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Simultaneous inhibition of ErbB1 and ErbB2 signaling significantly enhances the growth suppression of rat and human cholangiocarcinoma cell lines
Author(s) -
Zhang Zichen,
Sirica Alphonse Eugene
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a71
Subject(s) - lapatinib , growth inhibition , cancer research , cell growth , cell culture , apoptosis , protein kinase b , biology , signal transduction , medicine , microbiology and biotechnology , trastuzumab , cancer , biochemistry , genetics , breast cancer
Aberrant expression of ErbB1 and/or ErbB2 in cholangiocarcinomas suggests a strategy to target both ErbB1 and ErbB2 simultaneously might be more effective in suppressing cholangiocarcinoma growth than to target each of these receptors alone. To test this strategy, we investigated targeting with the selective ErbB1 and ErbB2 inhibitors tryphostin AG1517 and AG879, respectively, alone and in combination, as well as with the dual ErbB1/ErbB2 inhibitor lapatinib, to suppress growth of cultured rat C611B and human HuCCT1 cholangiocarcinoma cells. HuCCT1 cells were more sensitive to the growth suppressing effects of AG1517 alone than were C611B cells, whereas AG879 was more effective in suppressing the in vitro growth of C611B than of HuCCT1 cells. AG1517 and AG879 in combination produced a 3.0‐fold greater growth suppression of HuCCT1 cells than that elicited by either agent alone. Lapatinib on a μM basis was an even more potent inhibitor of cell growth than either tryphostin when tested against C611B and HuCCT1 cells. This response, in turn, correlated with a marked inhibition of ErbB2 and ErbB1 activation, suppression of downstream p42/44 MAP kinase and Akt phosphorylation, and prominent apoptosis. These results suggest that dual targeting of ErbB1 and ErbB2 could significantly enhance cholangiocarcinoma therapy over that of single agents targeting either ErbB1 or ErbB2 alone. Supported by CA 83650 and CA 39225 to A.E.S.