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


METHODS
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).


METHODS
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.


CONCLUSIONS
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.
Department of Surgery, University of Kentucky College of Medicine, Lexington, KY, USA.
Shinichi
S
Sakamoto
Steven
S
Schwarze
Natasha
N
Kyprianou
D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D023102:Anoikis / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D017292:Doxazosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D053218:Receptors, Death Domain / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
C525921:2-(4-(biphenyl-4-sulfonyl)-piperazin-1-yl)-6,7-dipropoxyquinazolin-4-yl-amine; D058668:Adrenergic alpha-1 Receptor Antagonists; D000970:Antineoplastic Agents; D053218:Receptors, Death Domain; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; C505530:CASP8 protein, human; D053181:Caspase 8; C497446:VHL protein, human; D017292:Doxazosin
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