Polo-like kinase 1 inhibitor BI 6727 induces DNA damage and exerts strong antitumor activity in small cell lung cancer

Wang, Yuehong; Wu, Linying; Yao, Yinan; Lü, Guohua; Xu, Liming; Zhou, Jianying

doi:10.1016/j.canlet.2018.08.007

Cited by 19 publications

(14 citation statements)

References 50 publications

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“…RNA-seq analysis of mouse embryonic fibroblasts with high expression of PLK1 indicated that PLK1 significantly affected the expression of DDR genes [40]. One previous study showed that receiving monotherapy with another PLK1 inhibitor, B6727, led to DNA damage in small cell lung cancer by activating the ATM/ATR-Chk1/Chk2 checkpoint pathway [41]. Regrettably, several phase II trials showed that receiving monotherapy with BI2536 had limited antitumour activity and dose-limiting side effects in different types of cancers [20,22,42].…”

Section: Discussionmentioning

confidence: 99%

A PLK1 kinase inhibitor enhances the chemosensitivity of cisplatin by inducing pyroptosis in oesophageal squamous cell carcinoma

et al. 2019

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Background Targeting PLK1 has recently been proven as a viable therapeutic strategy against oesophageal squamous cell carcinom (ESCC). Therefore, this study aimed to explore whether the PLK1 inhibitor BI2536 is able to sensitize ESCC cells to cisplatin (DDP) and determine the underlying mechanisms. Methods Viability, clonogenicity, cell cycle distribution and apoptosis were assessed in ESCC cells treated with BI2536 or DDP alone or in combination. Checkpoint activation was examined by immunoblotting and immunohistochemistry. Xenograft model was used to assess the efficacy of the co-treatment. The expression level of GSDME in tissue samples were examined by immunohistochemistry. Findings We found that the combination of BI2536 and DDP was synergistic in ESCC cells, which induced pyroptosis in ESCC cells at low doses. Mechanistic studies revealed that BI2536 significantly induced DNA damage and impaired the DNA damage repair pathway in DDP-treated cells both in vitro and in vivo . Interestingly, we found that co-treatment with BI2536 and DDP induced pyroptosis in ESCC cells depending on the caspase-3/GSDME pathway. Importantly, our study found that GSDME was more highly expressed in tumour tissue than that in normal adjacent tissues, and could serve as a prognostic factor. Interpretation BI2536 sensitizes ESCC cells to DDP by inhibiting the DNA damage repair pathway and inducing pyroptosis, which provides new information for understanding pyroptosis. Our study also reveals that the PLK1 inhibitor BI2536 may be an attractive candidate for ESCC targeted therapy, especially when combined with DDP for treating the GSDME overexpression subtype. Fund National 973 Program and National Natural Science Fundation of China.

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Section: Discussionmentioning

confidence: 99%

A PLK1 kinase inhibitor enhances the chemosensitivity of cisplatin by inducing pyroptosis in oesophageal squamous cell carcinoma

et al. 2019

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“…Likewise, volasertib‐induced DNA damage was increased in the mesenchymal cell lines compared with the epithelial parental cells (Fig B and D, and ), and mesenchymal cell lines were more sensitive to volasertib in vitro (). The Plk1 inhibitor–induced DNA damage (Driscoll et al , ; Wang et al , ; Yim & Erikson, ) may explain why apoptosis measured by BrdU was more striking than that measured by PARP cleavage. Target inhibition, measured by inhibition of the Plk1 substrate p‐NPM (S4), was similar in the isogenic pairs ().…”

Section: Resultsmentioning

confidence: 99%

Non‐canonical cM et regulation by vimentin mediates Plk1 inhibitor–induced apoptosis

et al. 2019

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To address the need for improved systemic therapy for non–small‐cell lung cancer ( NSCLC ), we previously demonstrated that mesenchymal NSCLC was sensitive to polo‐like kinase (Plk1) inhibitors, but the mechanisms of resistance in epithelial NSCLC remain unknown. Here, we show that cM et was differentially regulated in isogenic pairs of epithelial and mesenchymal cell lines. Plk1 inhibition inhibits cM et phosphorylation only in mesenchymal cells. Constitutively active cM et abrogates Plk1 inhibitor–induced apoptosis. Likewise, cM et silencing or inhibition enhances Plk1 inhibitor–induced apoptosis. Cells with acquired resistance to Plk1 inhibitors are more epithelial than their parental cells and maintain cM et activation after Plk1 inhibition. In four animal NSCLC models, mesenchymal tumors were more sensitive to Plk1 inhibition alone than were epithelial tumors. The combination of cM et and Plk1 inhibition led to regression of tumors that did not regrow when drug treatment was stopped. Plk1 inhibition did not affect HGF levels but did decrease vimentin phosphorylation, which regulates cM et phosphorylation via β1‐integrin. This research defines a heretofore unknown mechanism of ligand‐independent activation of cM et downstream of Plk1 and an effective combination therapy.

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“…48,49 PLK1 is a serine/threonine protein kinase that is an early trigger for G2/M conversion in the cell cycle. 50 Inhibition of PLK1 expression can arrest the cell cycle in the G2/M phase, thereby increasing the effectiveness of chemotherapy drugs. 27,28 Combining a PLK1 inhibitor and chemotherapy drugs has already been reported, and can alleviate the drugresistance of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

<p>Combined Delivery of Temozolomide and siPLK1 Using Targeted Nanoparticles to Enhance Temozolomide Sensitivity in Glioma</p>

Shi¹,

Sun²,

Xu³

et al. 2020

IJN

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Introduction: Temozolomide (TMZ) is the first-line chemotherapeutic option to treat glioma; however, its efficacy and clinical application are limited by its drug resistance properties. Polo-like kinase 1 (PLK1)-targeted therapy causes G2/M arrest and increases the sensitivity of glioma to TMZ. Therefore, to limit TMZ resistance in glioma, an angiopep-2 (A2)-modified polymeric micelle (A2PEC) embedded with TMZ and a small interfering RNA (siRNA) targeting PLK1 (siPLK1) was developed (TMZ-A2PEC/siPLK). Materials and Methods: TMZ was encapsulated by A2-PEG-PEI-PCL (A2PEC) through the hydrophobic interaction, and siPLK1 was complexed with the TMZ-A2PEC through electrostatic interaction. Then, an angiopep-2 (A2) modified polymeric micelle (A2PEC) embedding TMZ and siRNA targeting polo-like kinase 1 (siPLK1) was developed (TMZ-A2PEC/siPLK). Results: In vitro experiments indicated that TMZ-A2PEC/siPLK effectively enhanced the cellular uptake of TMZ and siPLK1 and resulted in significant cell apoptosis and cytotoxicity of glioma cells. In vivo experiments showed that glioma growth was inhibited, and the survival time of the animals was prolonged remarkably after TMZ-A2PEC/siPLK1 was injected via their tail vein. Discussion: The results demonstrate that the combination of TMZ and siPLK1 in A2PEC could enhance the efficacy of TMZ in treating glioma.

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Polo-like kinase 1 inhibitor BI 6727 induces DNA damage and exerts strong antitumor activity in small cell lung cancer

Cited by 19 publications

References 50 publications

A PLK1 kinase inhibitor enhances the chemosensitivity of cisplatin by inducing pyroptosis in oesophageal squamous cell carcinoma

A PLK1 kinase inhibitor enhances the chemosensitivity of cisplatin by inducing pyroptosis in oesophageal squamous cell carcinoma

Non‐canonical cM et regulation by vimentin mediates Plk1 inhibitor–induced apoptosis

<p>Combined Delivery of Temozolomide and siPLK1 Using Targeted Nanoparticles to Enhance Temozolomide Sensitivity in Glioma</p>

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