posted on 2010-04-07, 13:37authored byLynsey A. McHugh, A. Emre Sayan, Jakob Mejlvang, T. R. Leyshon Griffiths, Yiyang Sun, Margaret M. Manson, Eugene M. Tulchinsky, J. Kilian Mellon, Marina Kriajevska
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.
History
Citation
International Journal of Oncology, 2009, 34 (4), pp. 1155-1163.