A novel and selective PDK1 inhibitor reduces breast cancer cell invasion and tumour growth

Excerpt

Impairment of metastasis development is a critical target for cancer therapy. We recently reported that phospholipase Cγ1 (PLCγ1) is involved in regulation of motility and invasion of cancer cells and is required for metastasis development and progression. Experimental metastasis assays in nude mice revealed that inducible knockdown of PLCγ1 strongly inhibits development of MDA-MB-231-derived lung metastasis and reverts metastasis formation. In an effort to develop anti-metastatic drugs, different inositol phosphates compounds were tested to identify potential PLCγ1 inhibitors. We found that a synthetic derivative of inositol pentakisphosphate, Ins(1,3,4,5)P5, inhibits cell migration and 3D invasion in MDA-MB-231 and MDA-MB-435 human breast cancer cell lines and in TSA murine mammary adenocarcinoma cells and reduces calcium release upon EGF stimulation indicating a potential inhibition on PLCγ1 activity. Kinase profile assay, performed in vitro to test the potential inhibitory effect of the Ins(1,3,4,5)P5 synthetic derivative on different kinases showed a specific inhibition of the 3-phosphoinositide-dependent-protein kinase 1 (PDK1) with an IC₅₀ of 26 nM. Knockdown of PDK1 using the small interfering RNA technology in breast cancer cell line MDA-MB-231 showed an impairment in cell migration and invasion and inhibition of EGF-induced calcium mobilisation. In addition, it has been recently shown that PDK1 is a critical determinant for resistance to tamoxifen anti-cancer drug. Our experiments show that combined treatment of the Ins(1,3,4,5)P5 synthetic derivative with tamoxifen, paclitaxel, and curcumin in MCF7 and MDA-MB-468 cells results in additive or more than additive effects, and therefore suggest that this novel PDK1 inhibitor can be potentially used in combination with other drugs to increase their anti-cancer activity. …