mTOR inhibitors in breast cancer: A systematic review

Zagouri, Flora; Sergentanis, Theodoros N.; Chrysikos, Dimosthenis; Filipits, Martin; Bartsch, Rupert

doi:10.1016/j.ygyno.2012.08.040

Cited by 33 publications

(23 citation statements)

References 53 publications

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“…We used one ER+/PR+ breast cancer line, MCF-7, as mTOR inhibition has shown clinical benefit in ER+ breast cancer [13] and two triple negative breast cancer (TRNBC) cell lines, MDA-MB-231 and MDA-MB-468. Activation of the PI3K/AKT/mTOR pathway is frequently observed in TRNBC, but to date, the clinical application of mTOR inhibition as a strategy to treat this subtype of breast cancer has been less well studied [16]. We first confirmed that the mTOR inhibitor rapamycin induces a cytostatic effect on the growth of breast cancer cell lines (Fig.…”

Section: Resultsmentioning

confidence: 54%

Loss-of-function RNAi screens in breast cancer cells identify AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 as sensitizing targets of rapamycin activity

Hüppi

Chakka

et al. 2014

Cancer Letters

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The use of molecularly targeted drugs as single agents has shown limited utility in many tumor types, largely due to the complex and redundant nature of oncogenic signaling networks. Targeting of the PI3K/AKT/mTOR pathway through inhibition of mTOR in combination with aromatase inhibitors has seen success in particular sub-types of breast cancer and there is a need to identify additional synergistic combinations to maximize the clinical potential of mTOR inhibitors. We have used loss-of-function RNAi screens of the mTOR inhibitor rapamycin to identify sensitizers of mTOR inhibition. RNAi screens conducted in combination with rapamycin in multiple breast cancer cell lines identified six genes, AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 that when silenced, each enhanced the sensitivity of multiple breast cancer lines to rapamycin. Using selective pharmacological agents we confirmed that inhibition of AURKB or PLK1 synergizes with rapamycin. Compound-associated gene expression data suggested histone deacetylation (HDAC) inhibition as a strategy for reducing the expression of several of the rapamycin-sensitizing genes, and we tested and validated this using the HDAC inhibitor entinostat in vitro and in vivo. Our findings indicate new approaches for enhancing the efficacy of rapamycin including the use of combining its application with HDAC inhibition.

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Section: Resultsmentioning

confidence: 54%

Loss-of-function RNAi screens in breast cancer cells identify AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 as sensitizing targets of rapamycin activity

Hüppi

Chakka

et al. 2014

Cancer Letters

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“…mTOR pathway is a crucial mediator of tumor progression (Zagouri et al, 2012). To examine the G2⁄M phase block, 44.71% treated vs.19.21% control and a decrease of cells in G1⁄M phase, from 57.43% to 36.02% (Table 1).…”

Section: Oridonin Inhibits the Mtor Signaling Pathway In Skov Cellsmentioning

confidence: 99%

Oridonin Suppresses Proliferation of Human Ovarian Cancer Cells via Blockage of mTOR Signaling

Xiao¹,

Chen²,

Qin³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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Oridonin, an ent-kaurane diterpenoid compound isolated from the traditional Chinese herb Rabdosia rubescens, has shown various pharmacological and physiological effects such as anti-tumor, anti-bacterial, and anti-inflammatory properties. However, the effect of oridonin on human ovarian cancer cell lines has not been determined. In this study, we demonstrated that oridonin inhibited ovarian cancer cell proliferation, migration and invasion in a dose-dependent manner. Furthermore, we showed oridonin inhibited tumor growth of ovarian cancer cells (SKOV3) in vivo. We then assessed mechanisms and found that oridonin specifically abrogated the phosphorylation/activation of mTOR signaling. In summary, our results indicate that oridonin is a potential inhibitor of ovarian cancer by blocking the mTOR signaling pathway. Keywords

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“…It inhibits the proliferation of various tumor cell lines in vitro. The sensitivity of MCF-7 cells to RAPA have been reported when they are used intravenously, and the mTOR rapamycin derivatives have been shown previously in human breast cancer model (Law, 2005;Martin et al, 2013;Zagouri et al, 2012). Rouf et al (2009) also reported that the antiproliferative effects of conventional and PEGylated rapamycin liposomes were significantly more than hydroethanol solution of rapamycin.…”

Section: Antiproliferative Effect Of Rapamycin Liposomesmentioning

confidence: 82%

Fusogenic pH sensitive liposomal formulation for rapamycin: Improvement of antiproliferative effect

Ghanbarzadeh

Khorrami

Khosroshahi

et al. 2014

Pharmaceutical Biology

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Context: Liposomes are increasingly employed to deliver chemotherapeutic agents, antisense oligonucleotides, and genes to various therapeutic targets. Objective: The present investigation evaluates the ability of fusogenic pH-sensitive liposomes of rapamycin in increasing its antiproliferative effect on human breast adenocarcinoma (MCF-7) cell line. Materials and methods: Cholesterol (Chol) and dipalmitoylphosphatidylcholine (DPPC) (DPPC:Chol, 7:3) were used to prepare conventional rapamycin liposomes by a modified ethanol injection method. Dioleoylphosphatidylethanolamine (DOPE) was used to produce fusogenic and pH-sensitive properties in liposomes simultaneously (DPPC:Chol:DOPE, 7:3:4.2). The prepared liposomes were characterized by their size, zeta potential, encapsulation efficiency percent (EE%), and chemical stability during 6 months. The antiproliferative effects of both types of rapamycin liposomes (10, 25, and 50 nmol/L) with optimized formulations were assessed on MCF-7 cells, as cancerous cells, and human umbilical vein endothelial cells (HUVEC), as healthy cells, employing the diphenyltetrazolium bromide (MTT) assay for 72 h. Results and discussion: The particle size, zeta potential, and EE% of the liposomes were 165 AE 12.3 and 178 AE 15.4 nm, À39.6 AE 1.3, and À41.2 AE 2.1 mV as well as 76.9 AE 2.6 and 76.9 AE 2.6% in conventional and fusogenic pH-sensitive liposomes, respectively. Physicochemical stability results indicated that both liposome types were relatively stable at 4 C than 25 C. In vitro antiproliferative evaluation showed that fusogenic pH-sensitive liposomes had better antiproliferative effects on MCF-7 cells compared to the conventional liposomes. Conversely, fusogenic pH-sensitive liposomes had less cytotoxicity on HUVEC cell line. KeywordsAntiproliferative effect, breast cancer, fusogenic pH-sensitive liposome, rapamycin History

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mTOR inhibitors in breast cancer: A systematic review

Cited by 33 publications

References 53 publications

Loss-of-function RNAi screens in breast cancer cells identify AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 as sensitizing targets of rapamycin activity

Loss-of-function RNAi screens in breast cancer cells identify AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 as sensitizing targets of rapamycin activity

Oridonin Suppresses Proliferation of Human Ovarian Cancer Cells via Blockage of mTOR Signaling

Fusogenic pH sensitive liposomal formulation for rapamycin: Improvement of antiproliferative effect

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