Identification and testing of novel CARP-1 functional mimetic compounds as inhibitors of non-small cell lung and triple negative breast cancers

Identification and testing of novel CARP-1 functional mimetic compounds as inhibitors of non-small cell lung and triple negative breast cancers

The triple negative breast cancer (TNBCs) and non-small cell lung cancers (NSCLCs) often acquire mutations that contribute to failure of drugs in clinic and poor prognosis, thus presenting an urgent need to develop new and improved therapeutic modalities. Here we report that CARP-1 functional mimeti...

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Main Authors: Muthu, Magesh, Somagoni, Jaganmohan, Cheriyan, Vino T., Munie, Sara, Levi, Edi, Ashour, Abdelkader Elbadawy Abbas, Yassin, Alaa Eldeen B., Alafeefy, Ahmed M., Sochacki, Paula, Polin, Lisa A., Reddy, Kaladhar B., Larsen, Scott D., Singh, Mandip, Rishi, Arun K.
Format: Article
Language:English
Published: American Scientific Publishers 2015
Subjects:
RM300 Drugs and their action
Online Access:http://irep.iium.edu.my/64285/
http://irep.iium.edu.my/64285/
http://irep.iium.edu.my/64285/
http://irep.iium.edu.my/64285/1/Identification%20and%20Testing%20of%20Novel%20CARP-1%20Functional%20Mimetic%20Compounds%20as%20Inhibitors%20of%20Non-Small%20Cell%20Lung%20and%20Triple%20Negative%20Breast%20Cancers.pdf
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spelling iium-642852018-08-30T06:28:46Z http://irep.iium.edu.my/64285/ Identification and testing of novel CARP-1 functional mimetic compounds as inhibitors of non-small cell lung and triple negative breast cancers Muthu, Magesh Somagoni, Jaganmohan Cheriyan, Vino T. Munie, Sara Levi, Edi Ashour, Abdelkader Elbadawy Abbas Yassin, Alaa Eldeen B. Alafeefy, Ahmed M. Sochacki, Paula Polin, Lisa A. Reddy, Kaladhar B. Larsen, Scott D. Singh, Mandip Rishi, Arun K. RM300 Drugs and their action The triple negative breast cancer (TNBCs) and non-small cell lung cancers (NSCLCs) often acquire mutations that contribute to failure of drugs in clinic and poor prognosis, thus presenting an urgent need to develop new and improved therapeutic modalities. Here we report that CARP-1 functional mimetic (CFMs) compounds 4 and 5, and 4.6, a structurally related analog of CFM-4, are potent inhibitors of TNBC and NSCLC cells in vitro. Cell growth suppression by CFM-4 and -4.6 involved interaction and elevated expression of CARP-1/CCAR1 and Death Effector Domain (DED) containing DNA binding (DEDD)2 proteins. Apoptosis by these compounds also involved activation of pro-apoptotic stress-activated kinases p38 and JNK1/2, cleavage of PARP and loss of mitotic cyclin B1. Both the CFMs inhibited abilities of NSCLC and TNBC cells to migrate, invade, and form colonies in suspension, while disrupting tubule formation by the human umbilical vein endothelial cells (HUVECs). Nano-lipid formulation of CFM-4 (CFM-4 NLF) enhanced its serum bioavailability when compared with the free CFM-4. Oral administration of CFM-4 NLF reduced weights and volume of the xenografted tumors derived from A549 NSCLC and MDA-MB-231 TNBC cells. Although no gross tissue or histological toxicities were noticed, the immuno-histochemical analysis revealed increased CARP-1 and DNA fragmentation in tumors of the CFM-4 NLF-treated animals. In conclusion, while stimulation of pro-apoptotic CARP-1 and DEDD2 expression and their binding underscore a novel mechanism of apoptosis transduction by CFM compounds, our proof-of-concept xenograft studies demonstrate therapeutic potential of CFM-4 for TNBC and NSCLC. American Scientific Publishers 2015-09-01 Article PeerReviewed application/pdf en http://irep.iium.edu.my/64285/1/Identification%20and%20Testing%20of%20Novel%20CARP-1%20Functional%20Mimetic%20Compounds%20as%20Inhibitors%20of%20Non-Small%20Cell%20Lung%20and%20Triple%20Negative%20Breast%20Cancers.pdf Muthu, Magesh and Somagoni, Jaganmohan and Cheriyan, Vino T. and Munie, Sara and Levi, Edi and Ashour, Abdelkader Elbadawy Abbas and Yassin, Alaa Eldeen B. and Alafeefy, Ahmed M. and Sochacki, Paula and Polin, Lisa A. and Reddy, Kaladhar B. and Larsen, Scott D. and Singh, Mandip and Rishi, Arun K. (2015) Identification and testing of novel CARP-1 functional mimetic compounds as inhibitors of non-small cell lung and triple negative breast cancers. Journal of Biomedical Nanotechnology, 11 (9). pp. 1608-1627. ISSN 1550-7033 E-ISSN 1550-7041 http://www.ingentaconnect.com/content/asp/jbn/2015/00000011/00000009/art00008 10.1166/jbn.2015.2099
repository_type Digital Repository
institution_category Local University
institution International Islamic University Malaysia
building IIUM Repository
collection Online Access
language English
topic RM300 Drugs and their action
spellingShingle RM300 Drugs and their action
Muthu, Magesh
Somagoni, Jaganmohan
Cheriyan, Vino T.
Munie, Sara
Levi, Edi
Ashour, Abdelkader Elbadawy Abbas
Yassin, Alaa Eldeen B.
Alafeefy, Ahmed M.
Sochacki, Paula
Polin, Lisa A.
Reddy, Kaladhar B.
Larsen, Scott D.
Singh, Mandip
Rishi, Arun K.
Identification and testing of novel CARP-1 functional mimetic compounds as inhibitors of non-small cell lung and triple negative breast cancers
description The triple negative breast cancer (TNBCs) and non-small cell lung cancers (NSCLCs) often acquire mutations that contribute to failure of drugs in clinic and poor prognosis, thus presenting an urgent need to develop new and improved therapeutic modalities. Here we report that CARP-1 functional mimetic (CFMs) compounds 4 and 5, and 4.6, a structurally related analog of CFM-4, are potent inhibitors of TNBC and NSCLC cells in vitro. Cell growth suppression by CFM-4 and -4.6 involved interaction and elevated expression of CARP-1/CCAR1 and Death Effector Domain (DED) containing DNA binding (DEDD)2 proteins. Apoptosis by these compounds also involved activation of pro-apoptotic stress-activated kinases p38 and JNK1/2, cleavage of PARP and loss of mitotic cyclin B1. Both the CFMs inhibited abilities of NSCLC and TNBC cells to migrate, invade, and form colonies in suspension, while disrupting tubule formation by the human umbilical vein endothelial cells (HUVECs). Nano-lipid formulation of CFM-4 (CFM-4 NLF) enhanced its serum bioavailability when compared with the free CFM-4. Oral administration of CFM-4 NLF reduced weights and volume of the xenografted tumors derived from A549 NSCLC and MDA-MB-231 TNBC cells. Although no gross tissue or histological toxicities were noticed, the immuno-histochemical analysis revealed increased CARP-1 and DNA fragmentation in tumors of the CFM-4 NLF-treated animals. In conclusion, while stimulation of pro-apoptotic CARP-1 and DEDD2 expression and their binding underscore a novel mechanism of apoptosis transduction by CFM compounds, our proof-of-concept xenograft studies demonstrate therapeutic potential of CFM-4 for TNBC and NSCLC.
format Article
author Muthu, Magesh
Somagoni, Jaganmohan
Cheriyan, Vino T.
Munie, Sara
Levi, Edi
Ashour, Abdelkader Elbadawy Abbas
Yassin, Alaa Eldeen B.
Alafeefy, Ahmed M.
Sochacki, Paula
Polin, Lisa A.
Reddy, Kaladhar B.
Larsen, Scott D.
Singh, Mandip
Rishi, Arun K.
author_facet Muthu, Magesh
Somagoni, Jaganmohan
Cheriyan, Vino T.
Munie, Sara
Levi, Edi
Ashour, Abdelkader Elbadawy Abbas
Yassin, Alaa Eldeen B.
Alafeefy, Ahmed M.
Sochacki, Paula
Polin, Lisa A.
Reddy, Kaladhar B.
Larsen, Scott D.
Singh, Mandip
Rishi, Arun K.
author_sort Muthu, Magesh
title Identification and testing of novel CARP-1 functional mimetic compounds as inhibitors of non-small cell lung and triple negative breast cancers
title_short Identification and testing of novel CARP-1 functional mimetic compounds as inhibitors of non-small cell lung and triple negative breast cancers
title_full Identification and testing of novel CARP-1 functional mimetic compounds as inhibitors of non-small cell lung and triple negative breast cancers
title_fullStr Identification and testing of novel CARP-1 functional mimetic compounds as inhibitors of non-small cell lung and triple negative breast cancers
title_full_unstemmed Identification and testing of novel CARP-1 functional mimetic compounds as inhibitors of non-small cell lung and triple negative breast cancers
title_sort identification and testing of novel carp-1 functional mimetic compounds as inhibitors of non-small cell lung and triple negative breast cancers
publisher American Scientific Publishers
publishDate 2015
url http://irep.iium.edu.my/64285/
http://irep.iium.edu.my/64285/
http://irep.iium.edu.my/64285/
http://irep.iium.edu.my/64285/1/Identification%20and%20Testing%20of%20Novel%20CARP-1%20Functional%20Mimetic%20Compounds%20as%20Inhibitors%20of%20Non-Small%20Cell%20Lung%20and%20Triple%20Negative%20Breast%20Cancers.pdf
first_indexed 2023-09-18T21:31:13Z
last_indexed 2023-09-18T21:31:13Z
_version_ 1777412523222368256

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