Small molecule inhibitor of TLR4 inhibits ovarian cancer cell proliferation: new insight into the anticancer effect of TAK-242 (Resatorvid).

Abstract

Despite all advances in the treatment of ovarian cancer (OC), it remains the most lethal gynecological malignancy worldwide. There are growing amounts of evidence indicating the role of inflammation in initiating chemoresistance. Therefore, Toll-like receptor 4 (TLR4), a mediator of inflammation in cancer cells, may be a proper anticancer target. The effects of TLR4 activation by LPS was studied using MTT, colony formation, staining, scratch, and qRT-PCR assays as the first step. Then the same assays, in addition to anoikis resistance, cell cycle and annexin V/PI apoptosis tests, were used to investigate whether the inhibition of TLR4 using a small molecule inhibitor, TAK-242, could suppress the proliferation of various OC cell lines: A2780CP, 2008C13, SKOV3, and A2780S. The activation of TLR4 using LPS showed enhanced proliferation and invasion in the TLR4-expressing cell line (SKOV3). Next, treatment with the inhibitor revealed that TAK-242 suppressed the inflammatory condition of ovarian cancer cells, as evident by the down-regulation of IL-6 gene expression. We also found that TAK-242 halted cancer cell proliferation by inducing cell cycle arrest and apoptosis through the modulation of genes involved in these processes. Given the fact that the overexpression of TLR4 contributes to drug resistance, it was tempting to investigate the effect of TAK-242 in a combined-modality strategy. Interestingly, we found enhanced cytotoxicity when TAK-242 was used in combination with doxorubicin. TAK-242 serves as an appealing therapeutic strategy in the TLR4-expressing OC cells, either in the context of monotherapy or in combination with a chemotherapeutic drug.