Methylseleninic Acid Enhances Paclitaxel Efficacy for the Treatment of Triple-Negative Breast Cancer

Yanfeng Qi,Zhenggang Xiong,Brian G. Rowan,Xueqi Fu,Steven M. Hill,Haitao Zhang,Yan Dong,Pranela Rameshwar

doi:10.1371/journal.pone.0031539

Yanfeng Qi, Zhenggang Xiong + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0031539

Copy DOI

Journal: PloS one	Publication Date: Feb 14, 2012
Citations: 88	License type: CC BY 4.0

Affiliation: Tulane University, Jilin University

Abstract

A major challenge in breast cancer therapy is the lack of an effective therapeutic option for a particularly aggressive subtype of breast cancer, triple-negative breast cancer. Here we provide the first preclinical evidence that a second-generation selenium compound, methylseleninic acid, significantly enhances the anticancer efficacy of paclitaxel in triple-negative breast cancer. Through combination-index value calculation, we demonstrated that methylseleninic acid synergistically enhanced the growth inhibitory effect of paclitaxel in triple-negative breast cancer cells. The synergism was attributable to more pronounced induction of caspase-mediated apoptosis, arrest of cell cycle progression at the G2/M checkpoint, and inhibition of cell proliferation. Treatment of SCID mice bearing MDA-MB-231 triple-negative breast cancer xenografts for four weeks with methylseleninic acid (4.5 mg/kg/day, orally) and paclitaxel (10 mg/kg/week, through intraperitoneal injection) resulted in a more pronounced inhibition of tumor growth compared with either agent alone. The attenuated tumor growth correlated with a decrease in tumor cell proliferation and an induction of apoptosis. The in vivo study also indicated the safety of using methylseleninic acid in the combination regime. Our findings thus provide strong justification for the further development of methylseleninic acid and paclitaxel combination therapy for the treatment of triple-negative breast cancer.

Highlights

Triple-negative breast cancer (TNBC) refers to a subtype of breast cancer that is negative for expression of estrogen receptor and progesterone receptor, and lacks HER2 overexpression
The cell viability in all combination groups was lower than that in the respective single-agent treatment groups (Table 1). To determine whether these combinatory effects were synergistic, the data were analyzed with the Calcusyn software (Biosoft), which calculates combination index (CI) values using the median-effect principle [30] to delineate the interaction between two drugs
We evaluated the efficacy of Methylseleninic acid (MSA) in combination with paclitaxel for the treatment of TNBC

Summary

Introduction

Triple-negative breast cancer (TNBC) refers to a subtype of breast cancer that is negative for expression of estrogen receptor and progesterone receptor, and lacks HER2 overexpression. The majority of TNBCs bear the gene expression profile of basal-like phenotype [1] This subtype accounts for ,10–15% of all types of breast cancer. TNBC is aggressive, associated with rapid relapse following therapy, increased prevalence of distant metastases, and shorter survival comparing with other breast cancer subtypes [2]. It is more prevalent in Hispanic and African American women than in other ethnic groups, with the majority of the cases occurring in premenopausal women [3,4]. TNBC patients are usually managed with standard treatments, and chemotherapy is the primary, if not the only, choice of systemic therapy.

Methods

Results

Conclusion