title: Lapatinib, a dual inhibitor of ErbB-1/-2 receptors, enhances effects of combination chemotherapy in bladder cancer cells.
abstract: Survival rate of patients diagnosed with the invasive form of bladder cancer is low suggesting an urgent need to implement novel treatments. GTC (gemcitabine, paclitaxel and cisplatin) is a new chemotherapeutic regimen, which has shown promise in clinical trials. Given that receptor tyrosine kinases of the ErbB family are overexpressed in a high proportion of metastatic bladder tumours, approaches involving small-molecule inhibitors of ErbB receptors in combination with conventional cytostatic drugs are of potential interest. Here, we show that the dual inhibitor of ErbB receptors, lapatinib, enhances cytostatic and induces cytotoxic effects of GTC in two bladder cancer cell lines which differ with regard to expression levels of proteins taking part in the ErbB pathway. Lapatinib inhibited phosphorylation of ErbB receptors and also reduced the level of phosphorylated AKT. Flow cytometry analysis demonstrated that GTC treatment affects cell cycle distribution differently in the presence or absence of lapatinib. In RT112 cells, which express high levels of ErbB receptors and harbour wild-type p53, combined GTC/lapatinib treatment resulted in the phosphorylation of p53 at Ser46 and accumulation of sub-G1 cell populations. Our data indicate that a combinatorial approach involving GTC and lapatinib may have therapeutic potential in a subset of bladder tumours depending on the genetic context.
authors.affiliation: Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, LE1 9HN, UK.
authors.forename: Lynsey A
authors.initials: LA
authors.lastname: McHugh
authors.forename: A Emre
authors.initials: AE
authors.lastname: Sayan
authors.forename: Jakob
authors.initials: J
authors.lastname: Mejlvang
authors.forename: T R Leyshon
authors.initials: TR
authors.lastname: Griffiths
authors.forename: Yiyang
authors.initials: Y
authors.lastname: Sun
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Manson
authors.forename: Eugene
authors.initials: E
authors.lastname: Tulchinsky
authors.forename: J Kilian
authors.initials: JK
authors.lastname: Mellon
authors.forename: Marina
authors.initials: M
authors.lastname: Kriajevska
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002469:Cell Separation; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D000077341:Lapatinib; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases