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.
|Number of pages||11|
|State||Published - May 2011|
Bibliographical noteFunding Information:
Funding/Support and role of the sponsor: This work was supported by grants from the National Institutes of Health, R01 CA107575-6, and the Department of Defense, W81XWH-08-1-0431 (to N.K.). The sponsors were involved in design and conduct of the study; data collection, management, analysis, and interpretation; and preparation of the manuscript.
- Akt signaling
- Focal adhesion complex
- Renal cancer
ASJC Scopus subject areas