Two Natural Alkaloids Synergistically Induce Apoptosis in Breast Cancer Cells by Inhibiting STAT3 Activation.

Di Chen,Yuyu Hui,Yuru Wang,Zhiyu Guo,Yaru Yang,Luyang Wu,Wenjuan Yang,Li Liu,Bonan Pan,Yangmin Ma

doi:10.3390/molecules25010216

Abstract

Breast cancer has become a worldwide threat, and chemotherapy remains a routine treatment. Patients are forced to receive continuous chemotherapy and suffer from severe side effects and poor prognosis. Natural alkaloids, such as piperine (PP) and piperlongumine (PL), are expected to become a new strategy against breast cancer due to their reliable anticancer potential. In the present study, cell viability, flow cytometry, and Western blot assays were performed to evaluate the suppression effect of PP and PL, alone or in combination. Data showed that PP and PL synergistically inhibited breast cancer cells proliferation at lower doses, while only weak killing effect was observed in normal breast cells, indicating a good selectivity. Furthermore, apoptosis and STAT3 signaling pathway-associated protein levels were analyzed. We demonstrated that PP and PL in combination inhibit STAT3 phosphorylation and regulate downstream molecules to induce apoptosis in breast cancer cells. Taken together, these results revealed that inactivation of STAT3 was a novel mechanism with treatment of PP and PL, suggesting that combination application of natural alkaloids may be a potential strategy for prevention and therapy of breast cancer.

Highlights

Breast cancer has become a serious threat to women worldwide
We initially evaluated anti-proliferative activity of PP and PL against three human breast cell lines, including a triple-negative breast cancer (TNBC) cell line (MDA-MB-231), an estrogen receptor (ER)/progesterone receptor (PR)
PL inhibited the growth of all cell lines in a dose-dependent manner, showed stronger anti-proliferative activity, with IC50 values of 5.494 μM (MDA-MB-231), 7.297 μM

Summary

Introduction

There have been approved drugs targeted at hormone receptors, including the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) [1], chemotherapy remains a routine treatment for breast cancer, for triple-negative breast cancer (TNBC), which lacks major effective targets [2]. Piperine (PP) is a major plant alkaloid isolated from black pepper (Piper nigrum L.) and long pepper (Piper longum L.) [4], which have been used in food or traditional medicine worldwide. Piperine exhibits a variety of pharmacological properties, including acting as an anticonvulsant [5], an antioxidant [6], an anti-inflammatory [7], an anti-angiogenic [8], an anti-bacterial, and an anticancer compound.

Methods

Results

Conclusion