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.
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 humanrenal 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 humanRCC suggests a novel quinazoline-based therapy targeting renal cancer.
Authors: Michael L Megison; Lauren A Gillory; Jerry E Stewart; Hugh C Nabers; Elizabeth Mrozcek-Musulman; Elizabeth A Beierle Journal: Mol Cancer Res Date: 2014-01-24 Impact factor: 5.852
Authors: M Archer; N Dogra; Z Dovey; T Ganta; H-S Jang; J A Khusid; A Lantz; M Mihalopoulos; J A Stockert; A Zahalka; L Björnebo; S Gaglani; M R Noh; S A Kaplan; R Mehrazin; K K Badani; P Wiklund; K Tsao; D J Lundon; N Mohamed; F Lucien; B Padanilam; M Gupta; A K Tewari; N Kyprianou Journal: Cell Commun Signal Date: 2021-07-20 Impact factor: 5.712
Authors: Muhamad Mustafa; Amer Ali Abd El-Hafeez; Dalia A Abdelhafeez; Dalia Abdelhamid; Yaser A Mostafa; Pradipta Ghosh; Alaa M Hayallah; Gamal El-Din A Abuo-Rahma Journal: Future Med Chem Date: 2021-08-03 Impact factor: 4.767
Authors: Patrick J Hensley; Andreas Desiniotis; Chi Wang; Arnold Stromberg; Ching-Shih Chen; Natasha Kyprianou Journal: PLoS One Date: 2014-01-31 Impact factor: 3.240