Cotargeting Plk1 and androgen receptor enhances the therapeutic sensitivity of paclitaxel-resistant prostate cancer.
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ABSTRACT: Backgrounds:Despite the clinical success of taxanes, they still have limitations, such as chemoresistance. To overcome the limitations of paclitaxel, genetic alterations and targeting effects of altered genes were observed in paclitaxel-resistant cancer. Because paclitaxel-resistant cancer shows high levels of Plk1, a promising target in chemotherapy, the effectiveness of Plk1 inhibitors in paclitaxel-resistant cancer cells has been investigated. Methods:Paclitaxel-resistant cancer cells were developed by exposure of stepwise escalating levels of paclitaxel. Genetic alterations were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunoblotting. Using a cell viability assay, combined targeting effects for Plk1 and androgen receptor (AR) were determined. Clinical data were analyzed to understand the relationship between Plk1 and AR in prostate cancer patients. Results:Treatment with Plk1 inhibitors markedly reduced the expression of MDR1, MRP1, and Plk1 in the paclitaxel-resistant cancer. Among Plk1 inhibitors, genistein, recently found as a direct Plk1 inhibitor, tended to be more effective in the paclitaxel-resistant prostate cancer than the parental cancer cells, which was related to the suppression of the AR, as well as inhibition of Plk1 activity. A combination of Plk1 inhibitors and AR antagonist bicalutamide exhibited a synergistic effect in LNCaPTXR, as well as LNCaP cells, by inhibiting Plk1 and AR. Analysis of clinical data provides evidence for the relevance between Plk1 and AR in prostate cancer patients, showing that Plk1 and AR are strong predictors of poor survival rates. Conclusions:We suggest that cotargeting Plk1 and AR would be effective in advanced chemoresistant prostate cancer cells to overcome the limitations associated with paclitaxel.
SUBMITTER: Shin SB
PROVIDER: S-EPMC6515847 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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