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

Ewelina Motylewska,Hanna Ławnicka,Zygmunt Kazimierczuk,Marcin Braun,Henryk Stępień

doi:10.3390/ph13110354

Abstract

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.

Highlights

Neuroendocrine neoplasms (NENs) are rare malignancies, their incidence is increasing
ZKK3 has been demonstrated to act as a multi-kinase inhibitor, targeting the kinases implicated in carcinogenesis in different tumors, such as insulin-like growth factor 1 receptor (IGF1R), mitogen-activated protein kinase 15 (MAPK15) and protein kinase D1 (PKD1) [9]
The present study shows that ZKK1, ZKK2 and ZKK3 may be effective against bronchopulmonary neuroendocrine neoplasms (BP-neuroendocrine neoplasms (NENs)) in vitro

Summary

Introduction

Neuroendocrine neoplasms (NENs) are rare malignancies, their incidence is increasing. BP-NENs (bronchopulmonary neuroendocrine neoplasm) exist as four separate entities: typical carcinoid (TC), atypical carcinoid (AC), small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) [1]. According to the new nomenclature, well-differentiated TC and AC are classified as neuroendocrine tumors (NETs) and poorly differentiated SCLC and LCNEC as neuroendocrine carcinomas (NECs) [2]. The different biological and clinical characteristics of lung NETs and NECs result in a need for distinct therapeutic approaches. ZKK3 has been demonstrated to act as a multi-kinase inhibitor, targeting the kinases implicated in carcinogenesis in different tumors, such as insulin-like growth factor 1 receptor (IGF1R), mitogen-activated protein kinase 15 (MAPK15) and protein kinase D1 (PKD1) [9]

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