Acquired tamoxifen resistance is surmounted by GW8510 through ribonucleotide reductase M2 downregulation-mediated autophagy induction

Autor: Mei-Yu Li, Chen-Guo Chen, Shui Wang, Zhen-Nan Li, Jian Li, Yang Shu, Xiao-Qin Li, Xiaohui Zhao
Rok vydání: 2020
Předmět:
0301 basic medicine
Programmed cell death
Indoles
Antineoplastic Agents
Hormonal
Ribonucleoside Diphosphate Reductase
Biophysics
Down-Regulation
Mice
Nude
Breast Neoplasms
Ribonucleotide reductase M2
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Breast cancer
Downregulation and upregulation
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
Tamoxifen resistance
Autophagy
Medicine
Animals
Humans
skin and connective tissue diseases
Molecular Biology
Mice
Inbred BALB C
business.industry
Drug Synergism
Cell Biology
medicine.disease
Xenograft Model Antitumor Assays
Tamoxifen
030104 developmental biology
chemistry
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Cancer research
MCF-7 Cells
Female
Growth inhibition
business
hormones
hormone substitutes
and hormone antagonists
medicine.drug
Zdroj: Biochemical and biophysical research communications. 528(3)
ISSN: 1090-2104
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: