Volume 191, Issue 1, Pages (January 2014)

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Volume 191, Issue 1, Pages 227-234 (January 2014) Dual PI3K/mTOR Inhibitor NVP-BEZ235 Sensitizes Docetaxel in Castration Resistant Prostate Cancer Yota Yasumizu, Akira Miyajima, Takeo Kosaka, Yasumasa Miyazaki, Eiji Kikuchi, Mototsugu Oya The Journal of Urology Volume 191, Issue 1, Pages 227-234 (January 2014) DOI: 10.1016/j.juro.2013.07.101 Copyright © 2014 American Urological Association Education and Research, Inc. Terms and Conditions

Figure 1 A, inhibitory effects of 500 nM NVP-BEZ235 exposure for 24 hours on pAkt, pS6 and p4EBP1 expression in C4-2 and C4-2AT6 cells. Bactin, β-actin. B, inhibition of pAkt expression by 500 nM NVP-BEZ235 detected by immunocytochemistry in C4-2AT6 cells. Scale bars indicate 100 μm. C, C4-2AT6 cells were exposed for 24 hours to indicated NVP-BEZ235 concentrations. pAkT, pS6 and p4EBP1 were inhibited by 62.5 nM dose. D, Western blot revealed inhibitory effect of 500 nM NVPBEZ235 at 12 hours on pAkt, pS6 and p4EBP1 in C4-2AT6 cells. The Journal of Urology 2014 191, 227-234DOI: (10.1016/j.juro.2013.07.101) Copyright © 2014 American Urological Association Education and Research, Inc. Terms and Conditions

Figure 2 pAkt. A, expression was induced by 5 nM docetaxel. Co-administration of 500 nM NVP-BEZ235 and 5 nM docetaxel inhibited expression 12 hours after administration. Bactin, β-actin. B, immunofluorescence reveals inhibition in C4-2AT6 cells due to co-administration of 500 nM NVP-BEZ235 and 5 nM docetaxel. Bars indicate 50 μm. The Journal of Urology 2014 191, 227-234DOI: (10.1016/j.juro.2013.07.101) Copyright © 2014 American Urological Association Education and Research, Inc. Terms and Conditions

Figure 3 A, C4-2 and C4-2AT6 cells were treated with NVP-BEZ235 and viability was measured by WST assay. C4-2AT6 cells showed greater sensitivity to NVP-BEZ235 than C4-2 cells. Asterisk indicates p <0.01 vs C4-2 at same dose. B, C4-2AT6 cells showed marked sensitivity to docetaxel and NVP-BEZ235 combination. The Journal of Urology 2014 191, 227-234DOI: (10.1016/j.juro.2013.07.101) Copyright © 2014 American Urological Association Education and Research, Inc. Terms and Conditions

Figure 4 A, effect of NVP-BEZ235 and docetaxel on tumor growth in C4-2AT6 mouse xenograft model starting day that tumor volume was 300 mm3 and for 15 days. Eight to 12 mice per group were treated with 40 mg/kg NVP-BEZ235 monotherapy, 4 mg/kg docetaxel monotherapy, NVP-BEZ235 plus docetaxel combination or vehicle control. p.o., oral. i.p., intraperitoneal. Bars indicate SE. Asterisks indicate vs control. Double daggers indicate vs docetaxel monotherapy. Pound signs indicate vs NVP-BEZ235 monotherapy. B, effect of 12.5 mg/kg NVP-BEZ235 (BEZ235, BEZ) and 2 mg/kg docetaxel (Doce) on tumor growth in C4-2AT6 mouse xenograft model. Points indicate mean tumor volume relative to tumor volume at start. Bars indicate SE. Asterisks indicate vs control or monotherapy. Double daggers indicate vs docetaxel monotherapy. Pound signs indicate vs NVP-BEZ235 monotherapy. C, immunohistochemistry reveals pS6 expression in xenograft tumors at low dose. Expression of pS6 was significantly inhibited by NVP-BEZ235. Reduced from ×100. The Journal of Urology 2014 191, 227-234DOI: (10.1016/j.juro.2013.07.101) Copyright © 2014 American Urological Association Education and Research, Inc. Terms and Conditions

Figure 5 A, representative immunohistochemical staining for Ki67 in C4-2AT6 tumors. Expression was significantly lower for 12.5 mg/kg NVP-BEZ235 (BEZ235) and 2 mg/kg docetaxel combination than for each monotherapy. Reduced from ×200. B, significant decrease in semiquantitative Ki67 index was observed for combined 12.5 mg/kg NVP-BEZ235 and 2 mg/kg docetaxel compared to other groups. Daggers indicate vs combination or control group. The Journal of Urology 2014 191, 227-234DOI: (10.1016/j.juro.2013.07.101) Copyright © 2014 American Urological Association Education and Research, Inc. Terms and Conditions

Figure 6 A, 48-hour exposure to 100 nM NVP-BEZ235 and 2 nM docetaxel induced cleaved PARP signals in vitro in C4-2AT6 cells. B and C, apoptosis was measured by TUNEL assay. BEZ235, NVP-BEZ235. B, reduced from ×200. C, significant increase in apoptosis index was noted for NVP-BEZ235 and docetaxel combination compared to C4-2AT6 tumors. Daggers indicate vs combination or control group. The Journal of Urology 2014 191, 227-234DOI: (10.1016/j.juro.2013.07.101) Copyright © 2014 American Urological Association Education and Research, Inc. Terms and Conditions