Inhibition of hedgehog signaling improves the anti-carcinogenic effects of docetaxel in prostate cancer
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Murielle Mimeault1, Satyanarayana Rachagani1, Sakthivel Muniyan1, Parthasarathy Seshacharyulu1, Sonny L. Johansson2, Kaustubh Datta1,3, Ming-Fong Lin1,3, Surinder K. Batra1,3
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
2Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
3Buffet Cancer Center, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
Murielle Mimeault, e-mail: [email protected]
Surinder K. Batra, e-mail: [email protected]
Keywords: Prostate cancer, hedgehog signaling pathway, GDC-0449, docetaxel, PC stem/progenitor cells and PC3 xenograft
Received: October 19, 2014 Accepted: December 16, 2014 Published: January 21, 2015
The establishment of docetaxel-based chemotherapeutic treatments has improved the survival of castration-resistant prostate cancer (CRPC) patients. However, most patients develop resistance supporting the development of therapy. The current study was undertaken to establish the therapeutic benefit to target hedgehog signaling cascade using GDC-0449 to improve the efficacy of chemotherapeutic drug, docetaxel. Here, we show that the combination of GDC-0449 plus docetaxel inhibited the proliferation of WPE1-NB26 cells and PC3 cells via a blockade of G1 and G2M phases. The combined treatment significantly inhibited PC cell migration in vitro. Moreover, the apoptotic effect induced by GDC-0449 plus docetaxel on PC3 cells was mediated, at least partly, via the mitochondrial membrane depolarization, H2O2 production and caspase cascade activation. Interestingly, GDC-0449 was effective at inhibiting the prostasphere formation, inducing the prostasphere disintegration and apoptotic death of side population (SP) from PC3 cells and reversing the resistance of SP cells to docetaxel. In addition, GDC-0449 plus docetaxel also have shown a greater anti-tumoral growth inhibitory effect on PC3 cell xenografts. These findings support the use of the hedgehog inhibitor GDC-0449, which is currently in clinical trials, for improving the anticarcinogenic efficacy of docetaxel-based chemotherapeutic treatments against locally advanced, AI and metastatic PC.
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