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Article

IGF1R and MAPK15 Emerge as Potential Targets of Pentabromobenzylisothioureas in Lung Neuroendocrine Neoplasms

1
Department of Immunoendocrinology, Chair of Endocrinology, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland
2
Department of Pathology, Chair of Oncology, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland
3
Department of Chemistry, Warsaw University of Life Sciences, Nowoursynowska 159C, 02-787 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2020, 13(11), 354; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110354
Received: 1 October 2020 / Revised: 19 October 2020 / Accepted: 26 October 2020 / Published: 29 October 2020
(This article belongs to the Special Issue Lung Injury and Repair)
Pentabromobenzylisothioureas are antitumor agents with diverse properties, including the inhibition of MAPK15, IGF1R and PKD1 kinases. Their dysregulation has been implicated in the pathogenesis of several cancers, including bronchopulmonary neuroendocrine neoplasms (BP-NEN). The present study assesses the antitumor potential of ZKKs, a series of pentabromobenzylisothioureas, on the growth of the lung carcinoid H727 cell line. It also evaluates the expression of MAPK15, IGF1R and PKD1 kinases in different BP-NENs. The viability of the H727 cell line was assessed by colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) and its proliferation by BrdU (5-bromo-2′-deoxyuridine) assay. Tissue kinase expression was measured using TaqMan-based RT-PCR and immunohistochemistry. ZKKs (10−4 to 10−5 M) strongly inhibited H727 cell viability and proliferation and their antineoplastic effects correlated with their concentrations (p < 0.001). IGF1R and MAPK15 were expressed at high levels in all subtypes of BP-NENs. In addition, the SCLC (small cell lung carcinoma) patients demonstrated higher mRNA levels of IGF1R (p = 0.010) and MAPK15 (p = 0.040) than the other BP-NEN groups. BP-NENs were characterized by low PKD1 expression, and lung neuroendocrine cancers demonstrated lower PKD1 mRNA levels than carcinoids (p = 0.003). ZKKs may suppress BP-NEN growth by inhibiting protein kinase activity. Our results suggest also a possible link between high IGF1R and MAPK15 expression and the aggressive phenotype of BP-NEN tumors. View Full-Text
Keywords: bronchopulmonary neuroendocrine neoplasm; IGF1R; MAPK15; PKD1; ZKK; pentabromobenzylisothioureas; H727; small cell lung cancer; large cell neuroendocrine carcinoma; carcinoid bronchopulmonary neuroendocrine neoplasm; IGF1R; MAPK15; PKD1; ZKK; pentabromobenzylisothioureas; H727; small cell lung cancer; large cell neuroendocrine carcinoma; carcinoid
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MDPI and ACS Style

Motylewska, E.; Braun, M.; Kazimierczuk, Z.; Ławnicka, H.; Stępień, H. IGF1R and MAPK15 Emerge as Potential Targets of Pentabromobenzylisothioureas in Lung Neuroendocrine Neoplasms. Pharmaceuticals 2020, 13, 354. https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110354

AMA Style

Motylewska E, Braun M, Kazimierczuk Z, Ławnicka H, Stępień H. IGF1R and MAPK15 Emerge as Potential Targets of Pentabromobenzylisothioureas in Lung Neuroendocrine Neoplasms. Pharmaceuticals. 2020; 13(11):354. https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110354

Chicago/Turabian Style

Motylewska, Ewelina, Marcin Braun, Zygmunt Kazimierczuk, Hanna Ławnicka, and Henryk Stępień. 2020. "IGF1R and MAPK15 Emerge as Potential Targets of Pentabromobenzylisothioureas in Lung Neuroendocrine Neoplasms" Pharmaceuticals 13, no. 11: 354. https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110354

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