Alterations of Phosphoproteins in NCI-H526 Small Cell Lung Cancer Cells Involved in Cytotoxicity of Cisplatin and Titanocene Y

Abstract

First-line treatment of small cell lung cancer (SCLC) with combination chemotherapy consisting of cis-diamminedichloroplatinum(II) (cisplatin) and etoposide is frequently followed by early relapses and a dismal prognosis. Survival of a fraction of tumor cells and development of chemoresistance may be influenced by an initial cellular stress response against the administered xenobiotics. Therefore, we compared the short-term effects of cisplatin and non-cross-resistant bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) on phosphorylation of 46 sites of a total of 38 signaling proteins in tumor suppressor protein 53 (p53)-wild-type NCI-H526 SCLC cells. The functional significance of selected kinases for the cytotoxicity of both drugs was tested using specific inhibitors and an activator. The cisplatin-induced cellular stress response involved activation of p38α mitogen-activated protein kinase, whereas Titanocene Y-triggered signaling affected c-Jun N-terminal kinase. Phosphorylation of adenosine monophosphate (AMP)-activated protein kinase α1 (AMPKα1) was increased by both drugs, which promoted cell survival, as indicated by results obtained using AMPK inhibitor compound C and AMPK activator 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside. This is in good agreement with previous reports, where AMPKα1 was demonstrated to represent an important factor for the sensitivity to cisplatin in colon and ovarian cancers, most likely by induction of autophagy. Thus, AMPKα1 constitutes a potential target to be exploited for chemotherapeutic treatment of SCLC to circumvent resistance to metal-based compounds.

SRC family kinases in hamster spermatozoa: evidence for the presence of LCK

“…The phospho-antibody array analysis was performed using the Proteome Profiler Human Phospho-Kinase Array Kit (ARY003) from R&D Systems according to the manufacturer's instructions (Deharvengt et al 2012, Olszewski et al 2012. Although the antibodies were generated against human proteins, we could monitor the phosphorylation status of several kinases/factors in hamster spermatozoa, as these protein phosphorylation sites are conserved and thus the antibodies displayed crossreactivity with hamster proteins.…”

Organometallic Titanocene–Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties

“…16 The most promising candidates have been compounds described by the group of M. Tacke in Dublin. 17−22 Substituted titanocenes such as Titanocene Y (Chart 1) have shown activity in vivo against human breast 18 and epidermoid carcinoma 19 xenografts in mice.…”

Cancer adjuvant chemotherapy strategic classification by artificial neural network with gene expression data: An example for non-small cell lung cancer

“…Overexpression of DUSP6 was promotes tumor development to cause refractory to chemotherapy [32]. LCK is linked to higher resistance to platinum complexes and other chemotherapeutics [34]. In this study, DUSP6 and LCK are highly association with the effectiveness of adjuvant chemotherapy.…”