Pimavanserin: A Novel Autophagy Modulator for Pancreatic Cancer Treatment

Pancreatic tumors exhibit high basal autophagy compared to that of other cancers. Several studies including those from our laboratory reported that enhanced autophagy leads to apoptosis in cancer cells. In this study, we evaluated the autophagy and apoptosis inducing effects of Pimavanserin tartrate...

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Autores principales:	Sharavan Ramachandran, Itishree S. Kaushik, Sanjay K. Srivastava
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cancer autophagy cell death drug repurposing apoptosis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/1f6e1c8a531f4b8aa7d86425e43bdacd
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spelling	oai:doaj.org-article:1f6e1c8a531f4b8aa7d86425e43bdacd2021-11-25T17:02:21ZPimavanserin: A Novel Autophagy Modulator for Pancreatic Cancer Treatment10.3390/cancers132256612072-6694https://doaj.org/article/1f6e1c8a531f4b8aa7d86425e43bdacd2021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5661https://doaj.org/toc/2072-6694Pancreatic tumors exhibit high basal autophagy compared to that of other cancers. Several studies including those from our laboratory reported that enhanced autophagy leads to apoptosis in cancer cells. In this study, we evaluated the autophagy and apoptosis inducing effects of Pimavanserin tartrate (PVT). Autophagic effects of PVT were determined by Acridine Orange assay and Transmission Electron Microscopy analysis. Clinical significance of ULK1 in normal and pancreatic cancer patients was evaluated by R2 and GEPIA cancer genomic databases. Modulation of proteins in autophagy signaling was assessed by Western blotting and Immunofluorescence. Apoptotic effects of PVT was evaluated by Annexin-V/APC assay. Subcutaneous xenograft pancreatic tumor model was used to evaluate the autophagy-mediated apoptotic effects of PVT in vivo. Autophagy was induced upon PVT treatment in pancreatic ducal adenocarcinoma (PDAC) cells. Pancreatic cancer patients exhibit reduced levels of autophagy initiator gene, ULK1, which correlated with reduced patient survival. Interestingly, PVT induced the expression of autophagy markers ULK1, FIP200, Atg101, Beclin-1, Atg5, LC3A/B, and cleavage of caspase-3, an indicator of apoptosis in several PDAC cells. ULK1 agonist LYN-1604 enhanced the autophagic and apoptotic effects of PVT. On the other hand, autophagy inhibitors chloroquine and bafilomycin blocked the autophagic and apoptotic effects of PVT in PDAC cells. Notably, chloroquine abrogated the growth suppressive effects of PVT by 25% in BxPC3 tumor xenografts in nude mice. Collectively, our results indicate that PVT mediated pancreatic tumor growth suppression was associated with induction of autophagy mediated apoptosis.Sharavan RamachandranItishree S. KaushikSanjay K. SrivastavaMDPI AGarticlecancerautophagycell deathdrug repurposingapoptosisNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5661, p 5661 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cancer autophagy cell death drug repurposing apoptosis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	cancer autophagy cell death drug repurposing apoptosis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Sharavan Ramachandran Itishree S. Kaushik Sanjay K. Srivastava Pimavanserin: A Novel Autophagy Modulator for Pancreatic Cancer Treatment
description	Pancreatic tumors exhibit high basal autophagy compared to that of other cancers. Several studies including those from our laboratory reported that enhanced autophagy leads to apoptosis in cancer cells. In this study, we evaluated the autophagy and apoptosis inducing effects of Pimavanserin tartrate (PVT). Autophagic effects of PVT were determined by Acridine Orange assay and Transmission Electron Microscopy analysis. Clinical significance of ULK1 in normal and pancreatic cancer patients was evaluated by R2 and GEPIA cancer genomic databases. Modulation of proteins in autophagy signaling was assessed by Western blotting and Immunofluorescence. Apoptotic effects of PVT was evaluated by Annexin-V/APC assay. Subcutaneous xenograft pancreatic tumor model was used to evaluate the autophagy-mediated apoptotic effects of PVT in vivo. Autophagy was induced upon PVT treatment in pancreatic ducal adenocarcinoma (PDAC) cells. Pancreatic cancer patients exhibit reduced levels of autophagy initiator gene, ULK1, which correlated with reduced patient survival. Interestingly, PVT induced the expression of autophagy markers ULK1, FIP200, Atg101, Beclin-1, Atg5, LC3A/B, and cleavage of caspase-3, an indicator of apoptosis in several PDAC cells. ULK1 agonist LYN-1604 enhanced the autophagic and apoptotic effects of PVT. On the other hand, autophagy inhibitors chloroquine and bafilomycin blocked the autophagic and apoptotic effects of PVT in PDAC cells. Notably, chloroquine abrogated the growth suppressive effects of PVT by 25% in BxPC3 tumor xenografts in nude mice. Collectively, our results indicate that PVT mediated pancreatic tumor growth suppression was associated with induction of autophagy mediated apoptosis.
format	article
author	Sharavan Ramachandran Itishree S. Kaushik Sanjay K. Srivastava
author_facet	Sharavan Ramachandran Itishree S. Kaushik Sanjay K. Srivastava
author_sort	Sharavan Ramachandran
title	Pimavanserin: A Novel Autophagy Modulator for Pancreatic Cancer Treatment
title_short	Pimavanserin: A Novel Autophagy Modulator for Pancreatic Cancer Treatment
title_full	Pimavanserin: A Novel Autophagy Modulator for Pancreatic Cancer Treatment
title_fullStr	Pimavanserin: A Novel Autophagy Modulator for Pancreatic Cancer Treatment
title_full_unstemmed	Pimavanserin: A Novel Autophagy Modulator for Pancreatic Cancer Treatment
title_sort	pimavanserin: a novel autophagy modulator for pancreatic cancer treatment
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1f6e1c8a531f4b8aa7d86425e43bdacd
work_keys_str_mv	AT sharavanramachandran pimavanserinanovelautophagymodulatorforpancreaticcancertreatment AT itishreeskaushik pimavanserinanovelautophagymodulatorforpancreaticcancertreatment AT sanjayksrivastava pimavanserinanovelautophagymodulatorforpancreaticcancertreatment
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Pimavanserin: A Novel Autophagy Modulator for Pancreatic Cancer Treatment

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