Ginsenoside panaxatriol reverses TNBC paclitaxel resistance by inhibiting the IRAK1/NF-κB and ERK pathways

Abstract

Background Paclitaxel (PTX) resistance is a major obstacle in the treatment of triple-negative breast cancer (TNBC). Previously, we have reported that interleukin-1 receptor-associated kinase 1 (IRAK1) and its downstream pathways are associated with PTX resistance in TNBC cells. In this study, we sought to investigate the combination treatment of ginsenoside panaxatriol (GPT), one of the main active components in Panax ginseng, with PTX on viability and apoptosis of TNBC PTX resistant cells, and explore the role of IRAK1 mediated signaling pathways in the therapeutic effects. Methods CellTiter-Glo and colony formation assays were used to assess cell viability. Flow cytometry was used to analyze subG1 and apoptosis. Western blot was used to detect expressions of proteins involved in apoptosis and the IRAK1/NF-κB and ERK pathways. The mRNA expression of inflammatory cytokines, S100A7/8/9 and cancer stem cell (CSC)-related genes were examined by qPCR. Stem cells were identified by tumor sphere assay. Cell invasion ability was examined by transwell assay. Results We show that GPT inhibits MDA-MB-231 PTX resistant (MB231-PR) cell viability in a dose-dependent manner. When combined with PTX, GPT synergistically causes more cell death, induces subG1 accumulation and cell apoptosis. Besides, up-regulation of BAX/BCL-2 ratio, and down-regulation of MCL-1 are also observed. Moreover, this combination inhibits IRAK1, NF-κB and ERK1/2 activation, and leads to down-regulation of inflammatory cytokines (IL6, IL8, CXCL1, CCL2), S100A7/9 and CSC-related genes (OCT4, SOX2, NANOG, ALDH1, CD44) expression. In addition, the combination treatment suppresses MB231-PR cell invasion ability, and impairs tumor sphere growth both in MB231-PR and SUM159 PTX resistant (SUM159-PR) cells. Conclusion Our study demonstrates that GPT can resensitize TNBC PTX resistant cells to PTX by inhibiting the IRAK1/NF-κB and ERK pathways and reducing stem cell characteristics.

7-Epitaxol Induces Apoptosis and Autophagy in Head and Neck Squamous Cell Carcinoma through Inhibition of the ERK Pathway

“…These findings clearly indicate that 7-Epitaxol induces apoptotic and autophagic cell death in HNSCC by suppressing the ERK1/2 signaling pathway. In support of these findings, some recent studies have shown that, in paclitaxel-resistant cancer cells, combination therapies with paclitaxel and phytochemicals can make cancer cells sensitive to paclitaxel by suppressing the ERK1/2 signaling pathway [54][55][56].…”

Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells

“…Therefore, we deem that Cur reverse the NNMT-induced cell proliferation mainly through inducing cell cycle arrest rather than inducing cell apoptosis. Another important consideration is that subG1 changes is a marker of apoptosis and long exposures (at least 48 h) to some apoptosis-inducible drugs may lead to subG1 accumulation [ 26 , 27 , 28 ]. However, although Cur could induce apoptosis, no subG1 accumulation was detected following the Cur treatment for 24 h in the present study.…”

Zinc Complex of 3,5-di-tert-butyl Salicylate Inhibits the Proliferation, Migration, and Invasion of Triple-Negative Breast Cancer Cells

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