Abstract:Patients with metastatic castration-resistant prostate cancer (mCRPC) have poor outcomes. Docetaxel (DTX)-based therapy is a current standard treatment for patients with mCRPC. Approaches combining conventional chemotherapeutic agents and nanoparticles (NPs), particularly iron oxide NPs, may overcome the serious side effects and drug resistance, resulting in the establishment of new therapeutic strategies. We previously reported the combined effects of

Patients with metastatic castration-resistant prostate cancer (mCRPC) have a poor prognosis. Docetaxel (DTX)-based therapy is one of current standard treatments for mCRPC since 2004 although cabazitaxel, abiraterone acetate, and enzalutamide are three agents recently approved for the treatment of mCRPC. Although DTX-based chemotherapy has been shown to improve the quality of life in patients with the advanced disease, this needs to be improved because of limitations by lack of specificity, toxicity, and progression of docetaxel-resistance. Thus, combination of docetaxel with other compounds or drugs is needed to overcome these problems. We have investigated usefulness of magnetic iron oxide nanoparticles (MNPs- Fe3O4) for cancer diagnosis and therapy, showing that MNPs- Fe3O4 may modify the effect of chemotherapy in prostate cancer cells in vitro. The purpose of this study was to analyze the combined effect of docetaxel and MNPs- Fe3O4 on prostate cancer cell lines, DU145 and PC-3 and clarify their mechanisms. Electron microscopy, flow cytometry and Western blotting were used to study apoptosis and autophagic cell death with/without an autophagic inhibitor. Our results showed that MNPs- Fe3O4 produced reactive oxygen species (ROS) and 8-OHdG, and the combination of docetaxel and MNPs- Fe3O4 inhibited cancer cell growth and induced apoptosis and autophagic cell death. Although docetaxel induced nuclear factor-kappaB (NF-KB) expression, combination of docetaxel and MNPs inhibited NF-KB expression. These results suggest that MNPs- Fe3O4 may enhance effect of docetaxel on prostate cancer cells via ROS generation and inhibition of NF-KB signaling, leading to new tumor ablation therapies.<!–EndFragment–> Citation Format: Kanako Kojima, Sanai Takahashi, Shungo Saito, Tadashi Nittami, Eri Usugi, Kenichiro Ishii, Yoshifumi HIrokawa, Masatoshi Watanabe. Magnetic iron oxide nanoparticles induce apoptosis and autophagic cell death in prostate cancer cells treated with docetaxel via ROS generation and NF-KB signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4827.

In the previous study, we identified genes that were differentially expressed between monolayers and spheroids in prostate cancer cell lines. The KIF22 gene was extracted as one of candidate genes related with spheroid formation and multicellular resistance. KIF22 is one of the kinesin superfamily proteins that are microtubule-dependent molecular motor proteins with DNA-binding capacity. KIF22 plays an important role in eukaryotic cell mitosis and macromolecule transportation. Alteration of KIF22 expression and function may lead to cancer development and progression. In this study, we explored the function of the KIF22 in prostate cancer cell lines, DU145 and LNCaP using the KIF22 siRNA. The KIF22 mRNA levels in LNCaP and DU-145 monolayers were detected, and time-dependently increased in both spheroids. The inhibition of KIF22 mRNA using siRNA affected cell proliferation in DU145 and LNCaP spheroids as well as monolayers. In addition, this suppression caused G2/M arrest and apoptosis in both cell lines. In clinical samples, its mRNA expression was significantly higher in tumor portions than in non-cancerous portions. However, the inhibition of KIF22 mRNA did not affect cell migration and invasion in DU145 and LNCaP cells. These findings suggest that KIF22 may play an important role in prostate cancer proliferation, especially spheroid formation, and have the potential to be targeted for prostate cancer treatments such as combination therapy with docetaxel. Citation Format: Rina Sakamaki, Shungo Saito, Tatsuya Kitano, Tadashi Nittami, Jieun Seo, Akimitsu Takagi, Hitoshi Ishiguro, Hiroji Uemura, Masatoshi Watanabe. Functional analysis of the KIF22 in human prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3473. doi:10.1158/1538-7445.AM2017-3473