The impact of pyrvinium pamoate on colon cancer cell viability
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The in vitro and in vivo effects of pyrvinium pamoate (PP), a newly identified WNT signaling inhibitor, were evaluated against colon cancer cell lines and primary colon cancer samples.
Antiproliferative activity of PP and its effects on protein and RNA levels of WNT targets were evaluated on adenomatous polyposis coli (APC mut) and β-cateninmut cell lines, one WNTwt colon cancer cell line, as well as six primary colon cancer samples with mutant APC in vitro. In addition, the effect of PP on the growth of liver metastasis was examined.
PP blocked colon cancer cell growth in vitro in a dose-dependent manner with great differences in the inhibitory concentration (IC50), ranging from 0.6 × 10−6 to 65 × 10−6 mol/L for colon cancer cells with mutations in WNT signaling. In addition, PP demonstrated a cytotoxic effect on primary colon cancer samples. A combined cytotoxic effect of PP with 5-fluorouracil (5-FU) was observed for two cell lines. PP decreased messenger RNA (mRNA) and protein levels of known WNT target genes as c-MYC and thereby led to the induction of p21. PP inhibited the migration of HCT116 colon cancer cells in vitro and decreased tumor growth in vivo after intraportal injection of HCT116 cells in nude mice.
PP displays promising anticancer activity against a broad panel of human colon cancer cell lines, as well as primary colon cancer samples. However, our findings do not demonstrate a predominant cytotoxic effect of PP on colon cancer cells with mutations in WNT signaling.
KeywordsPyrvinium pamoate Colon cancer cell lines WNT pathway Myc
The work was supported by the German Research Foundation (DFG), grant 1516/2-1 (to AT), and by funds from the Interdisciplinary Centre for Clinical Research (IZKF) of the University of Würzburg (B-121 to AT and B-186 to AW). The authors assume full responsibility for the contents of the research. This publication was funded by the German Research Foundation (DFG), and the University of Würzburg is in the funding program Open Access Publishing.
Conflict of interest
The authors declare no conflict of interest.
Conceived and designed the experiments: AW, AT, FK, CTG, ML, CO; performed the experiments: AW, FWU, MH, BM, ML, CO. Analyzed the data: AW, FWU, MH, BM, AT, CO; contributed reagents/materials/analysis tools: AW, FWU, MH, BM, ML, CTG, FK; wrote the paper: AW, CTG, FK, AT, CO.
- 11.Thorne CA, Hanson AJ, Schneider J, Tahinci E, Orton D, Cselenyi CS, Jernigan KK, Meyers KC, Hang BI, Waterson AG, Kim K, Melancon B, Ghidu VP, Sulikowski GA, LaFleur B, Salic A, Lee LA, Miller DM 3rd, Lee E (2010) Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nat Chem Biol 6(11):829–836PubMedCrossRefPubMedCentralGoogle Scholar
- 14.Klingelhoeffer C, Kämmerer U, Koospal M, Mühling B, Schneider S, Kapp M, Kübler A, Germer C-T, Otto C (2012) Natural resistance to ascorbic acid induced oxidative stress is mainly mediated by catalase activity in human cancer cells and catalase-silencing sensitizes to oxidative stress. BMC Complement Altern Med 12:61PubMedCrossRefPubMedCentralGoogle Scholar
- 16.Senger DR, Perruzzi CA, Streit M, Koteliansky VE, de Fougerolles AR, Detmar M (2002) The alpha(1)beta(1) and alpha(2)beta(1) integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis. Am J Pathol 160(1):195–204PubMedCrossRefPubMedCentralGoogle Scholar
- 18.Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):RESEARCH0034Google Scholar
- 19.Thalheimer A, Korb D, Boenicke L, Wiegering A, Muehling B, Schneider M, Koch S, Riedel S, Germer C-T, Braendlein S, Otto C (2013) Non-invasive visualisation of tumour growth in a human colorectal liver metastases xenograft model using bioluminescence in vivo imaging. J Surg Res 195(1):143–151CrossRefGoogle Scholar
- 20.van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, Tjon-Pon-Fong M, Moerer P, van den Born M, Soete G, Pals S, Eilers M, Medema R, Clevers H (2002) The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111(2):241–250PubMedCrossRefGoogle Scholar
- 21.Esumi H, Lu J, Kurashima Y, Hanaoka T (2004) Antitumor activity of pyrvinium pamoate, 6-(dimethylamino)-2-[2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)ethenyl]-1-methyl-quinolinium pamoate salt, showing preferential cytotoxicity during glucose starvation. Cancer Sci 95(8):685–690PubMedCrossRefGoogle Scholar