Anti-invasion, anti-proliferation and anoikis-sensitization activities of lapatinib in nasopharyngeal carcinoma cells.
Nasopharyngeal cancer (NPC) is a highly prevalent and invasive head and neck cancer in Asia. Disease recurrence and distant metastasis account for major NPC deaths. Therefore, more effective therapy is needed. Lapatinib, a dual tyrosine kinase inhibitor (TKI) against both EGFR and HER-2, has been known to exert potent antitumor activity against several cancer models. Given that both EGFR and HER-2 are co-expressed in NPC, we hypothesized that dual targeting of EGFR and HER-2 by this small molecule EGFR/HER-2 TKI would elicit anti-tumor activity in NPC. Using in vitro models of NPC, we demonstrated that lapatinib was able to efficiently inhibit the phosphorylation of both EGFR and HER-2. This was accompanied by significant growth inhibition of NPC cells (with maximal growth inhibition >90%). For the most lapatinib-sensitive cell line (HK1-LMP1, with IC(50) ∼ 600 nM), which harbored the highest levels of both EGFR and HER-2, inhibition of cell growth was associated G(0)/G(1) cell cycle arrest, marked PARP cleavage, caspase-3 cleavage, as well as significant downregulation of several important survival proteins (e.g. survivin, Mcl-1 and cyclin D1). NPC cells are intrinsically invasive. We found that lapatinib was able to inhibit cellular invasion of both HK1-LMP1 and HONE-1 cells. Furthermore, our data demonstrated for the first time that lapatinib harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced apoptosis) in human cancer cells overexpressing both EGFR and HER-2 (HK1-LMP1 and HK1). Taken together, our findings suggest that lapatinib is a promising anti-cancer agent for NPC with anti-invasion and anoikis-sensitization activities.
Lui
Vivian Wai Yan
VW
Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, SAR, Hong Kong. vivian@clo.cuhk.edu.hk
Lau
Cecilia Pik Yuk
CP
Ho
Kakiu
K
Ng
Margaret Heung Ling
MH
Cheng
Suk Hang
SH
Tsao
Sai-Wah
SW
Tsang
Chi Man
CM
Lei
Kenny Ieng Kit
KI
Chan
Anthony Tc
AT
Mok
Tony Shu Kam
TS
D023102:Anoikis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D000077341:Lapatinib; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D053148:Caspase 3; D066246:ErbB Receptors; D000077341:Lapatinib; D011065:Poly(ADP-ribose) Polymerases; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human