Synergistic Effect of Curcuma longa Extract in Combination with Phyllanthus niruri Extract in Regulating Annexin A2, Epidermal Growth Factor Receptor, Matrix Metalloproteinases, and Pyruvate Kinase M1/2 Signaling Pathway on Breast Cancer Stem Cell

Abstract

AIM: This study aimed to investigate the synergistic effects of the combination between Curcuma longa extract (CL) and Phyllanthus niruri extract (PN) in inhibiting optimally the MDA-MB-231 breast cancer stem cells (BCSCs) growth and metastatic by exploring the target and molecular mechanism using integrative bioinformatics approaches and in vitro. METHODS: CL and PN extracts were prepared by maceration method using ethanol 70%. The antiproliferative effect of CL and PN single and combination treatment was examined by 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide assay. The bioinformatic approach was performed to identify molecular targets, key proteins, and molecular mechanism of curcumin and phyllanthin as CL and PN secondary metabolite, respectively, targeted at stemness and migration pathway of BCSCs. RESULTS: The in vitro study showed that CL and PN possess cytotoxic activity in time- and dose-dependent manner. The combination of CL and PN has a synergistic effect by modulating the sensitivity of cells. Using a bioinformatics approach, the annexin A2 (ANXA2), epidermal growth factor receptor (EGFR), matrix metalloproteinases (MMPs), and pyruvate kinase M1/2 (PKM) as potential targets of curcumin and phyllanthin correlated with metastatic inhibition of BC. In addition, molecular docking showed that curcumin and phyllanthin performed similar or better interaction to stemness differentiation regulator pathway particularly histone deacetylase 1, EGFR, Heat Shock Protein 90 Alpha Family Class B Member 1, Hypoxia Inducible Factor 1 Subunit Alpha, and MMP9. CONCLUSION: Combination of CL and PN has potential for the treatment of metastatic BCSCs by targeting ANXA2, EGFR, MMPs, and PKM to resolve stemness and inhibit of BCSCs.

The Combination of Mesenchymal Stem Cells and Bovine Colostrum in Reducing α-SMA Expression and NLR Levels in Wistar Rats After 50% Fibrotic Liver Resection

“…This finding supported the previous study revealed that MSCs-mediated immunosuppression mainly acts through the secretion of soluble molecules that are induces or upregulated indoleamine 2,3-dioxygenase [23], [26]. In addition, MSCs released soluble factor of anti-inflammation such as IL-10 and growth factor including transforming growth factor-ß, fibroblast growth factor, platelet-derived growth factor, and VEGF [27], [28]. This obvious reduction even exceeds the combination of MSCs and bovine colostrum due to insignificant role of bovine colostrum in the early inflammatory phase of liver fibrosis.…”

Hypophyllanthin and Phyllanthin from Phyllanthus niruri Synergize Doxorubicin Anticancer Properties against Resistant Breast Cancer Cells

“… 43 Recently in 2021, a study showed the effective combination of P. niruri extract with Curcuma longa extract for treating metastatic breast cancer stem cells. 18 Herein, this is the first study investigating the potential anticancer activity of compounds derived from Phyllanthus species against resistant breast cancer cells.…”

“…Phyllanthus niruri L. (Syn Phyllanthus amarus Schum & Thonn, family Phyllanthaceae) is a small herb widely distributed in tropical areas worldwide (such as India, China, Java, Southern Florida, and Bahamas), extensively used in ethnopharmacology for the treatment of diabetes, hypertension, and jaundice . Recently, researchers have shown a growing interest in evaluating the anticancer activity of this herb . The whole plant has diverse biological activities such as anti-inflammatory, antitumor, antinociceptive, and antioxidant properties .…”

“… 17 Recently, researchers have shown a growing interest in evaluating the anticancer activity of this herb. 18 The whole plant has diverse biological activities such as anti-inflammatory, antitumor, antinociceptive, and antioxidant properties. 19 The aqueous extract of the aerial parts of P. niruri showed an antiproliferative effect on human hepatocellular carcinoma cells (HepG2 and Huh-7) and colorectal carcinoma cells (HT-29).…”

Alpinia galanga Extract Inhibits MCF-7/HER2+ Cells by Inducing Apoptosis

“…To identify the different pathways of cell death-either necrosis or apoptosis in treated cancer cells with extracts, staining with annexin V and propidium iodide (PI) were used for determination of the early stages of apoptosis and both necrosis and late apoptosis, respectively 11 - 13 . In MCF-7/HER2+ breast cancer cells, extracts increased significantly the apoptotic cells in dose-dependent manner than untreated cells.…”