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Eur Urol. 2011 May;59(5):734-44. doi: 10.1016/j.eururo.2010.12.038. Epub 2011 Jan 12.

Anoikis disruption of focal adhesion-Akt signaling impairs renal cell carcinoma.

Author information

1
Department of Surgery, University of Kentucky College of Medicine, Lexington, KY, USA.

Abstract

BACKGROUND:

Quinazoline-based α1-adrenoceptor antagonists suppress tumor growth by inducing apoptosis via an α1-adrenoceptor-independent action. Anoikis is a unique mode of apoptosis consequential to insufficient cell-matrix interactions.

OBJECTIVE:

This study investigated the apoptotic effect of novel quinazoline-based compounds on human renal cancer cells.

DESIGN, SETTING, AND PARTICIPANTS:

Two cell lines were used: renal cell carcinoma (RCC) 786-0, harboring a von Hippel-Lindau (VHL) tumor-suppressor gene mutation with a highly angiogenic phenotype, and Caki cells (no VHL mutation).

MEASUREMENTS:

The lead compound DZ-50 (10 μM) led to significant inhibition of tumor-cell adhesion, migration, and invasion at a lower dose than doxazosin (25 μM) in both RCC lines.

RESULTS AND LIMITATIONS:

Doxazosin induced death-receptor-mediated apoptosis, while DZ-50 led to anoikis via targeting of the focal adhesion complex and AKT signaling that subsequently increased RCC susceptibility to caspase-8-mediated apoptosis. Both quinazoline compounds, doxazosin and DZ-50, significantly reduced RCC metastatic potential in vivo.

CONCLUSIONS:

Quinazoline-based drugs trigger anoikis in RCC by targeting the focal adhesion survival signaling. This potent antitumor action against human RCC suggests a novel quinazoline-based therapy targeting renal cancer.

PMID:
21269758
PMCID:
PMC5458734
DOI:
10.1016/j.eururo.2010.12.038
[Indexed for MEDLINE]
Free PMC Article

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