Abstract
Tamoxifen is an effective drug for treating patients with advanced estrogen receptor-positive (ER+) breast cancer (BC), but not for all ER + BC patients. Drug tolerance is the biggest obstacle. In this study, we designed an experiment to investigate whether paeoniflorin affects the ER + BC cell's sensitivity to tamoxifen in the T47D and MCF-7 cell lines. Herein, we found that paeoniflorin inhibited cell proliferation without inducing apoptosis. However, it enhanced tamoxifen-induced apoptosis in both cell lines. Immunoblotting revealed that paeoniflorin significantly increased the already elevated Bax/Bcl2 protein expression ratio and the caspase 3 activity levels, both induced by tamoxifen. Paeoniflorin was also found to increase SIRT4 expression, and deletion of SIRT4 could significantly reverse the inhibition of cell proliferation induced by paeoniflorin and significantly decrease paeoniflorin-enhanced apoptosis induced by tamoxifen. Moreover, protein expression detection revealed that paeoniflorin enhanced the tamoxifen-induced inhibition of STAT3 activation. Besides, the deletion of SIRT4 could significantly increase STAT3 activation in the T47D and MCF-7 cells. In conclusion, paeoniflorin suppressed STAT3 activation to enhance the sensitivity of ER-positive breast cancer cells to tamoxifen through promoting SIRT4 expression.
Highlights
Endocrine therapy is an essential part of a comprehensive treatment for patients with estrogen receptor-positive (ER+)breast cancer (BC), including drugs that act as antagonists of the estrogen receptors, aromatase inhibitors, and drugs that promote the downregulation of the estrogen receptor [1, 2].Tamoxifen (TAM) is the first-line drug for endocrine therapy for patients with ER + breast cancer
The results revealed that paeoniflorin significantly inhibited the T47D and MCF-7 proliferation (Figures 1(b) and 1(c)), and this effect was time and dose dependent
We detected the apoptosis of the T47D and MCF-7 cells after being treated with 60 μM paeoniflorin for different times (0, 24, 48, and 72 hours)
Summary
Tamoxifen (TAM) is the first-line drug for endocrine therapy for patients with ER + breast cancer. Statistics show that one-third of patients resistant to TAM are primary TAM resistant and 30–40% of patients who are sensitive to TAM in the early stage have secondary TAM resistance [3, 4]. Such long treatment with tamoxifen causes severe side effects and tamoxifen resistance, leading to breast cancer metastasis and even death [5, 6]. Regulating the ER-positive breast cancer cell’s sensitivity to tamoxifen can reduce its dosage and resistance
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