Dual PI3K/mTOR inhibitor NVP-BEZ235 sensitizes docetaxel in castration resistant prostate cancer.

Abstract

PURPOSE:

Effective therapeutic strategies that can achieve long-term improvement in patients with castration resistant prostate cancer are urgently needed. We recently reported that the activated PI3K/Akt/mTOR signaling pathway induced by docetaxel explains resistance to docetaxel in castration resistant prostate cancer. In this study we explored the efficacy of NVP-BEZ235, a dual PI3K and mTORC1/2 inhibitor, for docetaxel resistant castration resistant prostate cancer.

MATERIALS AND METHODS:

We used the 2 human castration resistant prostate cancer cell lines C4-2 and C4-2AT6. At our laboratory C4-2AT6 cells were established from C4-2 under androgen ablated treatment for 6 months. We investigated the efficacy of NVP-BEZ235 monotherapy and NVP-BEZ235 combined with docetaxel in vitro and in vivo.

RESULTS:

Increased phosphorylated Akt in C4-2AT6 cells was significantly inhibited by NVP-BEZ235 in a dose and time dependent manner. WST cell proliferation assay results in C4-2AT6 cells revealed that combined administration of NVP-BEZ235 and docetaxel had significant, synergistically greater cytotoxicity than NVP-BEZ235 or docetaxel monotherapy. Combined NVP-BEZ235 (40 mg/kg) and docetaxel (4 mg/kg) in vivo in a castrated mouse xenograft model inhibited C4-2AT6 tumor growth to a greater degree than in the monotherapy groups. Also, NVP-BEZ235 showed significant efficacy with docetaxel at a low concentration in vivo, suggesting that NVP-BEZ235 effectively decreased resistance to docetaxel.

CONCLUSIONS:

Results suggest that inhibition of the PI3K/Akt/mTOR signaling pathway by NVP-BEZ235 can overcome docetaxel resistance in human castration resistant prostate cancer. Our findings provide a molecular basis for the clinical use of combined administration of NVP-BEZ235 and docetaxel in patients with castration resistant prostate cancer.

• Authors: Yota Yasumizu, Akira Miyajima, Takeo Kosaka, Yasumasa Miyazaki, Eiji Kikuchi, Mototsugu Oya
• Journal: The Journal of urology (J Urol) Vol. 191 Issue 1 Pg. 227-34 (Jan 2014) ISSN: 1527-3792 [Electronic] United States
• PMID: 23954373 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Imidazoles
• Phosphoinositide-3 Kinase Inhibitors
• Quinolines
• Taxoids
• Docetaxel
• MTOR protein, human
• TOR Serine-Threonine Kinases
• dactolisib

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cell Line, Tumor
• Disease Models, Animal
• Docetaxel
• Humans
• Imidazoles (administration & dosage)
• Male
• Mice
• Mice, Inbred BALB C
• Orchiectomy
• Phosphoinositide-3 Kinase Inhibitors
• Prostatic Neoplasms, Castration-Resistant (drug therapy, surgery)
• Quinolines (administration & dosage)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Taxoids (administration & dosage)
• Xenograft Model Antitumor Assays