Maslinic Acid Enhances Docetaxel Response in Human Docetaxel-Resistant Triple Negative Breast Carcinoma MDA-MB-231 Cells via Regulating MELK-FoxM1-ABCB1 Signaling Cascade.

Ke Wang,Xue Zhu,Yongxiang Yin

doi:10.3389/fphar.2020.00835

Abstract

Docetaxel (DOC) is the most important chemotherapeutic drug for the treatment of triple negative breast cancer (TNBC); however, acquired drug resistance upon the long-term treatment limits its therapeutic effect. Maslinic acid (MA), a natural triterpene from Olea europaea L., attracts increasing interest in recent years because of its promising anti-cancer activity, but the reversal effect of MA on drug resistance in cancer therapy is rarely explored. In this study, the combined effect of DOC and MA on human docetaxel-resistant triple negative breast carcinoma MDA-MB-231 (MDA-MB-231/DOC) cells was investigated. The enhanced effect of MA on DOC cytotoxicity and DOC accumulation was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and HPLC (high performance liquid chromatography) analysis in MDA-MB-231/DOC cells. Western blot, co-immunoprecipitation assay, luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay were performed for exploring the underlying mechanisms. Our data indicated that the co-treatment of MA could dose-dependently enhance DOC sensitivity and cellular DOC accumulation in MDA-MB-231/DOC cells. Moreover, MELK-FoxM1-ABCB1 signaling cascade was confirmed to contribute to DOC resistance in MDA-MB-231/DOC cells. In such process, MA directly suppressed expressions and interaction of MELK and FoxM1 as well as the transcriptional activity of FoxM1, and thus reducing the expression of ABCB1. Overall, our study suggests that the combined use of DOC and MA may be helpful for overcoming DOC resistance in human TNBC therapy.

Highlights

Though the improvement of surgical technique and the development of adjuvant chemotherapeutic regimens over the last 30 years, the survival rate of triple negative breast cancer (TNBC) is still low and which is the leading cause of cancerrelated women death (Collignon et al, 2016; Lebert et al, 2018)
Some of the triterpenes have already passed the clinical trial for cancer treatment, which induce the progression of tumor cell death by targeting multiple cancer-specific targets by the proteasome, B cell lymphoma 2 (Bcl-2), NF-kB, STAT3, TNF, angiogenesis, PI3K/Akt/mTOR, and (TLR) and improve the cytotoxic action of anticancer chemotherapy by inhibiting the function of the multidrug resistant (MDR)-efflux proteins such as MDR1 (Molnar et al, 2006; Gill et al, 2016)
We found that Maslinic acid (MA) cotreatment could significantly reverse DOC resistance in human docetaxel-resistant breast carcinoma MDA-MB-231 cells via enhancing cellular DOC accumulation

Summary

Introduction

Though the improvement of surgical technique and the development of adjuvant chemotherapeutic regimens over the last 30 years, the survival rate of triple negative breast cancer (TNBC) is still low and which is the leading cause of cancerrelated women death (Collignon et al, 2016; Lebert et al, 2018). Among generation chemotherapy regimen for TNBC, docetaxel (DOC) is widely used as one of first-line chemotherapeutic drugs (Sharma, 2016). Resistance to DOC is the main reason for the failure of chemotherapy regimens (O’Reilly et al, 2015), investigation of novel therapeutic strategy that may allow reversion of docetaxel resistance is important for improving chemotherapeutic effect in TNBC. The oncogenic properties of MELK make it to be a key functional regulator of drug resistance in several lines of cancers. Marisa et al have reported that the expression of MELK is increased in mammary stem cells from undifferentiated cancers, which is associated with poor prognosis and potentially mediates treatment resistance (Simon et al, 2017). MELK forms a protein complex with the oncogene FoxM1, a typical proliferation-associated transcription factor involved in tumorigenesis. Targeting MELK-FoxM1 signaling may provide a novel strategy to benefit patients of TNBC undergoing chemotherapy treatment

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Conclusion