The Identification of Small Molecule Inhibitors That Reduce Invasion and Metastasis of Aggressive Cancers
Transformed epithelial cells can activate programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype. This process is linked to the acquisition of an invasive phenotype and the formation of distant metastases. The development of compounds tha...
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Published in | International journal of molecular sciences Vol. 22; no. 4; p. 1688 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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08.02.2021
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Abstract | Transformed epithelial cells can activate programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype. This process is linked to the acquisition of an invasive phenotype and the formation of distant metastases. The development of compounds that block the acquisition of an invasive phenotype or revert the invasive mesenchymal phenotype into a more differentiated epithelial phenotype represent a promising anticancer strategy. In a high-throughput assay based on E-cadherin (re)induction and the inhibition of tumor cell invasion, 44,475 low molecular weight (LMW) compounds were screened. The screening resulted in the identification of candidate compounds from the PROAM02 class. Selected LMW compounds activated E-cadherin promoter activity and inhibited cancer cell invasion in multiple metastatic human cancer cell lines. The intraperitoneal administration of selected LMW compounds reduced the tumor burden in human prostate and breast cancer in vivo mouse models. Moreover, selected LMW compounds decreased the intra-bone growth of xenografted human prostate cancer cells. This study describes the identification of the PROAM02 class of small molecules that can be exploited to reduce cancer cell invasion and metastases. Further clinical evaluation of selected candidate inhibitors is warranted to address their safety, bioavailability and antitumor efficacy in the management of patients with aggressive cancers. |
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AbstractList | Transformed epithelial cells can activate programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype. This process is linked to the acquisition of an invasive phenotype and the formation of distant metastases. The development of compounds that block the acquisition of an invasive phenotype or revert the invasive mesenchymal phenotype into a more differentiated epithelial phenotype represent a promising anticancer strategy. In a high-throughput assay based on E-cadherin (re)induction and the inhibition of tumor cell invasion, 44,475 low molecular weight (LMW) compounds were screened. The screening resulted in the identification of candidate compounds from the PROAM02 class. Selected LMW compounds activated E-cadherin promoter activity and inhibited cancer cell invasion in multiple metastatic human cancer cell lines. The intraperitoneal administration of selected LMW compounds reduced the tumor burden in human prostate and breast cancer in vivo mouse models. Moreover, selected LMW compounds decreased the intra-bone growth of xenografted human prostate cancer cells. This study describes the identification of the PROAM02 class of small molecules that can be exploited to reduce cancer cell invasion and metastases. Further clinical evaluation of selected candidate inhibitors is warranted to address their safety, bioavailability and antitumor efficacy in the management of patients with aggressive cancers. |
Author | Cheung, Henry Maas, Peter Viëtor, Henk van de Merbel, Arjanneke F van der Mark, Maaike H Tijhuis, Johan van Rijt-van de Westerlo, Cindy C M Schalken, Jack A van Hooij, Onno van der Pluijm, Gabri van der Horst, Geertje Wellink, Antoine Kroon, Jan Verhaegh, Gerald W |
AuthorAffiliation | 3 Oncodrone BV, 6525 GA Nijmegen, The Netherlands; antoine.wellink@ru.nl (A.W.); henk.vietor@ffund.nl (H.V.) 4 Department of Endocrinology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands 2 Department of Urology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; onno.vanhooij@radboudumc.nl (O.v.H.); cindy.vandewesterlo-vanrijt@radboudumc.nl (C.C.M.v.R.-v.d.W.); Gerald.verhaegh@radboudumc.nl (G.W.V.); jack.schalken@radboudumc.nl (J.A.S.) 1 Department of Urology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; a.f.van_de_merbel@lumc.nl (A.F.v.d.M.); g.van_der_horst@lumc.nl (G.v.d.H.); m.h.van_der_mark@lumc.nl (M.H.v.d.M.); h.cheung@omnigen.nl (H.C.); j.kroon@lumc.nl (J.K.) 5 Specs, 2712 PB Zoetermeer, The Netherlands; johan.tijhuis@specs.net (J.T.); peter.maas@specs.net (P.M.) |
AuthorAffiliation_xml | – name: 3 Oncodrone BV, 6525 GA Nijmegen, The Netherlands; antoine.wellink@ru.nl (A.W.); henk.vietor@ffund.nl (H.V.) – name: 4 Department of Endocrinology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands – name: 1 Department of Urology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; a.f.van_de_merbel@lumc.nl (A.F.v.d.M.); g.van_der_horst@lumc.nl (G.v.d.H.); m.h.van_der_mark@lumc.nl (M.H.v.d.M.); h.cheung@omnigen.nl (H.C.); j.kroon@lumc.nl (J.K.) – name: 5 Specs, 2712 PB Zoetermeer, The Netherlands; johan.tijhuis@specs.net (J.T.); peter.maas@specs.net (P.M.) – name: 2 Department of Urology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; onno.vanhooij@radboudumc.nl (O.v.H.); cindy.vandewesterlo-vanrijt@radboudumc.nl (C.C.M.v.R.-v.d.W.); Gerald.verhaegh@radboudumc.nl (G.W.V.); jack.schalken@radboudumc.nl (J.A.S.) |
Author_xml | – sequence: 1 givenname: Arjanneke F orcidid: 0000-0002-2439-8047 surname: van de Merbel fullname: van de Merbel, Arjanneke F organization: Department of Urology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands – sequence: 2 givenname: Onno orcidid: 0000-0002-1258-2146 surname: van Hooij fullname: van Hooij, Onno organization: Department of Urology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands – sequence: 3 givenname: Geertje surname: van der Horst fullname: van der Horst, Geertje organization: Department of Urology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands – sequence: 4 givenname: Cindy C M surname: van Rijt-van de Westerlo fullname: van Rijt-van de Westerlo, Cindy C M organization: Oncodrone BV, 6525 GA Nijmegen, The Netherlands – sequence: 5 givenname: Maaike H orcidid: 0000-0002-2061-0020 surname: van der Mark fullname: van der Mark, Maaike H organization: Department of Urology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands – sequence: 6 givenname: Henry surname: Cheung fullname: Cheung, Henry organization: Department of Urology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands – sequence: 7 givenname: Jan surname: Kroon fullname: Kroon, Jan organization: Department of Endocrinology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands – sequence: 8 givenname: Gerald W surname: Verhaegh fullname: Verhaegh, Gerald W organization: Department of Urology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands – sequence: 9 givenname: Johan surname: Tijhuis fullname: Tijhuis, Johan organization: Specs, 2712 PB Zoetermeer, The Netherlands – sequence: 10 givenname: Antoine surname: Wellink fullname: Wellink, Antoine organization: Oncodrone BV, 6525 GA Nijmegen, The Netherlands – sequence: 11 givenname: Peter surname: Maas fullname: Maas, Peter organization: Specs, 2712 PB Zoetermeer, The Netherlands – sequence: 12 givenname: Henk surname: Viëtor fullname: Viëtor, Henk organization: Oncodrone BV, 6525 GA Nijmegen, The Netherlands – sequence: 13 givenname: Jack A surname: Schalken fullname: Schalken, Jack A organization: Oncodrone BV, 6525 GA Nijmegen, The Netherlands – sequence: 14 givenname: Gabri surname: van der Pluijm fullname: van der Pluijm, Gabri organization: Department of Urology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands |
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Keywords | small molecule inhibitors invasiveness prostate cancer metastasis bladder cancer breast cancer E-cadherin |
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Snippet | Transformed epithelial cells can activate programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype.... |
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SubjectTerms | Animal models Animals Antitumor activity Apoptosis Bioavailability Bladder cancer Bone growth Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell adhesion & migration Cell Movement Cell Proliferation Drug Discovery E-cadherin Epithelial cells Female Gene Expression Regulation, Neoplastic - drug effects Genotype & phenotype High-Throughput Screening Assays Humans Inhibitors Invasiveness Libraries Low molecular weights Male Mesenchyme Metastases Metastasis Mice Mice, Inbred BALB C Mice, Nude Molecular weight Neoplasm Invasiveness Phenotypes Physiology Prostate cancer Prostatic Neoplasms - drug therapy Prostatic Neoplasms - genetics Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology small molecule inhibitors Small Molecule Libraries - pharmacology Transcription factors Tumor cell lines Tumor Cells, Cultured Xenograft Model Antitumor Assays Xenografts |
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Title | The Identification of Small Molecule Inhibitors That Reduce Invasion and Metastasis of Aggressive Cancers |
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