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

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 anticancer 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.

FOXM1 and Cancer: Faulty Cellular Signaling Derails Homeostasis

“…FOXM1 has been demonstrated to promote these functions of stemness through regulation of OCT4, NANOG and SOX2 ( 191 ). Drug resistance phenotypes in cancer cells have been gained by the action of FOXM1 regulating the expression of ABCB1 ( 192 ), ABCC4 ( 193 ), ABCC5 ( 194 ), NBS1 ( 195 ) and BRIP1 ( 169 ). Figure 6 summarizes the downstream factors of FOXM1 in mediating Hallmarks of cancer.…”

The Anticancer Potential of Maslinic Acid and Its Derivatives: A Review

“… ↑Smac, ↓ c-IAP1, c-IAP2, X-linked inhibitor of apoptosis protein, ↓(XIAP) and Survivin [ 58 ] A549 cells 0, 4, 8, 16, 32, 64 μM – – ↓ Bcl-2, ↓Na+-K+-ATPase activity, ↑caspase-3/8, ↑cytochrome c, ↓HIF-1α, ↓VEGF, ↓ survivin, ↓iNOS [ 59 ] Triple negative breast carcinoma MDA-MB-231, MDA-MB-468, MCF7 cells 30–50 µM – 24h ↓ CDK4, ↓ CDK2 (TNBCs) ↑ CDK2 (MCF7); ↑ Bax, ↓ BCL2, ↑ Bax/Bcl-2 ratio. ↓survivin [ 64 ] MDA-MB-231 cells 0–20µM – 24h MA+DOC: ↓MELK, ↓FoxM1, ↓ FoxM1, ↓ ABCB1 [ 65 ] Ovarian cancer A2780 cells 1, 24, 60 μM – 6, 12, 24h – [ 104 ] Gastric Cancer SGC-790 cells 0–50μM 33.09±3.15 6, 24h ↑p38 MAPK, ↑ caspase [ 69 ] MKN28 cells 0, 0.1, 1, 10 µM 8.45 µM 24h ↓Bcl2, Bax and Bad; ↓IL-6/JAK/STAT3 signaling cascade: (↓ p-STAT3 and JAK2, ↓ IL-6 [ 70 ] Pancreatic cancer er Panc‐28 cells 6.25, 12.5, 25, 50, 100, and 200 μM 49.2±0.5 μM 48 h ↑LC3‐II/LC3‐I, ↑ Atg7, Atg16L, Atg5, Atg12 and Atg3, ↓p‐mTOR, ↑p‐ULK1(via ↑HSPA8) [ 73 ] …”

“…Wang K et al proved that docetaxel combined with different doses of MA (2.5, 5, and 10 µM) could significantly improve the sensitivity of MDA-MB-231 cells to docetaxel and reduce drug resistance in a dose-dependent manner, which supports MA as a promising contributor of docetaxel resistance in human TNBC therapy. 65 …”

“…In addition, for melanoma 518A2 cells, the IC 50 value of MA was 13.7 μM, and when acting on GC MKN28 cells, the IC 50 value was less than 10 μM. Further, different doses of MA (2.5, 5, and 10 μM) combined with docetaxel in MDA-MB-231 cells significantly increased sensitivity of MDA-MB-231 cells to docetaxel in a dose-dependent manner 65. Similarly, MA can increase the proliferation inhibitory effect of TNF-α on pancreatic cancer cells, which was significant at concentrations of 1.5 μM 112.…”

“…However, drug resistance caused by longterm use reduces its therapeutic effects. Wang K et al proved that docetaxel combined with different doses of MA (2.5, 5, and 10 µM) could significantly improve the sensitivity of MDA-MB-231 cells to docetaxel and reduce drug resistance in a dose-dependent manner, which supports MA as a promising contributor of docetaxel resistance in human TNBC therapy 65. Gastric CancerGastric cancer (GC) is a leading global cause of cancer mortality.…”