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

Abstract

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