MLN0905, a Small-Molecule <i>PLK1</i> Inhibitor, Induces Antitumor Responses in Human Models of Diffuse Large B-cell Lymphoma

Shi, Judy Quiju; Lasky, Kerri; Shinde, Vaishali; Stringer, Bradley; Qian, Mark G.; Liao, Debra; Liu, Ray; Driscoll, Denise L.; Nestor, Michelle Tighe; Amidon, Benjamin S.; Rao, Youlan; Duffey, Matt O.; Manfredi, Mark; Vos, Tricia J.; Amore, Natalie D'; Hyer, Marc L.

doi:10.1158/1535-7163.mct-11-1036

Cited by 18 publications

(18 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A previous study showed that inhibition of PLK1 function suppresses cell growth and increases radiation sensitivity in medulloblastoma cell lines (34). In a diffuse large B-cell lymphoma study, a small-molecule PLK1 inhibitor, MLN0905, was confirmed to have antitumor effects (35). MLN0905 induces mitotic arrest and inhibits in vivo tumorigenicity (35).…”

Section: Discussionmentioning

confidence: 98%

“…In a diffuse large B-cell lymphoma study, a small-molecule PLK1 inhibitor, MLN0905, was confirmed to have antitumor effects (35). MLN0905 induces mitotic arrest and inhibits in vivo tumorigenicity (35). In recent clinical trial studies, a PLK1 inhibitor, BI2536, was used in a randomized phase II clinical trial of pancreatic exocrine adenocarcinoma (36).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Polo-like Kinase Inhibitor Ro5203280 Has Potent Antitumor Activity in Nasopharyngeal Carcinoma

Cheung

Lung

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Nasopharyngeal carcinoma is a cancer with its highest prevalence among the southern Chinese and is rare elsewhere in the world. The main treatment modalities include chemotherapy and radiotherapy. However, tumor chemoresistance often limits the efficacy of nasopharyngeal carcinoma treatment and reduces survival rates. Thus, identifying new selective chemotherapeutic drugs for nasopharyngeal carcinoma treatment is needed. In this current study, the antitumor efficacy of a polo-like kinase inhibitor, Ro5203280, was investigated. Ro5203280 induces tumor suppression both in vitro and in vivo. An inhibitory effect was observed with the highly proliferating cancer cell lines tested, but not with the nontumorigenic cell line. Real-time cell proliferation and fluorescence-activated cell sorting (FACS) analysis, together with immunohistochemical (IHC), immunofluorescence, and Annexin V staining assays, were used to evaluate the impact of drug treatment on cell cycle and apoptosis. Ro5203280 induces G 2 -M cell-cycle arrest and apoptosis. Western blotting shows it inhibits PLK1 phosphorylation and downregulates the downstream signaling molecule, Cdc25c, and upregulates two important mitosis regulators, Wee1 and Securin, as well as the DNA damagerelated factor Chk2 in vitro and in vivo. In vivo tumorigenicity assays with Ro5203280 intravenous injection showed its potent ability to inhibit tumor growth in mice, with no observable signs of toxicity. These findings suggest the potential usefulness of Ro5203280 as a chemotherapeutic targeting drug for nasopharyngeal carcinoma treatment. Mol Cancer Ther; 12(8); 1393-401. Ó2013 AACR.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Polo-like Kinase Inhibitor Ro5203280 Has Potent Antitumor Activity in Nasopharyngeal Carcinoma

Cheung

Lung

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Cells were transfected with 10 nM of GL2 (sense, 5′ CGUACGCGGAAUACUUCGA 3′) or Plk1 (sense, 5′CCGAGUUAUUCAUCGAGAC3′) siRNAs using DharmaFECT 2 (DH2) reagent (Dharmacon) in a BioCoat poly-D-lysine(PDL)-coated 60-mm dishes (BD Biosciences) [39]. A reverse transfection was performed as described in [39].…”

Section: Methodsmentioning

confidence: 99%

Plk1 Inhibition Causes Post-Mitotic DNA Damage and Senescence in a Range of Human Tumor Cell Lines

et al. 2014

Self Cite

View full text Add to dashboard Cite

Plk1 is a checkpoint protein whose role spans all of mitosis and includes DNA repair, and is highly conserved in eukaryotes from yeast to man. Consistent with this wide array of functions for Plk1, the cellular consequences of Plk1 disruption are diverse, spanning delays in mitotic entry, mitotic spindle abnormalities, and transient mitotic arrest leading to mitotic slippage and failures in cytokinesis. In this work, we present the in vitro and in vivo consequences of Plk1 inhibition in cancer cells using potent, selective small-molecule Plk1 inhibitors and Plk1 genetic knock-down approaches. We demonstrate for the first time that cellular senescence is the predominant outcome of Plk1 inhibition in some cancer cell lines, whereas in other cancer cell lines the dominant outcome appears to be apoptosis, as has been reported in the literature. We also demonstrate strong induction of DNA double-strand breaks in all six lines examined (as assayed by γH2AX), which occurs either during mitotic arrest or mitotic-exit, and may be linked to the downstream induction of senescence. Taken together, our findings expand the view of Plk1 inhibition, demonstrating the occurrence of a non-apoptotic outcome in some settings. Our findings are also consistent with the possibility that mitotic arrest observed as a result of Plk1 inhibition is at least partially due to the presence of unrepaired double-strand breaks in mitosis. These novel findings may lead to alternative strategies for the development of novel therapeutic agents targeting Plk1, in the selection of biomarkers, patient populations, combination partners and dosing regimens.

show abstract

“…Importantly, the combination of MLN4924 and mitomycin C in A375 xenograft was synergistic when assessed through day 21 (P < 0.001; ref. 23). …”

Section: Mln4924 and Mitomycin C Are Synergistic In The A375 Xenografmentioning

confidence: 99%

Nedd8-Activating Enzyme Inhibitor MLN4924 Provides Synergy with Mitomycin C through Interactions with ATR, BRCA1/BRCA2, and Chromatin Dynamics Pathways

Garcia

Blank

Bouck

et al. 2014

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

MLN4924 is an investigational small-molecule inhibitor of the Nedd8-activating enzyme currently in phase I clinical trials. MLN4924 induces DNA damage via rereplication in most cell lines. This distinct mechanism of DNA damage may affect its ability to combine with standard-of-care agents and may affect the clinical development of MLN4924. As such, we studied its interaction with other DNA-damaging agents. Mitomycin C, cisplatin, cytarabine, UV radiation, SN-38, and gemcitabine demonstrated synergy in combination with MLN4924 in vitro. The combination of mitomycin C and MLN4924 was shown to be synergistic in a mouse xenograft model. Importantly, depletion of genes within the ataxia telangiectasia and Rad3 related (ATR) and BRCA1/BRCA2 pathways, chromatin modification, and transcription-coupled repair reduced the synergy between mitomycin C and MLN4924. In addition, comet assay demonstrated increased DNA strand breaks with the combination of MLN4924 and mitomycin C. Our data suggest that mitomycin C causes stalled replication forks, which when combined with rereplication induced by MLN4924 results in frequent replication fork collisions, leading to cell death. This study provides a straightforward approach to understand the mechanism of synergy, which may provide useful information for the clinical development of these combinations. Mol Cancer Ther; 13(6); 1625-35. Ó2014 AACR.

show abstract

MLN0905, a Small-Molecule PLK1 Inhibitor, Induces Antitumor Responses in Human Models of Diffuse Large B-cell Lymphoma

Cited by 18 publications

References 20 publications

Polo-like Kinase Inhibitor Ro5203280 Has Potent Antitumor Activity in Nasopharyngeal Carcinoma

Polo-like Kinase Inhibitor Ro5203280 Has Potent Antitumor Activity in Nasopharyngeal Carcinoma

Plk1 Inhibition Causes Post-Mitotic DNA Damage and Senescence in a Range of Human Tumor Cell Lines

Nedd8-Activating Enzyme Inhibitor MLN4924 Provides Synergy with Mitomycin C through Interactions with ATR, BRCA1/BRCA2, and Chromatin Dynamics Pathways

Contact Info

Product

Resources

About