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International Journal of Colorectal Disease

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01-10-2014 | Original Article

The impact of pyrvinium pamoate on colon cancer cell viability

Authors: Armin Wiegering, Friedrich-Wilhelm Uthe, Melanie Hüttenrauch, Bettina Mühling, Michael Linnebacher, Franziska Krummenast, Christoph-Thomas Germer, Andreas Thalheimer, Christoph Otto

Published in: International Journal of Colorectal Disease | Issue 10/2014

Abstract

Purpose

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.

Experimental design

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-catenin^mut cell lines, one WNT^wt 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.

Results

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.

Conclusions

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.

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Jemal A, Bray F, Center MM, Ferlay J, Ward E et al (2011) Global cancer statistics. Cancer J Clin 61:69–90CrossRef

Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B et al (2010) Colorectal cancer. Lancet 375:1030–1047PubMedCrossRef

Knudson AG (2001) Two genetic hits (more or less) to cancer. Nat Rev Cancer 1(2):157–162PubMedCrossRef

Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–337CrossRef

Sansom OJ, Meniel VS, Muncan V, Phesse TJ, Wilkins JA, Reed KR, Vass JK, Athineos D, Clevers H, Clarke AR (2007) Myc deletion rescues Apc deficiency in the small intestine. Nature 446(7136):676–769PubMedCrossRef

Kumamoto K, Ishibashi K, Okada N, Tajima Y, Kuwabara K, Kumagai Y, Baba H, Haga N, Ishida H (2013) Polymorphisms of GSTP1, ERCC2 and TS-3’UTR are associated with the clinical outcome of mFOLFOX6 in colorectal cancer patients. Oncol Lett 6(3):648–654PubMedPubMedCentral

Luo J, Solimini NL, Elledge SJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136(5):823–837PubMedCrossRefPubMedCentral

Barker N, Clevers H (2006) Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 5(12):997–1014PubMedCrossRef

Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F et al (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461(7264):614–620PubMedCrossRef

10.

Tian XH, Hou WJ, Fang Y, Fan J, Tong H, Bai SL, Chen Q, Xu H, Li Y (2013) XAV939, a tankyrase 1 inhibitior, promotes cell apoptosis in neuroblastoma cell lines by inhibiting Wnt/β-catenin signaling pathway. J Exp Clin Cancer Res 32(1):100PubMedCrossRefPubMedCentral

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):829–836PubMedCrossRefPubMedCentral

12.

Venerando A, Girardi C, Ruzzene M, Pinna LA (2013) Pyrvinium pamoate does not activate protein kinase CK1, but promotes Akt/PKB down-regulation and GSK3 activation. Biochem J 452(1):131–137PubMed

13.

Maletzki C, Stier S, Gruenert U, Gock M, Ostwald C, Prall F, Linnebacher M (2012) Establishment, characterization and chemosensitivity of three mismatch repair deficient cell lines from sporadic and inherited colorectal carcinomas. PLoS One 7(12):e52485PubMedCrossRefPubMedCentral

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 12:61PubMedCrossRefPubMedCentral

15.

Langendorf H (1958) Direct complexometric calcium determination in serum with calcein as indicator. Klin Wochenschr 36(17):829–831PubMedCrossRef

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):195–204PubMedCrossRefPubMedCentral

17.

Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29(9):e45PubMedCrossRefPubMedCentral

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):RESEARCH0034

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):143–151CrossRef

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):241–250PubMedCrossRef

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):685–690PubMedCrossRef

22.

Tomitsuka E, Kita K, Esumi H (2010) The NADH-fumarate reductase system, a novel mitochondrial energy metabolism, is a new target for anticancer therapy in tumor microenvironments. Ann N Y Acad Sci 1201:44–49PubMedCrossRef

23.

Tomitsuka E, Kita K, Esumi H (2012) An anticancer agent, pyrvinium pamoate inhibits the NADH-fumarate reductase system—a unique mitochondrial energy metabolism in tumour microenvironments. J Biochem 152(2):171–183PubMedCrossRef

24.

Harada Y, Ishii I, Hatake K, Kasahara T (2012) Pyrvinium pamoate inhibits proliferation of myeloma/erythroleukemia cells by suppressing mitochondrial respiratory complex I and STAT3. Cancer Lett 319(1):83–88PubMedCrossRef

25.

Yu DH, Macdonald J, Liu G, Lee AS, Ly M, Davis T, Ke N, Zhou D, Wong-Staal F, Li QX (2008) Pyrvinium targets the unfolded protein response to hypoglycemia and its anti-tumor activity is enhanced by combination therapy. PLoS One 3(12):e3951PubMedCrossRefPubMedCentral

26.

Deng L, Lei Y, Liu R, Li J, Yuan K, Li Y, Chen Y, Liu Y, Lu Y, Edwards CK 3rd, Huang C, Wei Y (2013) Pyrvinium targets autophagy addiction to promote cancer cell death. Cell Death Dis 4:e614PubMedCrossRefPubMedCentral

27.

Domínguez-Cáceres MA, García-Martínez JM, Calcabrini A, González L, Porque PG, León J, Martín-Pérez J (2004) Prolactin induces Myc expression and cell survival through activation of Src/Akt pathway in lymphoid cells. Oncogene 23(44):7378–7390PubMedCrossRef

28.

Torti D, Trusolino L (2011) Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. EMBO Mol Med 3(11):623–636PubMedCrossRefPubMedCentral

29.

Mologni L, Brussolo S, Ceccon M, Gambacorti-Passerini C (2012) Synergistic effects of combined Wnt/KRAS inhibition in colorectal cancer cells. PLoS One 7(12):e514492CrossRef

Title: The impact of pyrvinium pamoate on colon cancer cell viability
Authors: Armin Wiegering
Friedrich-Wilhelm Uthe
Melanie Hüttenrauch
Bettina Mühling
Michael Linnebacher
Franziska Krummenast
Christoph-Thomas Germer
Andreas Thalheimer
Christoph Otto
Publication date: 01-10-2014
Publisher: Springer Berlin Heidelberg
Published in: International Journal of Colorectal Disease / Issue 10/2014
Print ISSN: 0179-1958
Electronic ISSN: 1432-1262
DOI: https://doi.org/10.1007/s00384-014-1975-y

At a glance: The STEP trials

Springer Medicine

The impact of pyrvinium pamoate on colon cancer cell viability

Abstract

Purpose

Experimental design

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Experimental design

Results

Conclusions

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