LCRF‐0006, a small molecule mimetic of the N‐cadherin antagonist peptide ADH‐1, synergistically increases multiple myeloma response to bortezomib
Abstract N‐cadherin is a homophilic cell‐cell adhesion molecule that plays a critical role in maintaining vascular stability and modulating endothelial barrier permeability. Pre‐clinical studies have shown that the N‐cadherin antagonist peptide, ADH‐1, increases the permeability of tumor‐associated...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-06-01
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| Series: | FASEB BioAdvances |
| Subjects: | |
| Online Access: | https://doi.org/10.1096/fba.2019-00073 |
| _version_ | 1818945051511750656 |
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| author | Krzysztof M. Mrozik Chee M. Cheong Duncan R. Hewett Jacqueline E. Noll Khatora S. Opperman Alaknanda Adwal Darryl L. Russell Orest W. Blaschuk Kate Vandyke Andrew C. W. Zannettino |
| author_facet | Krzysztof M. Mrozik Chee M. Cheong Duncan R. Hewett Jacqueline E. Noll Khatora S. Opperman Alaknanda Adwal Darryl L. Russell Orest W. Blaschuk Kate Vandyke Andrew C. W. Zannettino |
| author_sort | Krzysztof M. Mrozik |
| collection | DOAJ |
| description | Abstract N‐cadherin is a homophilic cell‐cell adhesion molecule that plays a critical role in maintaining vascular stability and modulating endothelial barrier permeability. Pre‐clinical studies have shown that the N‐cadherin antagonist peptide, ADH‐1, increases the permeability of tumor‐associated vasculature thereby increasing anti‐cancer drug delivery to tumors and enhancing tumor response. Small molecule library screens have identified a novel compound, LCRF‐0006, that is a mimetic of the classical cadherin His‐Ala‐Val sequence‐containing region of ADH‐1. Here, we evaluated the vascular permeability‐enhancing and anti‐cancer properties of LCRF‐0006 using in vitro vascular disruption and cell apoptosis assays, and a well‐established pre‐clinical model (C57BL/KaLwRij/5TGM1) of the hematological cancer multiple myeloma (MM). We found that LCRF‐0006 disrupted endothelial cell junctions in a rapid, transient and reversible manner, and increased vascular permeability in vitro and at sites of MM tumor in vivo. Notably, LCRF‐0006 synergistically increased the in vivo anti‐MM tumor response to low‐dose bortezomib, a frontline anti‐MM agent, leading to regression of disease in 100% of mice. Moreover, LCRF‐0006 and bortezomib synergistically induced 5TGM1 MM tumor cell apoptosis in vitro. Our findings demonstrate the potential clinical utility of LCRF‐0006 to significantly increase bortezomib effectiveness and enhance the depth of tumor response in patients with MM. |
| first_indexed | 2024-12-20T07:52:58Z |
| format | Article |
| id | doaj.art-c6826197d1b54a479b78471d9ab82b5d |
| institution | Directory Open Access Journal |
| issn | 2573-9832 |
| language | English |
| last_indexed | 2024-12-20T07:52:58Z |
| publishDate | 2020-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | FASEB BioAdvances |
| spelling | doaj.art-c6826197d1b54a479b78471d9ab82b5d2022-12-21T19:47:47ZengWileyFASEB BioAdvances2573-98322020-06-012633935310.1096/fba.2019-00073LCRF‐0006, a small molecule mimetic of the N‐cadherin antagonist peptide ADH‐1, synergistically increases multiple myeloma response to bortezomibKrzysztof M. Mrozik0Chee M. Cheong1Duncan R. Hewett2Jacqueline E. Noll3Khatora S. Opperman4Alaknanda Adwal5Darryl L. Russell6Orest W. Blaschuk7Kate Vandyke8Andrew C. W. Zannettino9Myeloma Research Laboratory Adelaide Medical School Faculty of Health and Medical Sciences The University of Adelaide Adelaide AustraliaMyeloma Research Laboratory Adelaide Medical School Faculty of Health and Medical Sciences The University of Adelaide Adelaide AustraliaMyeloma Research Laboratory Adelaide Medical School Faculty of Health and Medical Sciences The University of Adelaide Adelaide AustraliaMyeloma Research Laboratory Adelaide Medical School Faculty of Health and Medical Sciences The University of Adelaide Adelaide AustraliaMyeloma Research Laboratory Adelaide Medical School Faculty of Health and Medical Sciences The University of Adelaide Adelaide AustraliaOvarian and Reproductive Cancer Biology Laboratory Robinson Research InstituteThe University of Adelaide Adelaide AustraliaOvarian and Reproductive Cancer Biology Laboratory Robinson Research InstituteThe University of Adelaide Adelaide AustraliaDivision of Urology Department of Surgery McGill University Montreal CanadaMyeloma Research Laboratory Adelaide Medical School Faculty of Health and Medical Sciences The University of Adelaide Adelaide AustraliaMyeloma Research Laboratory Adelaide Medical School Faculty of Health and Medical Sciences The University of Adelaide Adelaide AustraliaAbstract N‐cadherin is a homophilic cell‐cell adhesion molecule that plays a critical role in maintaining vascular stability and modulating endothelial barrier permeability. Pre‐clinical studies have shown that the N‐cadherin antagonist peptide, ADH‐1, increases the permeability of tumor‐associated vasculature thereby increasing anti‐cancer drug delivery to tumors and enhancing tumor response. Small molecule library screens have identified a novel compound, LCRF‐0006, that is a mimetic of the classical cadherin His‐Ala‐Val sequence‐containing region of ADH‐1. Here, we evaluated the vascular permeability‐enhancing and anti‐cancer properties of LCRF‐0006 using in vitro vascular disruption and cell apoptosis assays, and a well‐established pre‐clinical model (C57BL/KaLwRij/5TGM1) of the hematological cancer multiple myeloma (MM). We found that LCRF‐0006 disrupted endothelial cell junctions in a rapid, transient and reversible manner, and increased vascular permeability in vitro and at sites of MM tumor in vivo. Notably, LCRF‐0006 synergistically increased the in vivo anti‐MM tumor response to low‐dose bortezomib, a frontline anti‐MM agent, leading to regression of disease in 100% of mice. Moreover, LCRF‐0006 and bortezomib synergistically induced 5TGM1 MM tumor cell apoptosis in vitro. Our findings demonstrate the potential clinical utility of LCRF‐0006 to significantly increase bortezomib effectiveness and enhance the depth of tumor response in patients with MM.https://doi.org/10.1096/fba.2019-00073combination therapyendothelial cellmultiple myelomatumor‐associated vasculaturevascular permeability |
| spellingShingle | Krzysztof M. Mrozik Chee M. Cheong Duncan R. Hewett Jacqueline E. Noll Khatora S. Opperman Alaknanda Adwal Darryl L. Russell Orest W. Blaschuk Kate Vandyke Andrew C. W. Zannettino LCRF‐0006, a small molecule mimetic of the N‐cadherin antagonist peptide ADH‐1, synergistically increases multiple myeloma response to bortezomib FASEB BioAdvances combination therapy endothelial cell multiple myeloma tumor‐associated vasculature vascular permeability |
| title | LCRF‐0006, a small molecule mimetic of the N‐cadherin antagonist peptide ADH‐1, synergistically increases multiple myeloma response to bortezomib |
| title_full | LCRF‐0006, a small molecule mimetic of the N‐cadherin antagonist peptide ADH‐1, synergistically increases multiple myeloma response to bortezomib |
| title_fullStr | LCRF‐0006, a small molecule mimetic of the N‐cadherin antagonist peptide ADH‐1, synergistically increases multiple myeloma response to bortezomib |
| title_full_unstemmed | LCRF‐0006, a small molecule mimetic of the N‐cadherin antagonist peptide ADH‐1, synergistically increases multiple myeloma response to bortezomib |
| title_short | LCRF‐0006, a small molecule mimetic of the N‐cadherin antagonist peptide ADH‐1, synergistically increases multiple myeloma response to bortezomib |
| title_sort | lcrf 0006 a small molecule mimetic of the n cadherin antagonist peptide adh 1 synergistically increases multiple myeloma response to bortezomib |
| topic | combination therapy endothelial cell multiple myeloma tumor‐associated vasculature vascular permeability |
| url | https://doi.org/10.1096/fba.2019-00073 |
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