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Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice

BACKGROUND: Levamisole, an imidazo(2,1-b)thiazole derivative, has been reported to be a potential antitumor agent. In the present study, we have investigated the mechanism of action of one of the recently identified analogues, 4a (2-benzyl-6-(4′-fluorophenyl)-5-thiocyanato-imidazo[2,1-b][1], [3], [4...

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Autores principales: Hegde, Mahesh, Karki, Subhas S., Thomas, Elizabeth, Kumar, Sujeet, Panjamurthy, Kuppusamy, Ranganatha, Somasagara R., Rangappa, Kanchugarakoppal S., Choudhary, Bibha, Raghavan, Sathees C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3438185/
https://www.ncbi.nlm.nih.gov/pubmed/22970136
http://dx.doi.org/10.1371/journal.pone.0043632
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author Hegde, Mahesh
Karki, Subhas S.
Thomas, Elizabeth
Kumar, Sujeet
Panjamurthy, Kuppusamy
Ranganatha, Somasagara R.
Rangappa, Kanchugarakoppal S.
Choudhary, Bibha
Raghavan, Sathees C.
author_facet Hegde, Mahesh
Karki, Subhas S.
Thomas, Elizabeth
Kumar, Sujeet
Panjamurthy, Kuppusamy
Ranganatha, Somasagara R.
Rangappa, Kanchugarakoppal S.
Choudhary, Bibha
Raghavan, Sathees C.
author_sort Hegde, Mahesh
collection PubMed
description BACKGROUND: Levamisole, an imidazo(2,1-b)thiazole derivative, has been reported to be a potential antitumor agent. In the present study, we have investigated the mechanism of action of one of the recently identified analogues, 4a (2-benzyl-6-(4′-fluorophenyl)-5-thiocyanato-imidazo[2,1-b][1], [3], [4]thiadiazole). MATERIALS AND METHODS: ROS production and expression of various apoptotic proteins were measured following 4a treatment in leukemia cell lines. Tumor animal models were used to evaluate the effect of 4a in comparison with Levamisole on progression of breast adenocarcinoma and survival. Immunohistochemistry and western blotting studies were performed to understand the mechanism of 4a action both ex vivo and in vivo. RESULTS: We have determined the IC(50) value of 4a in many leukemic and breast cancer cell lines and found CEM cells most sensitive (IC(50) 5 µM). Results showed that 4a treatment leads to the accumulation of ROS. Western blot analysis showed upregulation of pro-apoptotic proteins t-BID and BAX, upon treatment with 4a. Besides, dose-dependent activation of p53 along with FAS, FAS-L, and cleavage of CASPASE-8 suggest that it induces death receptor mediated apoptotic pathway in CEM cells. More importantly, we observed a reduction in tumor growth and significant increase in survival upon oral administration of 4a (20 mg/kg, six doses) in mice. In comparison, 4a was found to be more potent than its parental analogue Levamisole based on both ex vivo and in vivo studies. Further, immunohistochemistry and western blotting studies indicate that 4a treatment led to abrogation of tumor cell proliferation and activation of apoptosis by the extrinsic pathway even in animal models. CONCLUSION: Thus, our results suggest that 4a could be used as a potent chemotherapeutic agent.
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spelling pubmed-34381852012-09-11 Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice Hegde, Mahesh Karki, Subhas S. Thomas, Elizabeth Kumar, Sujeet Panjamurthy, Kuppusamy Ranganatha, Somasagara R. Rangappa, Kanchugarakoppal S. Choudhary, Bibha Raghavan, Sathees C. PLoS One Research Article BACKGROUND: Levamisole, an imidazo(2,1-b)thiazole derivative, has been reported to be a potential antitumor agent. In the present study, we have investigated the mechanism of action of one of the recently identified analogues, 4a (2-benzyl-6-(4′-fluorophenyl)-5-thiocyanato-imidazo[2,1-b][1], [3], [4]thiadiazole). MATERIALS AND METHODS: ROS production and expression of various apoptotic proteins were measured following 4a treatment in leukemia cell lines. Tumor animal models were used to evaluate the effect of 4a in comparison with Levamisole on progression of breast adenocarcinoma and survival. Immunohistochemistry and western blotting studies were performed to understand the mechanism of 4a action both ex vivo and in vivo. RESULTS: We have determined the IC(50) value of 4a in many leukemic and breast cancer cell lines and found CEM cells most sensitive (IC(50) 5 µM). Results showed that 4a treatment leads to the accumulation of ROS. Western blot analysis showed upregulation of pro-apoptotic proteins t-BID and BAX, upon treatment with 4a. Besides, dose-dependent activation of p53 along with FAS, FAS-L, and cleavage of CASPASE-8 suggest that it induces death receptor mediated apoptotic pathway in CEM cells. More importantly, we observed a reduction in tumor growth and significant increase in survival upon oral administration of 4a (20 mg/kg, six doses) in mice. In comparison, 4a was found to be more potent than its parental analogue Levamisole based on both ex vivo and in vivo studies. Further, immunohistochemistry and western blotting studies indicate that 4a treatment led to abrogation of tumor cell proliferation and activation of apoptosis by the extrinsic pathway even in animal models. CONCLUSION: Thus, our results suggest that 4a could be used as a potent chemotherapeutic agent. Public Library of Science 2012-09-10 /pmc/articles/PMC3438185/ /pubmed/22970136 http://dx.doi.org/10.1371/journal.pone.0043632 Text en © 2012 Hegde et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Hegde, Mahesh
Karki, Subhas S.
Thomas, Elizabeth
Kumar, Sujeet
Panjamurthy, Kuppusamy
Ranganatha, Somasagara R.
Rangappa, Kanchugarakoppal S.
Choudhary, Bibha
Raghavan, Sathees C.
Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice
title Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice
title_full Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice
title_fullStr Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice
title_full_unstemmed Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice
title_short Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice
title_sort novel levamisole derivative induces extrinsic pathway of apoptosis in cancer cells and inhibits tumor progression in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3438185/
https://www.ncbi.nlm.nih.gov/pubmed/22970136
http://dx.doi.org/10.1371/journal.pone.0043632
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