Blockade of TLR4 using TAK-242 (resatorvid) enhances anti-cancer effects of chemotherapeutic agents: a novel synergistic approach for breast and ovarian cancers.

Abstract

It is believed that pathways of the immune system are responsible for eradicating cancer cells; however, their over-activation and also their ectopic expression in tumor cells and microenvironment are major contributors to tumor growth and chemoresistance. Toll-like receptor 4 (TLR4) pathway is an innate immune-related pathway which is usually overexpressed in tumor cells that leads to excessive pro-inflammatory cytokines and eventually results in tumor survival, drug resistance, and metastasis. In this study, we investigated whether TLR4 expression is affected upon the treatment of breast and ovarian cancer cells with common chemotherapeutics (paclitaxel, cisplatin, doxorubicin, and arsenic trioxide) and if TLR4 inhibition using its specific inhibitor TAK-242 could enhance cancer cells' response to the drugs. Both breast (MCF7) and ovarian (2008C13) cancer cells experienced an elevated expression of TLR4 after treatment with the drugs. The expression of this receptor was also upregulated in cisplatin-resistant 2008C13 cells; however, it was significantly higher upon short-term treatment with cisplatin. More importantly, the combination treatment of the drugs with TAK-242 intensified the chemosensitivity of six different breast and ovarian cancer cells to chemotherapeutic drugs. It was also identified that co-treatment of paclitaxel and TAK-242 not only led to enhanced G2/M arrest and apoptosis but also satisfactorily decreased the expression of TLR4 and different interleukins in these cells. Taken together, the results of the present study emphasize that chemotherapy may lead to chemoresistance through inducing TLR4 expression, and therefore inhibiting this receptor using TAK-242 could be a promising approach to improve the outcome of chemotherapy in foreseeable future.