YM155 inhibits topoisomerase function

Ren, Ming; Silva, Jeane; Schroeder, Carsten; Weinberger, Paul M.; Janik, John E.; Hao, Zhonglin

doi:10.1097/cad.0000000000000441

Cited by 19 publications

(19 citation statements)

References 47 publications

(49 reference statements)

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“…The mechanism of action of YM155 as anticancer drug is still a matter of debate. Although initially proposed as a BIRC5 transcriptional repressor, YM155 has been subsequently shown to induce DNA damage [50] and to inhibit double-strand break repair [51] . In most of the carcinoma models, survivin inhibition induces apoptosis, whereas for MLS as well as for chondrosarcoma [20] , survivin expression was predominantly nuclear.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth

Graaff

Malu

Guardiola

et al. 2017

Translational Oncology

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Myxoid liposarcoma (MLS) is a soft tissue sarcoma characterized by a recurrent t(12;16) translocation. Although tumors are initially radio- and chemosensitive, the management of inoperable or metastatic MLS can be challenging. Therefore, our aim was to identify novel targets for systemic therapy. We performed an in vitro high-throughput drug screen using three MLS cell lines (402091, 1765092, DL-221), which were treated with 273 different drugs at four different concentrations. Cell lines and tissue microarrays were used for validation. As expected, all cell lines revealed a strong growth inhibition to conventional chemotherapeutic agents, such as anthracyclines and taxanes. A good response was observed to compounds interfering with Src and the mTOR pathway, which are known to be affected in these tumors. Moreover, BIRC5 was important for MLS survival because a strong inhibitory effect was seen at low concentration using the survivin inhibitor YM155, and siRNA for BIRC5 decreased cell viability. Immunohistochemistry revealed abundant expression of survivin restricted to the nucleus in all 32 tested primary tumor specimens. Inhibition of survivin in 402-91 and 1765-92 by YM155 increased the percentage S-phase but did not induce apoptosis, which warrants further investigation before application in the treatment of metastatic MLS. Thus, using a 273-compound drug screen, we confirmed previously identified targets (mTOR, Src) in MLS and demonstrate survivin as essential for MLS survival.

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Section: Discussionmentioning

confidence: 99%

High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth

Graaff

Malu

Guardiola

et al. 2017

Translational Oncology

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“…These findings suggest that the effect of YM155 on some of its targets in the IAP and Bcl-2 families could be cancer cell type-dependent. Interestingly, a study demonstrated that both YM155 and its structural analog NSC80467 induce a DNA damage response [46]; and a recent study even showed that YM155 inhibits topoisomerase 2α decatenation and topoisomerase 1 (Top1)mediated cleavage of DNA, suggesting that YM155 inhibits the Top1 enzyme activity [47]. Nevertheless, YM155 was much better than NSC80467 in terms of its potential to inhibit the expression of survivin [46].…”

Section: Inhibitors That Decrease Survivin Gene Transcriptionmentioning

confidence: 99%

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Aljahdali

Ling

2019

J Exp Clin Cancer Res

187

171

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Survivin (also named BIRC5) is a well-known cancer therapeutic target. Since its discovery more than two decades ago, the use of survivin as a target for cancer therapeutics has remained a central goal of survivin studies in the cancer field. Many studies have provided intriguing insight into survivin's functional role in cancers, thus providing promise for survivin as a cancer therapeutic target. Despite this, moving survivin-targeting agents into and through the clinic remains a challenge. In order to address this challenge, we may need to rethink current strategies in order to develop a new mindset for targeting survivin. In this Review, we will first summarize the current survivin mechanistic studies, and then review the status of survivin cancer therapeutics, which is classified into five categories: (i) survivin-partner protein interaction inhibitors, (ii) survivin homodimerization inhibitors, (iii) survivin gene transcription inhibitors, (iv) survivin mRNA inhibitors and (v) survivin immunotherapy. We will then provide our opinions on cancer therapeutics using survivin as a target, with the goal of stimulating discussion that might facilitate translational research for discovering improved strategies and/or more effective anticancer agents that target survivin for cancer therapy.

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“…al. [13] performed in an in vitro study of lung cancer showed that topoisomerase IIα (Top2α) was a target of YM155. Uncovering the effects and mechanism of YM155 in ATC is essential to predict patient response to therapy, identify synergistic drug combinations, and minimize toxicity.…”

Section: Introductionmentioning

confidence: 99%

“…YM155 also targets interleukin enhancer-binding factor 3/NF110 in PC-3, Calu-6, and HeLa cells [ 12 ]. A recent report of YM155 by Hong et al [ 13 ] performed in an in vitro study of lung cancer showed that topoisomerase IIα (Top2α) was a target of YM155. Uncovering the effects and mechanism of YM155 in ATC is essential to predict patient response to therapy, identify synergistic drug combinations, and minimize toxicity.…”

Section: Introductionmentioning

confidence: 99%

Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells

Mackay

Xiao

et al. 2021

IJMS

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Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies with a median survival time of about 4 months. Currently, there is no effective treatment, and the development of new therapies is an important and urgent issue for ATC patients. YM155 is a small molecule that was identified as the top candidate in a high-throughput screen of small molecule inhibitors performed against a panel of ATC cell lines by the National Cancer Institute. However, there were no follow-up studies investigating YM155 in ATC. Here, we determined the effects of YM155 on ATC and human primary benign thyroid cell (PBTC) survival with alamarBlue assay. Our data show that YM155 inhibited proliferation of ATC cell lines while sparing normal thyroid cells, suggesting a high therapeutic window. YM155-induced DNA damage was detected by measuring phosphorylation of -H2AX as a marker for DNA double-strand breaks. The formamidopyrimidine-DNA glycosylase (FPG)-modified alkaline comet assay in conjunction with reactive oxygen species (ROS) assay and glutathione (GSH)/glutathione (GSSG) assay suggests that YM155-mediated oxidative stress contributes to DNA damage. In addition, we provide evidence that YM155 causes cell cycle arrest in S phase and in the G2/M transition and causes apoptosis, as seen with flow cytometry. In this study, we show for the first time the multiple effects of YM155 in ATC cells, furthering a potential therapeutic approach for ATC.

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YM155 inhibits topoisomerase function

Cited by 19 publications

References 47 publications

High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth

High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Ym155 Induces Oxidative Stress-Mediated DNA Damage and Cell Cycle Arrest, and Causes Programmed Cell Death in Anaplastic Thyroid Cancer Cells

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