<scp>YM155</scp> down‐regulates survivin and <scp>XIAP</scp>, modulates autophagy and induces autophagy‐dependent <scp>DNA</scp> damage in breast cancer cells

Cheng, Sheng-Shung; Chang, Yung Sheng; Liu, C Y; Lee, J Y C; Chan, Hsiu Han; Kuo, Ching Wen; Lin, Kun; Tsai, Shing Ling; Chen, S H; Li, C F; Leung, Euphemia; Kanwar, Jagat R.; Huang, Chunlong; Chang, J Y; Cheung, Chun Hei Antonio

doi:10.1111/bph.12935

Cited by 82 publications

(76 citation statements)

References 42 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Claspin is required for efficient DNA replication during normal S phase and is highly expressed in more aggressive cancers (17, 31–33). YM155 treatment did affect cell morphology in ATC cells and increased LC3B expressing consistent with its effect on autophagy in other cancer cells (15, 16, 34). Mechanistically, then, by suppressing both survivin and claspin expression and increasing the expression of LC3B, YM155 inhibits growth and metastasis in vitro and in vivo .…”

Section: Discussionsupporting

confidence: 72%

Inhibition of Survivin with YM155 Induces Durable Tumor Response in Anaplastic Thyroid Cancer

Mehta

Zhang

Boufraqech

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy without any effective therapy. The aim of the present study was to use a high-throughput drug library screening to identify a novel therapeutic agent that targets dysregulated genes/pathways in ATC. Experimental Design We performed quantitative high-throughput screening (qHTS) in ATC cell lines using a compound library of 3,282 drugs. Dysregulated genes in ATC were analyzed using genome-wide expression analysis and immunohistochemistry in human ATC tissue samples and ATC cell lines. In vitro and in vivo studies were performed for determining drug activity, effectiveness of targeting, and the mechanism of action. Results qHTS identified 100 active compounds in three ATC cell lines. One of the most active agents was the first-in-class survivin inhibitor YM155. Genome-wide expression analysis and immunohistochemistry showed overexpression of survivin in human ATC tissue samples, and survivin was highly expressed in all ATC cell lines tested. YM155 significantly inhibited ATC cellular proliferation. Mechanistically, YM155 inhibited survivin expression in ATC cells. Furthermore, YM155 treatment reduced claspin expression, which was associated with S-phase arrest in ATC cells. In vivo, YM155 significantly inhibited growth and metastases and prolonged survival. Conclusions Our data show that YM155 is a promising anticancer agent for ATC and that its target, survivin, is overexpressed in ATC. Our findings support the use of YM155 in clinical trials as a therapeutic option in advanced and metastatic ATC.

show abstract

Section: Discussionsupporting

confidence: 72%

Inhibition of Survivin with YM155 Induces Durable Tumor Response in Anaplastic Thyroid Cancer

Mehta

Zhang

Boufraqech

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Finally, survivin depletion-mediated X-linked inhibitor of apoptosis (XIAP) degradation had been shown to contribute to the effects of YM155 against breast cancer cells. 34 However, survivin depletion did not decrease XIAP levels in our models (Figures 2 and 5). …”

Section: Discussionmentioning

confidence: 56%

Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance

Voges¹,

Michaelis²,

Rothweiler³

et al. 2016

Cell Death Dis

View full text Add to dashboard Cite

Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs. Survivin levels, Mcl-1 levels, and DNA damage formation were determined in response to YM155. RNAi-mediated depletion of survivin, Mcl-1, and p53 was performed to investigate their roles during YM155 treatment. Clinical YM155 concentrations affected the viability of drug-resistant neuroblastoma cells through survivin depletion and p53 activation. MDM2 inhibitor-induced p53 activation further enhanced YM155 activity. Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin. Upregulation of ABCB1 (causes YM155 efflux) and downregulation of SLC35F2 (causes YM155 uptake) mediated YM155-specific resistance. YM155-adapted cells displayed increased ABCB1 levels, decreased SLC35F2 levels, and a p53 mutation. YM155-adapted neuroblastoma cells were also characterized by decreased sensitivity to RNAi-mediated survivin depletion, further confirming survivin as a critical YM155 target in neuroblastoma. In conclusion, YM155 targets survivin in neuroblastoma. Furthermore, survivin is a promising therapeutic target for p53 wild-type neuroblastomas after resistance acquisition (neuroblastomas are rarely p53-mutated), potentially in combination with p53 activators. In addition, we show that the adaptation of cancer cells to molecular-targeted anticancer drugs is an effective strategy to elucidate a drug's mechanism of action.

show abstract

“…YM155 is a selective suppressant of survivin, a member of the inhibitor of antiapoptosis (IAP) family that has higher nuclear activity in TNBC compared to other subtypes (17). Interestingly, MDA-MB-231 TNBC cells were more sensitive to YM155 induced growth inhibition than SKBR3 or MCF7 non-TNBC cell lines (18). AKT inhibitor KP372-1, dactinomycin, digoxin and triptolide were a few other highly potent drugs that similarly inhibited growth of all TNBCs.…”

Section: Resultsmentioning

confidence: 99%

Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer

et al. 2017

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation. Medium-throughput results were scrutinized and extensively analyzed for sensitivity patterns, synergy, anticancer activity and validation in low-throughput experiments. Principal component analysis revealed that a fraction of all upregulated or downregulated genes of a particular targeted pathway could partly explain cell sensitivity towards agents targeting that pathway. Combination therapies deemed immediately tractable to translation included ABT-263/crizotinib, ABT-263/paclitaxel, paclitaxel/JQ1, ABT-263/XL184 and paclitaxel/nutlin-3, all of which exhibited synergistic antiproliferative and apoptotic activity in multiple TNBC backgrounds. Mechanistic investigations of the ABT-263/crizotinib combination offering a potentially rapid path to clinic demonstrated RTK blockade, inhibition of mitogenic signaling and pro-apoptotic signal induction in basal and mesenchymal stem-like TNBC. Our findings provide preclinical proof of concept for several combination treatments of TNBC which offer near-term prospects for clinical translation.

show abstract

YM155 down‐regulates survivin and XIAP, modulates autophagy and induces autophagy‐dependent DNA damage in breast cancer cells

Cited by 82 publications

References 42 publications

Inhibition of Survivin with YM155 Induces Durable Tumor Response in Anaplastic Thyroid Cancer

Inhibition of Survivin with YM155 Induces Durable Tumor Response in Anaplastic Thyroid Cancer

Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance

Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer

Contact Info

Product

Resources

About