Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress.

The aqueous extract of Anemarrhena asphodeloides (BN108) induces apoptosis in various cancer cell lines but is significantly less cytotoxic in non-transformed cells. Chemical fractionation of BN108 showed that its cytotoxicity is associated with timosaponins, steroidal saponins of coprostane type. T...

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Autores principales:	Frank W King, Sylvia Fong, Chandi Griffin, Mark Shoemaker, Rick Staub, Yan-Ling Zhang, Isaac Cohen, Emma Shtivelman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bbba70b854f04f94bbbfb81984ca8160
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spelling	oai:doaj.org-article:bbba70b854f04f94bbbfb81984ca81602021-11-25T06:20:02ZTimosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress.1932-620310.1371/journal.pone.0007283https://doaj.org/article/bbba70b854f04f94bbbfb81984ca81602009-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19789631/?tool=EBIhttps://doaj.org/toc/1932-6203The aqueous extract of Anemarrhena asphodeloides (BN108) induces apoptosis in various cancer cell lines but is significantly less cytotoxic in non-transformed cells. Chemical fractionation of BN108 showed that its cytotoxicity is associated with timosaponins, steroidal saponins of coprostane type. Timosaponin BII (TBII) is a major saponin in BN108, but it shows little cytotoxicity. A much less abundant TAIII induces cell death in tumor cells but not in normal cells, reproducing the selectivity of the total extract BN108. Glycosidase treatment, by removing the extra sugar moiety in TBII, converts it to TAIII and confers cytotoxic activity. Analysis of the mechanisms of death induced by TAIII revealed activation of two distinct pro-apoptotic pathways: first, inhibition of mTORC1 manifested in much reduced phosphorylation of mTORC1 targets; second, induction of endoplasmic reticulum stress culminating in phosphorylation of eIF2alpha and activation of caspase 4. These pro-apoptotic pathways are activated by TAIII selectively in tumor cells but not in normal cells. Both pathways play a causative role in TAIII cytotoxicity, as restoration of either mTOR activity or relief of ER stress alone offer only partial protection from TAIII. Inhibition of mTORC1 and induction of ER stress apparently contribute to the induction of the previously reported autophagic response in TAIII-treated cells. TAIII induced autophagy plays a protective role in TAIII induced death signaling, and failure to mount autophagic response is associated with heightened sensitivity to TAIII induced apoptosis. The multiple death-promoting and apparently tumor-selective responses to TAIII, its ability to inhibit mTORC1, and the possibility of further enhancing its cytotoxicity by pharmacological inhibition of autophagy, make TAIII an attractive candidate for development as a cancer therapeutic agent.Frank W KingSylvia FongChandi GriffinMark ShoemakerRick StaubYan-Ling ZhangIsaac CohenEmma ShtivelmanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 9, p e7283 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Frank W King Sylvia Fong Chandi Griffin Mark Shoemaker Rick Staub Yan-Ling Zhang Isaac Cohen Emma Shtivelman Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress.
description	The aqueous extract of Anemarrhena asphodeloides (BN108) induces apoptosis in various cancer cell lines but is significantly less cytotoxic in non-transformed cells. Chemical fractionation of BN108 showed that its cytotoxicity is associated with timosaponins, steroidal saponins of coprostane type. Timosaponin BII (TBII) is a major saponin in BN108, but it shows little cytotoxicity. A much less abundant TAIII induces cell death in tumor cells but not in normal cells, reproducing the selectivity of the total extract BN108. Glycosidase treatment, by removing the extra sugar moiety in TBII, converts it to TAIII and confers cytotoxic activity. Analysis of the mechanisms of death induced by TAIII revealed activation of two distinct pro-apoptotic pathways: first, inhibition of mTORC1 manifested in much reduced phosphorylation of mTORC1 targets; second, induction of endoplasmic reticulum stress culminating in phosphorylation of eIF2alpha and activation of caspase 4. These pro-apoptotic pathways are activated by TAIII selectively in tumor cells but not in normal cells. Both pathways play a causative role in TAIII cytotoxicity, as restoration of either mTOR activity or relief of ER stress alone offer only partial protection from TAIII. Inhibition of mTORC1 and induction of ER stress apparently contribute to the induction of the previously reported autophagic response in TAIII-treated cells. TAIII induced autophagy plays a protective role in TAIII induced death signaling, and failure to mount autophagic response is associated with heightened sensitivity to TAIII induced apoptosis. The multiple death-promoting and apparently tumor-selective responses to TAIII, its ability to inhibit mTORC1, and the possibility of further enhancing its cytotoxicity by pharmacological inhibition of autophagy, make TAIII an attractive candidate for development as a cancer therapeutic agent.
format	article
author	Frank W King Sylvia Fong Chandi Griffin Mark Shoemaker Rick Staub Yan-Ling Zhang Isaac Cohen Emma Shtivelman
author_facet	Frank W King Sylvia Fong Chandi Griffin Mark Shoemaker Rick Staub Yan-Ling Zhang Isaac Cohen Emma Shtivelman
author_sort	Frank W King
title	Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress.
title_short	Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress.
title_full	Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress.
title_fullStr	Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress.
title_full_unstemmed	Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress.
title_sort	timosaponin aiii is preferentially cytotoxic to tumor cells through inhibition of mtor and induction of er stress.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/bbba70b854f04f94bbbfb81984ca8160
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Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress.

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