Influence of five potential anticancer drugs on wnt pathway and cell survival in human biliary tract cancer cells.
BACKGROUND
The role of Wnt signalling in carcinogenesis suggests compounds targeting this pathway as potential anti-cancer drugs. Several studies report activation of Wnt signalling in biliary tract cancer (BTC) thus rendering Wnt inhibitory drugs as potential candidates for targeted therapy of this highly chemoresistant disease.


METHODS
In this study we analysed five compounds with suggested inhibitory effects on Wnt signalling (DMAT, FH535, myricetin, quercetin, and TBB) for their cytotoxic efficiency, mode of cell death, time- and cell line-dependent characteristics as well as their effects on Wnt pathway activity in nine different BTC cell lines.


RESULTS
Exposure of cancer cells to different concentrations of the compounds results in a clear dose-dependent reduction of viability for all drugs in the order FH535 > DMAT > TBB > myricetin > quercetin. The first three substances show high cytotoxicity in all tested cell lines, cause a direct cytotoxic effect by induction of apoptosis and inhibit pathway-specific signal transduction in a Wnt transcription factor reporter activity assay. Selected target genes such as growth-promoting cyclin D1 and the cell cycle progression inhibitor p27 are down- and up-regulated after treatment, respectively.


CONCLUSIONS
Taken together, these data demonstrate that the small molecular weight inhibitors DMAT, F535 and TBB have a considerable cytotoxic and possibly Wnt-specific effect on BTC cell lines in vitro. Further in vivo investigation of these drugs as well as of new Wnt inhibitors may provide a promising approach for targeted therapy of this difficult-to-treat tumour.
Department of Internal Medicine I, Paracelsus Medical University / Salzburger Landeskliniken (SALK), Muellner Hauptstrasse 48, 5020 Salzburg, Austria.
Julia
J
Wachter
Daniel
D
Neureiter
Beate
B
Alinger
Martin
M
Pichler
Julia
J
Fuereder
Christian
C
Oberdanner
Pietro
P
Di Fazio
Matthias
M
Ocker
Frieder
F
Berr
Tobias
T
Kiesslich
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002986:Clinical Trials as Topic; D019938:Cyclin D1 / Q000235:genetics; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016158:Genes, p53; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014746:Vimentin / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
C492322:2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole; C103118:4,5,6,7-tetrabromo-2-azabenzimidazole; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D015820:Cadherins; C575430:FH535; D005419:Flavonoids; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D013449:Sulfonamides; D014230:Triazoles; D014746:Vimentin; D051176:beta Catenin; C413374:p27 antigen; D019938:Cyclin D1; C040015:myricetin; D011794:Quercetin