Pharmacological inhibition of LIMK effect on breast tumors

LIM kinases (LIMK) are emerging targets for cancer therapy and they function as network hubs to coordinate actin and microtubule dynamics. When LIMK are inhibited, actin microfilaments are disorganized and microtubules are stabilized. Owing to their stabilizing effect on microtubules, LIMK inhibitors may provide an therapeutic strategy to treat taxane-resistant cancers. In this study, we investigated the effect of LIMK inhibition on breast tumor development and on paclitaxel resistant tumors, using a novel selective LIMK inhibitor termed Pyr1. Treatment of breast cancer cells, including paclitaxel-resistant cells, blocked their invasion and proliferation in vitro and their growth in vivo in tumor xenograft assays. The tumor invasive properties of Pyr1 were investigated in vivo by intravital microscopy of tumor xenografts. A striking change in cell morphology was observed with a rounded phenotype arising in a subpopulation of cells while other cells remained elongated. Notably, although Pyr1 decreased the motility of elongated cells it increased the motility of rounded cells in the tumor. Pyr1 administration prevented the growth of metastasis but not their spread. Overall, our results provided a preclinical proof of concept concerning how a small molecule inhibitor of LIMK kinases may offer a strategy to treat taxane-resistant breast tumors and metastases.

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