PARP inhibitors for prostate cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed the treatment landscape for patients with metastatic castration-resistant prostate cancer (mCRPC) and alterations in DNA damage response genes. This has also led to widespread use of genomic testing in all patients with mCRPC. The current review will give an overview of (1) the current understanding of the interplay between DNA damage response and PARP enzymes; (2) the clinical landscape of PARP inhibitors, including the combination of PARP inhibitors with other agents such as androgen-receptor signaling agents; (3) biomarkers related to PARP inhibitor response and resistance; and (4) considerations for interpreting genomic testing results and treating patients with PARP inhibitors.

Paclitaxel resistance is mediated by NF-κB on mesenchymal primary breast cancer cells.

Paclitaxel has been used widely to treat breast cancer and other types of cancer. However, resistance is a major cause of failure for treatment and results in cancer progression. The present study investigated the association between paclitaxel resistance and the mesenchymal phenotype, using a model of primary breast cancer cells and employing four different cultures, two with an epithelial phenotype (MBCDF and MBCD17) and two with a mesenchymal phenotype (MBCDF-D5 and MBCD3). Epithelial-mesenchymal markers were evaluated by western blotting; MBCDF and MBCD17 cells expressed E-cadherin, SNAIL, Slug, and Twist, low levels of N-cadherin, but not vimentin. MBCDF-D5 and MBCD3 cells expressed N-cadherin, vimentin, and higher levels of SNAIL, and low levels of E-cadherin, Slug, and Twist. Cell viability was evaluated using a crystal violet assay after paclitaxel treatment; primary breast cancer cells with mesenchymal phenotype were resistant to paclitaxel compared with the epithelial primary breast cancer cells. Furthermore, using western blotting, it was revealed that mesenchymal cells had elevated levels of nuclear factor-κΒ (NF-κB) p65 and IκB kinase (IKK). Additionally, it was demonstrated that paclitaxel-induced degradation of the inhibitor of NF-κB, activation of NF-κB in a dose-dependent manner, and Bcl-2 and Bcl-xL upregulation. Finally, employing western blotting and crystal violet assays, the effects of the proteasome inhibitor ALLN were assessed. ALLN inhibited paclitaxel-induced NF-κB activation and restored the sensitivity to paclitaxel. Together, these data suggest that targeting the NF-κB/IKK axis might be a promising strategy to overcome paclitaxel resistance.