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Adriano Angelucci, Giovanni Luca Gravina, Nadia Rucci, Danilo Millimaggi, Claudio Festuccia, Paola Muzi, Anna Teti, Carlo Vicentini, and Mauro Bologna

The activation of epidermal growth factor receptor (EGF-R) plays a key role in the promotion of proliferation and invasion in prostatic carcinoma (PCa). Gefitinib (Iressa; ZD1839), an orally active EGF-R tyrosine kinase inhibitor, has shown an important anti-proliferative activity in tumors expressing EGF-R both in vitro and in vivo. Our aim was to elucidate the role of gefitinib in the modulation of the metastatic spread of PCa cells. The therapeutic role of gefitinib was investigated by evaluating the proliferative and invasive ability of the PCa cell line PC3 and of its high metastatic sub-line, PCb2, by in vitro assays and intracardiac injection in nude mice. The inhibitory effect of gefitinib was tested in vivo by injecting PCa cells subcutaneously or in the left ventricle of nude mice and by administrating daily 150 mg/kg of gefitinib. While xenograft growth was equally reduced in all PCa lines (about 50%), the bone metastasis formation was inhibited especially for the high metastatic PCb2 sub-line (81%) in comparison to PC3 cells (47%). The comparative in vitro analysis among PCa cell lines showed that PCb2 cells were more sensitive to the inhibitory effect of gefitinib in their invasive ability compared to parental PC3 cells but not in their proliferation rate. Moreover, PCb2 cells demonstrated an increased invasive ability in vitro in response to bone stromal cell conditioned medium (BCM). The simultaneous presence of 0.1 ng/ml gefitinib was sufficient to reduce the number of invaded cells in the presence of both EGF and BCM. The molecular characterization of the highly aggressive PCa sub-lines demonstrated that this phenomenon was associated with an increment in uPA/uPAR axis but not in EGF-R expression. In conclusion, our data suggest that the use of gefitinib as a therapeutic agent may be indicated in the control of PCa spreading to bone.

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Claudio Festuccia, Giovanni Luca Gravina, Anna Maria D'Alessandro, Paola Muzi, Danilo Millimaggi, Vincenza Dolo, Enrico Ricevuto, Carlo Vicentini, and Mauro Bologna

One of the major obstacles in the treatment of hormone-refractory prostate cancer (HRPC) is the development of chemoresistant tumors. The aim of this study is to evaluate the role of azacitidine as chemosensitizing agent in association with docetaxel (DTX) and cisplatin using two models of aggressive prostate cancer, the 22rv1, and PC3 cell lines. Azacitidine shows antiproliferative effects associated with increased proportion of cells in G0/G1 and evident apoptosis in 22rv1 cells and increased proportion of cells in G2/M phase with the absence of acute cell killing in PC3 cells. In vivo, azacitidine (0.8 mg/kg i.p.) reduced tumor proliferation and induced apoptosis in both xenografts upmodulating the expression of p16INKA, Bax, Bak, p21/WAF1, and p27/KIP1, and inhibiting the activation of Akt activity and the expression of cyclin D1, Bcl-2, and Bcl-XL. In vitro treatments with azacitidine lead to upregulation of cleaved caspase 3 and PARP. BCl2 antagonists, such as HA-14-1, enhanced the effects of azacitidine in these two prostate cancer models. In addition, azacitidine showed synergistic effects with both DTX and cisplatin. In vivo this agent caused tumor growth delay without complete regression in xenograft systems. Azacitidine sensitized PC3 and 22rv1 xenografts to DTX and cisplatin treatments. These combinations were also tolerable in mice and superior to either agent alone. As DTX is the standard first-line chemotherapy for HRPC, the development of DTX-based combination therapies is of great interest in this disease stage. Our results provide a rationale for clinical trials on combination treatments with azacitidine in patients with hormone-refractory and chemoresistant prostate tumors.

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Claudio Festuccia, Giovanni Luca Gravina, Paola Muzi, Roberto Pomante, Luca Ventura, Robert L Vessella, Carlo Vicentini, and Mauro Bologna

Bicalutamide monotherapy is emerging as an alternative in the treatment of locally advanced prostate cancer. However, a significant number of these patients will recur and be in need of second-line therapies. The knowledge of molecular arrangements after pharmacological therapy seems to be a new primary prerequisite to predict the efficacy or the failure of a secondary therapy. Based on these considerations, we have conducted this study in order to analyze the expressions of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), Akt, epidermal growth factor receptor (EGFR), phospho-EGFR (p-EGFR), human EGFR2 (Her2), and phospho-Her2 (p-Her2) after bicalutamide treatment. For this purpose, we evaluated retrospectively 69 prostate cancer tissues derived from patients who received radical prostatectomy as the only treatment, and 81 from patients who received bicalutamide for 120 days before surgery. In addition, we analyzed at different time points the effects of castration performed on athymic mice bearing the LuCaP 35 xenograft line at different times. We observed that bicalutamide treatment increased significantly the levels of p-Akt, EGFR, and Her2 with a concomitant reduction in PTEN. This effect was time dependent and required of sufficient time to be evident as indicated by data obtained with the LuCaP 35 tumors. A logistic multiple regression analysis revealed that a switch of p-Akt control from a PTEN/EGFR- to Her2-after bicalutamide treatment was possible. Since Akt and Her2 can be associated with reduced drug sensitivity, our report suggests that the evaluation of molecular arrangements after bicalutamide treatment could be useful to identify subsets of patients who will be molecular permissive for new adjuvant anti-target therapies.

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Giovanni Luca Gravina, Francesco Marampon, Foteini Petini, Leda Biordi, David Sherris, Emmanuele A Jannini, Vincenzo Tombolini, and Claudio Festuccia

One of the major obstacles in the treatment of hormone-refractory prostate cancer (HRPC) is the development of chemo-resistant tumors. The aim of this study is to evaluate the role of Palomid 529 (P529), a novel TORC1/TORC2 inhibitor, in association with docetaxel (DTX) and cisplatin (CP). This work utilizes a wide panel of prostatic cancer cell lines with or without basal activation of Akt as well as two in vivo models of aggressive HRPC. The blockade of Akt/mTOR activity was associated to reduced cell proliferation and induction of apoptosis. Comparison of IC50 values calculated for PTEN-positive and PTEN-negative cell lines as well as the PTEN transfection in PC3 cells or PTEN silencing in DU145 cells revealed that absence of PTEN was indicative for a better activity of the drug. In addition, P529 synergized with DTX and CP. The strongest synergism was achieved when prostate cancer (PCa) cells were sequentially exposed to CP or DTX followed by treatment with P529. Treatment with P529 before the exposure to chemotherapeutic drugs resulted in a moderate synergism, whereas intermediated values of combination index were found when drugs were administered simultaneously. In vivo treatment of a combination of P529 with DTX or CP increased the percentage of complete responses and reduced the number of mice with tumor progression. Our results provide a rationale for combinatorial treatment using conventional chemotherapy and a Akt/mTOR inhibitor as promising therapeutic approach for the treatment of HRPC, a disease largely resistant to conventional therapies.

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Giovanni Luca Gravina, Francesco Marampon, Paola Muzi, Andrea Mancini, Margherita Piccolella, Paola Negri-Cesi, Marcella Motta, Andrea Lenzi, Ernesto Di Cesare, Vincenzo Tombolini, Emmanuele A Jannini, and Claudio Festuccia

Aberrant activation or ‘reactivation’ of androgen receptor (AR) during androgen ablation therapy shows a potential cause for the development of castration-resistant prostate cancer. This study tested the hypothesis that PXD101, a potent pan histone deacetylase (HDAC) inhibitor, may prevent onset of castration-resistant phenotype and potentiate hormonal therapy. A panel of human prostate cancer cells with graded castration-resistant phenotype and in vivo models were used to verify this hypothesis. In this report, we demonstrated that hormonal manipulation favors the onset of castration-resistant phenotype increasing HDAC expression and activity as well as modulating expression and activity of AR, EGFR, HER2, and Akt. Consistent with these observations, the functional knockdown of HDACs by PXD101 prevented the onset of castration-resistant phenotype with a significant downregulation of AR, EGFR, HER2, and Akt expression/activity. The dysregulation of functional cooperation between HDAC6 with hsp90, on the one hand, and between GSK-3β with CRM1, on the other hand, may explain the biological effects of PXD101. In this regard, the HDAC6 silencing or the functional knockdown of hsp90 by 17AAG resulted in the selective downregulation of AR, EGFR, HER2, and Akt expression/activity, while the decreased phosphorylation of GSK-3β mediated by PXD101 increased the nuclear expression of CRM1, which in turn modified the AR and survivin recycling with increased caspase 3 activity. HDAC inhibitors retain the ability to prevent the onset of castration-resistant phenotype and, therefore, merit clinical investigation in this setting. However, additional data are needed to develop clinical treatment strategies for this disease stage.