Acute toxicity analysis of an inhibitor of BCL2, Disarib, in rats

Abstract Apoptosis or programmed cell death is a highly regulated process, which eliminates unwanted and damaged cells. Inhibition of apoptosis is a hallmark of cancer cells. BCL2 family proteins are known to play a vital role in the regulation of apoptosis. Overexpression of BCL2, an antiapoptotic...

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Autores principales:	Shivangi Sharma, Kontham Kulangara Varsha, Ujjayinee Ray, Humaira Siddiqua, Anjana Elizabeth Jose, Sridhar Muninarasimaiah, Sathees C. Raghavan, Bibha Choudhary
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/95c19df855bd4a1f9bf8d01f14ff0c73
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spelling	oai:doaj.org-article:95c19df855bd4a1f9bf8d01f14ff0c732021-12-02T16:58:09ZAcute toxicity analysis of an inhibitor of BCL2, Disarib, in rats10.1038/s41598-021-89387-x2045-2322https://doaj.org/article/95c19df855bd4a1f9bf8d01f14ff0c732021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89387-xhttps://doaj.org/toc/2045-2322Abstract Apoptosis or programmed cell death is a highly regulated process, which eliminates unwanted and damaged cells. Inhibition of apoptosis is a hallmark of cancer cells. BCL2 family proteins are known to play a vital role in the regulation of apoptosis. Overexpression of BCL2, an antiapoptotic protein, provides the advantage of prolonged survival to cancer cells. Over the years, several BCL2 inhibitors have been investigated extensively for their anticancer potential. However, most of them were abolished before clinical use due to their side effects. Previously, we had identified and characterized a novel BCL2 inhibitor, Disarib, with the potential to eliminate tumor cells in a BCL2 specific manner leading to reduction in tumor burden in multiple mouse models. Notably, a head-to-head comparison of Disarib to ABT199, the only FDA approved BCL2 inhibitor revealed that Disarib is as potent as ABT199. Recent studies using mice revealed that Disarib did not invoke significant side effects in mice. In the present study, we have investigated the acute toxicity of Disarib in Wistar rats. The bioavailability studies following exposure of Disarib in Wistar rats revealed its maximum availability in serum at 24 h following oral administration. Acute toxicity analysis revealed that even a dose as high as 2000 mg/kg of Disarib did not cause significant toxicity in rats. There was no significant variation in blood parameters or kidney and liver functions following administration of Disarib. Histological analysis of different tissues from Disarib treated groups revealed standard architecture with no observable cellular damage. Importantly, exposure to Diasrib did not result in genotoxicity as determined by micronucleus assay. Further, solubility assays revealed that besides DMSO, Disarib is also soluble in alcohol. While the high acidic condition can increase the solubility of Disarib, even a lower percentage of alcohol with acidic conditions can improve its solubility. Thus, the toxicological profile in the current study revealed no significant side effects when Disarib was administered orally to rats.Shivangi SharmaKontham Kulangara VarshaUjjayinee RayHumaira SiddiquaAnjana Elizabeth JoseSridhar MuninarasimaiahSathees C. RaghavanBibha ChoudharyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shivangi Sharma Kontham Kulangara Varsha Ujjayinee Ray Humaira Siddiqua Anjana Elizabeth Jose Sridhar Muninarasimaiah Sathees C. Raghavan Bibha Choudhary Acute toxicity analysis of an inhibitor of BCL2, Disarib, in rats
description	Abstract Apoptosis or programmed cell death is a highly regulated process, which eliminates unwanted and damaged cells. Inhibition of apoptosis is a hallmark of cancer cells. BCL2 family proteins are known to play a vital role in the regulation of apoptosis. Overexpression of BCL2, an antiapoptotic protein, provides the advantage of prolonged survival to cancer cells. Over the years, several BCL2 inhibitors have been investigated extensively for their anticancer potential. However, most of them were abolished before clinical use due to their side effects. Previously, we had identified and characterized a novel BCL2 inhibitor, Disarib, with the potential to eliminate tumor cells in a BCL2 specific manner leading to reduction in tumor burden in multiple mouse models. Notably, a head-to-head comparison of Disarib to ABT199, the only FDA approved BCL2 inhibitor revealed that Disarib is as potent as ABT199. Recent studies using mice revealed that Disarib did not invoke significant side effects in mice. In the present study, we have investigated the acute toxicity of Disarib in Wistar rats. The bioavailability studies following exposure of Disarib in Wistar rats revealed its maximum availability in serum at 24 h following oral administration. Acute toxicity analysis revealed that even a dose as high as 2000 mg/kg of Disarib did not cause significant toxicity in rats. There was no significant variation in blood parameters or kidney and liver functions following administration of Disarib. Histological analysis of different tissues from Disarib treated groups revealed standard architecture with no observable cellular damage. Importantly, exposure to Diasrib did not result in genotoxicity as determined by micronucleus assay. Further, solubility assays revealed that besides DMSO, Disarib is also soluble in alcohol. While the high acidic condition can increase the solubility of Disarib, even a lower percentage of alcohol with acidic conditions can improve its solubility. Thus, the toxicological profile in the current study revealed no significant side effects when Disarib was administered orally to rats.
format	article
author	Shivangi Sharma Kontham Kulangara Varsha Ujjayinee Ray Humaira Siddiqua Anjana Elizabeth Jose Sridhar Muninarasimaiah Sathees C. Raghavan Bibha Choudhary
author_facet	Shivangi Sharma Kontham Kulangara Varsha Ujjayinee Ray Humaira Siddiqua Anjana Elizabeth Jose Sridhar Muninarasimaiah Sathees C. Raghavan Bibha Choudhary
author_sort	Shivangi Sharma
title	Acute toxicity analysis of an inhibitor of BCL2, Disarib, in rats
title_short	Acute toxicity analysis of an inhibitor of BCL2, Disarib, in rats
title_full	Acute toxicity analysis of an inhibitor of BCL2, Disarib, in rats
title_fullStr	Acute toxicity analysis of an inhibitor of BCL2, Disarib, in rats
title_full_unstemmed	Acute toxicity analysis of an inhibitor of BCL2, Disarib, in rats
title_sort	acute toxicity analysis of an inhibitor of bcl2, disarib, in rats
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/95c19df855bd4a1f9bf8d01f14ff0c73
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Acute toxicity analysis of an inhibitor of BCL2, Disarib, in rats

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