MiR-34a attenuates paclitaxel-resistance of hormone-refractory prostate cancer PC3 cells through direct and indirect mechanisms

The Prostate ◽  
2010 ◽  
Vol 70 (14) ◽  
pp. 1501-1512 ◽  
Author(s):  
Keitaro Kojima ◽  
Yasunori Fujita ◽  
Yoshinori Nozawa ◽  
Takashi Deguchi ◽  
Masafumi Ito
Keyword(s):  
Prostate Cancer ◽  
Hormone Refractory Prostate Cancer ◽  
Paclitaxel Resistance ◽  
Pc3 Cells ◽  
Hormone Refractory

Identification of candidate biomarkers of therapeutic response to docetaxel in hormone-refractory prostate cancer by proteomic profiling

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11010-11010
Author(s):  
L. Horvath ◽  
L. Zhao ◽  
B. Lee ◽  
D. Brown ◽  
M. Molloy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Plasma Levels ◽  
Therapeutic Targets ◽  
Predictive Biomarkers ◽  
Protein Profiling ◽  
Hormone Refractory Prostate Cancer ◽  
Psa Response ◽  
Pc3 Cells ◽  
Hormone Refractory

11010 Background: Docetaxel (DTX)-based chemotherapy improves symptoms and survival in men with advanced hormone-refractory prostate cancer (HRPC). However, approximately 50% of patients do not respond to DTX but are exposed to significant toxicity without direct benefit. This study aimed to identify novel therapeutic targets and predictive biomarkers of DTX-resistance in HRPC. Methods: Protein profiling using iTRAQ mass spectrometry compared the PC3-Rx and DTX-sensitive PC3 cells and DTX-resistant PC3-Rx developed by DTX dose-escalation. Functional validation experiments were performed using recombinant protein treatment and siRNA knockdown experiments. Plasma/serum samples were collected from 41 men with metastatic HRPC treated with DTX-based chemotherapy (36 with paired samples pre- and post- cycle 1 DTX). Serum/plasma levels of MIC-1 were measured by ELISA. The association between MIC-1 levels, PSA response and overall survival (OS) were assessed by non-parametric tests and Kaplan-Meier survival analysis. Results: The IC50 for DTX in PC3-Rx was 10-fold higher than that in parent PC-3 cells. Protein profiling identified that MIC-1 levels were elevated 2.4 fold and AGR2 decreased 2.4 fold in DTX resistant cells. Knockdown of AGR2 expression in PC3 cells resulted in increased DTX resistance (p=0.03). PC-3 cells treated with recombinant MIC-1 also became resistant to DTX (p=0.001). Conversely, treating PC3-Rx cells with MIC1-siRNA restored sensitivity to DTX (p=0.002). In HRPC patients, pre-treatment MIC-1 levels did not correlate with PSA response to treatment (p=0.6). In contrast, increased serum/plasma levels of MIC-1 after cycle one of chemotherapy were associated with DTX resistance (p=0.006) and shorter overall survival (p=0.002). Conclusions: These results suggest that both AGR2 and MIC-1 play a role in DTX resistance in HRPC. Furthermore, changes in serum/plasma MIC-1 levels are associated with DTX resistance in a correlative human cohort. While a larger study is needed to validate these findings, the data provide evidence that MIC-1 as a potential predictive biomarker and both MIC-1 and AGR2 are potential therapeutic targets in DTX resistance. No significant financial relationships to disclose.

scholarly journals MiR-148a Attenuates Paclitaxel Resistance of Hormone-refractory, Drug-resistant Prostate Cancer PC3 Cells by Regulating MSK1 Expression

2010 ◽  
Vol 285 (25) ◽  
pp. 19076-19084 ◽  
Author(s):  
Yasunori Fujita ◽  
Keitaro Kojima ◽  
Riyako Ohhashi ◽  
Nanako Hamada ◽  
Yoshinori Nozawa ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Resistant ◽  
Paclitaxel Resistance ◽  
Pc3 Cells ◽  
Hormone Refractory

The TORC1/TORC2 inhibitor, Palomid 529, reduces tumor growth and sensitizes to docetaxel and cisplatin in aggressive and hormone-refractory prostate cancer cells

2011 ◽  
Vol 18 (4) ◽  
pp. 385-400 ◽  
Author(s):  
Giovanni Luca Gravina ◽  
Francesco Marampon ◽  
Foteini Petini ◽  
Leda Biordi ◽  
David Sherris ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Hormone Refractory Prostate Cancer ◽  
Promising Therapeutic Approach ◽  
Ic50 Values ◽  
Pc3 Cells ◽  
Hormone Refractory ◽  
Mtor Activity

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 twoin vivomodels 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 vivotreatment 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.

604: A Phase I Trial of Vaccination of Personalized Peptides for HLA-A2/A24 Positive Patients with Hormone-Refractory Prostate Cancer

2007 ◽  
Vol 177 (4S) ◽  
pp. 202-202
Author(s):  
Hirotsugu Uemura ◽  
Motoyoshi Tanaka ◽  
Shigeya Uejima ◽  
Takafumi Minami ◽  
Kiyohide Fujimoto ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Phase I Trial ◽  
Hormone Refractory Prostate Cancer ◽  
Hormone Refractory

829: PSA-Flare up in Docetaxel Therapy of Hormone-Refractory Prostate cancer (HRPCA): Incidence and Clinical Impact?

2005 ◽  
Vol 173 (4S) ◽  
pp. 225-225
Author(s):  
Peter Olbert ◽  
Andres J. Schrader ◽  
Axel Hegele ◽  
Zoltan Varga ◽  
Axel Heidenreich ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Impact ◽  
Hormone Refractory Prostate Cancer ◽  
Hormone Refractory
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