a rational therapeutic approach against breast cancer with high RRM2 expression.
Keywords: Autophagy Breast cancer cell GW8510 Ribonucleotide reductase M2 Tamoxifen resistance
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Biochem Biophys Res Communbiochemical and biophysical research communications
Metadata
LocationUnited States
FromACADEMIC PRESS INC ELSEVIER SCIENCE

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