Abstract
SummaryIn the absence of suitable molecular markers, non-small cell lung cancer (NSCLC) patients have to be treated with chemotherapy with poor results at advanced stages. Therefore, the activity of the anticancer marine drug fascaplysin was tested against primary NSCLC cell lines established from pleural effusions. Cytotoxicity of the drug or combinations were determined using MTT assays and changes in intracellular phosphorylation by Western blot arrays. Fascaplysin revealed high cytotoxicity against NSCLC cells and exhibit an activity pattern different of the standard drug cisplatin. Furthermore, fascaplysin synergizes with the EGFR tyrosine kinase inhibitor (TKI) afatinib to yield a twofold increased antitumor effect. Interaction with the Chk1/2 inhibitor AZD7762 confirm the differential effects of fascplysin and cisplatin. Protein phosphorylation assays showed hypophosphorylation of Akt1/2/3 and ERK1/2 as well as hyperphosphorylation of stress response mediators of H1299 NSCLC cells. In conclusion, fascaplysin shows high cytotoxicity against pleural primary NSCLC lines that could be further boosted when combined with the EGFR TKI afatinib.
Highlights
80% of all lung cancers are of the Non-small Cell Lung Cancer (NSCLC) type that is often detected at an advanced stage and portends a dismal prognosis [1]
The results demonstrate that afatinib acts synergistically with fascaplysin to sensitize the NSCLC cancer cells against this marine drug
Cytotoxicity of fascaplysin, cisplatin and afatinib were determined in MTT assays employing primary NSCLC cell lines and the permanent NSCLC cell lines H23, H1299, PC9 and A549 (Fig. 1A-C). IC50 values for fascaplysin varied from 0.48 – 1.37 μg/ml, with 8/17 cell lines exhibiting high chemosensitivity (Fig. 1A)
Summary
80% of all lung cancers are of the Non-small Cell Lung Cancer (NSCLC) type that is often detected at an advanced stage and portends a dismal prognosis [1]. The platinum drug combinations with either gemcitabine, docetaxel or pemetrexed have reached a plateau offering a mean survival of approximately one year in advanced NSCLC [2]. The focus of NSCLC treatment shifted significantly with availability of inhibitors of targetable driver kinases such as mutated epidermal growth factor (EGFR) and anaplastic lymphoma kinase (ALK) rearrangements, among others [5]. The first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib bind reversibly to the kinase domain of the receptor, but second-generation drugs such as the pan-ErbB inhibitor afatinib show irreversible inhibition of the kinase activity [6].
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