Blockage of epidermal growth factor receptor by quinazoline tyrosine kinase inhibitors suppresses growth of human hepatocellular carcinoma.
Epidermal growth factor receptor (EGFR) is highly expressed in many human tumors including hepatocellular carcinoma (HCC). Therefore, inhibition of EGF receptors could be a potential target for anticancer therapy. In this study, we investigated the effects of two EGFR tyrosine kinase inhibitors, PD153035 and its analogue 4-[[3-chloro-4-fluorophenyl]amino]-6,7-dimethoxyquinazoline hydrochloride (ANAPD) on human HCC cell lines by cell proliferation assay, flow cytometry and Western blot. Our results demonstrated that both EGFR inhibitors inhibited tumor cell growth in a dose-dependent manner, but ANAPD was more potent than PD153035. These specific inhibitors not only blocked EGF-stimulated EGFR autophosphorylation but also targeted EGFR signaling including MAPK and Akt pathways. Furthermore, EGFR inhibitors induced a delay in cell cycle progression and a G(1) arrest together with a partial G(2)/M block. EGFR inhibitors also induced tumor cells to undergo apoptosis. In conclusion, this study demonstrated that both PD153035 and ANAPD inhibit tumor cell growth in HCC through inhibition of EGFR signaling pathway, and ANAPD is a more potent inhibitor than PD153035. This suggested that blockage of EGF receptors may provide an effective therapeutic approach for human HCC and ANAPD could be a potential drug candidate for the treatment of HCC.
Liu
Yuqing
Y
Centre for the Study of Liver Disease, Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China. ayliu@hkucc.hku.hk
Poon
Ronnie T P
RT
Shao
Weibin
W
Sun
Xiaoli
X
Chen
Hui
H
Kok
Tsz Wai
TW
Fan
Sheung Tat
ST
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*
C519234:4-((3-chloro-4-fluorophenyl)amino)-6,7-dimethoxyquinazoline hydrochloride; D004791:Enzyme Inhibitors; D011799:Quinazolines; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline