Evaluation of Polo‐like kinase 1 as a potential therapeutic target in Merkel cell carcinoma

Kadletz, Lorenz; Bigenzahn, Johannes W.; Thurnher, Dietmar; Stanisz, Isabella; Erovic, Boban M.; Schneider, Sven; Schmid, Rainer; Seemann, Rudolf; Birner, Peter; Heiduschka, Gregor

doi:10.1002/hed.24349

Cited by 11 publications

(6 citation statements)

References 40 publications

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“…In line with our findings, several other studies reported that the combination of Plk1 inhibition with radiotherapy leads to synergistic cell killing in vitro in multiple cancer types such as breast cancer, NSCLC, cervical epithelial adenocarcinoma, medulloblastoma, osteocarcinoma, glioblastoma, Merkel cell carcinoma, colorectal cancer, bladder carcinoma, oral cancer, and esophageal squamous cell carcinoma [8,[28][29][30][31][32][33][34][35][36][37][38][39][40]. In vivo, Dong et al demonstrated a synergistic inhibition of tumor growth and prolonged median survival in a tumor xenograft murine model with glioblastoma stem cells after treatment with volasertib and radiation [38].…”

Section: Discussionsupporting

confidence: 92%

Radiosensitization of Non-Small Cell Lung Cancer Cells by the Plk1 Inhibitor Volasertib Is Dependent on the p53 Status

Bossche

Domen

Peeters

et al. 2019

Cancers

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Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division, is highly expressed in non-small cell lung cancer (NSCLC) making it an interesting drug target. We examined the in vitro therapeutic effects of volasertib, a Plk1 inhibitor, in combination with irradiation in a panel of NSCLC cell lines with different p53 backgrounds. Pretreatment with volasertib efficiently sensitized p53 wild type cells to irradiation. Flow cytometric analysis revealed that significantly more cells were arrested in the G2/M phase of the cell cycle after the combination therapy compared to either treatment alone (p < 0.005). No significant synergistic induction of apoptotic cell death was observed, but, importantly, significantly more senescent cells were detected when cells were pretreated with volasertib before irradiation compared to both monotherapies alone (p < 0.001), especially in cells with functional p53. Consequently, while most cells with functional p53 showed permanent growth arrest, more p53 knockdown/mutant cells could re-enter the cell cycle, resulting in colony formation and cell survival. Our findings assign functional p53 as a determining factor for the observed radiosensitizing effect of volasertib in combination with radiotherapy for the treatment of NSCLC.

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Section: Discussionsupporting

confidence: 92%

Radiosensitization of Non-Small Cell Lung Cancer Cells by the Plk1 Inhibitor Volasertib Is Dependent on the p53 Status

Bossche

Domen

Peeters

et al. 2019

Cancers

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“…In gastric cancer, BI2536 increased the anti-tumour of DDP in PLK1 overexpressed tumour cell, the Wnt/ β -catenin and MEK/ERK/RSK1 signaling pathways changed under the co-treatment [26]. In several research, the researchers compared the sensitization of various PLK1 inhibitions to radiotherapy and chemotherapy, and found that PLK1 combined with radiotherapy had a better synergistic effect in Medulloblastoma, Merkel cell carcinoma and bladder carcinoma [27,45,46]. Our study is the first to confirm that inhibiting PLK1 could enhance the chemosensitivity of ESCC cells to DDP.…”

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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“…Immunohistochemical staining was performed as described elsewhere using the Lab Vision Ultra V Block kit (Thermo Fisher Scientific, Waltham, MA, USA) and the Lab Vision Ultravision LP detection system (Thermo Fisher Scientific, Waltham, MA, USA) according to manufacturers protocol [ 16 ]. Briefly, citrate buffer (pH 6.0) was used for antigen retrieval.…”

Section: Methodsmentioning

confidence: 99%

ELMO3 – a Negative Prognostic Marker in Minor Salivary Gland Carcinoma

Kotowski

Kadletz

Schneider

et al. 2018

Pathol. Oncol. Res.

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Engulfment and cell motility 3 protein (ELMO3) is a protein that is involved in cell migration and promotes the remodeling of the cytoskeleton. Moreover, it is described as a prognostic marker in several cancers. The aim of this study was to evaluate ELMO3 expression in patients with minor salivary gland carcinoma. The expression of ELMO3 was examined by immunohistochemistry. The intensity of staining was evaluated and data was correlated to clinical outcome. Forty-six patients with complete clinical data were included into statistical analysis. ELMO3 expression was observed in 85% of the cases. High staining intensity of ELMO3 correlated with a significantly worse disease free survival ( p = .0495) and a higher recurrence rate ( p = .0071). In conclusion, it is still difficult to predict the clinical outcome of patients with minor salivary gland carcinoma. Evaluation of ELMO3 might serve as a clinical prognostic marker in future.

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Evaluation of Polo‐like kinase 1 as a potential therapeutic target in Merkel cell carcinoma

Cited by 11 publications

References 40 publications

Radiosensitization of Non-Small Cell Lung Cancer Cells by the Plk1 Inhibitor Volasertib Is Dependent on the p53 Status

Radiosensitization of Non-Small Cell Lung Cancer Cells by the Plk1 Inhibitor Volasertib Is Dependent on the p53 Status

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

ELMO3 – a Negative Prognostic Marker in Minor Salivary Gland Carcinoma

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