A novel HSP90 modulator with selective activity against thyroid cancers in vitro

Samadi, Abbas; Loo, Peter Van; Mukerji, Rithwi; O'Donnell, G.; Tong, Xiaqin; Timmermann, Barbara N.; Cohen, Mark S.

doi:10.1016/j.surg.2009.09.028

Cited by 25 publications

(19 citation statements)

References 24 publications

(17 reference statements)

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“…The first Solanaceae species we investigated was the Latin American spiny shrub V. breviflora , where cytotoxicity-guided purification led to the isolation and characterization of withaferin A ( 1 ) (Samadi et al 2009; Samadi et al 2010). Preliminary results revealed 1 as a promising chemotherapeutic candidate for antitumor therapy, and that further translational evaluation of 1 was warranted (Grogan et al 2013; Samadi et al 2012).…”

Section: Withanolides Isolated From Natural Sourcesmentioning

confidence: 99%

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Antiproliferative withanolides from several solanaceous species

Zhang

Cao

Gallagher

et al. 2014

Natural Product Research

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To date, our work on Solanaceous species (Datura wrightii, Jaborosa caulescens, Physalis hispida, P. longifolia, Vassobia breviflora, and Withania somnifera) has resulted in the isolation of 65 withanolides, 31 of which were new, as well as the semi-synthesis of a further 30 withanolides. Structure identification and MTS assay-based antiproliferative evaluation of these 95 compounds revealed that a Δ2-1-oxo functionality in ring A; in conjunction with either a 5β,6β-epoxy or 5α-chloro-6β-hydroxy moiety in ring B; are the minimum structural requirements for withanolides to produce potent cytotoxic activity. Such structural-activity relationship analysis (SARA) also revealed that oxygenation (the –OH or –OR groups) at C-4, 7, 11, and 12; as well as C-14 to C-28; did not contribute toward the observed antiproliferative activity. Herein we present a complete overview of our work as it relates to the withanolides reported from 1965 to 2013.

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Section: Withanolides Isolated From Natural Sourcesmentioning

confidence: 99%

“…Furthermore, mechanistic studies showed that 1 inhibits proliferation by inducing a dose-dependent G2/M cell cycle arrest while promoting cell death through both intrinsic and extrinsic apoptotic pathways (Grogan et al 2013; Samadi et al 2009; Samadi et al 2010; Samadi et al 2012). …”

Section: Antiproliferative Evaluation Of Withanolide Librarymentioning

confidence: 99%

Antiproliferative withanolides from several solanaceous species

Zhang

Cao

Gallagher

et al. 2014

Natural Product Research

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“…These compounds also affect cell-cycle arrest, with significant shift of cells into G2/M arrest, as reported with WA. 21 …”

Section: Discussionmentioning

confidence: 99%

Novel withanolides target medullary thyroid cancer through inhibition of both RET phosphorylation and the mammalian target of rapamycin pathway

Samadi

Bazzill

Zhang

et al. 2012

Surgery

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Background Despite development of current targeted therapies for medullary thyroid cancer (MTC), long-term survival remains unchanged. Recently isolated novel withanolide compounds from Solanaceae physalis are highly potent against MTCs. We hypothesize that these withanolides uniquely inhibit RET phosphorylation and the mammalian target of rapamycin (mTOR) pathway in MTC cells as a mechanism of antiproliferation and apoptosis. Methods MTC cells were treated with novel withanolides and MTC-targeted drugs. In vitro studies assessed cell viability and proliferation (MTS; trypan blue assays), apoptosis (flow cytometry with Annexin V/PI staining; confirmed by Western blot analysis), long-term cytotoxic effects (clonogenic assay), and suppression of key regulatory proteins such as RET, Akt, and mTOR (by Western blot analysis). Results The novel withanolides potently reduced MTC cell viability (half maximal inhibitory concentration [IC50], 270–2,850 nmol/L; 250–1,380 nmol/L for vandetanib; 360–1,640 nmol/L for cabozantinib) with induction of apoptosis at <1,000 nmol/L of drug. Unique from other targeted therapies, withanolides suppressed RET and Akt phosphorylation and protein expression (in a concentration- and time-dependent manner) as well as mTOR activity and translational activity of 4E-BP1 and protein synthesis mediated by p70S6kinase activation at IC50 concentrations. Conclusion Novel withanolides from Physalis selectively and potently inhibit MTC cells in vitro. Unlike other MTC-targeted therapies, these compounds uniquely inhibit both RET kinase activity and the Akt/mTOR prosurvival pathway. Further translational studies are warranted to evaluate their clinical potential.

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“…This drug compound, Withaferin A, has been shown to inhibit human MTC cell proliferation (TT cells and DRO81-1) in vitro by MTS assay and confirmed by trypan-blue exclusion assay 18. This inhibition occurred at a higher potency than drugs like 17-AAG, a popular heat shock protein 90 inhibitor that is currently in phase 1/2 clinical trials in patients including MTC patients.…”

Section: Introductionmentioning

confidence: 88%

A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo

Samadi

Mukerji

Shah

et al. 2010

Surgery

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A novel HSP90 modulator with selective activity against thyroid cancers in vitro

Abstract: Background-HSP90 is a chaperone protein regulating several client proteins involved in thyroid cancer development. The purpose of this study is to mechanisticially evaluate a novel natural-product HSP90 inhibitor in thyroid cancer cell lines for future translational applications.

Cited by 25 publications

References 24 publications

Antiproliferative withanolides from several solanaceous species

Antiproliferative withanolides from several solanaceous species

Novel withanolides target medullary thyroid cancer through inhibition of both RET phosphorylation and the mammalian target of rapamycin pathway

A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo

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