Abstract
Lung cancer is a leading cause of tumor-associated mortality. Fascaplysin, a bis-indole of a marine sponge, exhibit broad anticancer activity as specific CDK4 inhibitor among several other mechanisms, and is investigated as a drug to overcome chemoresistance after the failure of targeted agents or immunotherapy. The cytotoxic activity of fascaplysin was studied using lung cancer cell lines, primary Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC) cells, as well as SCLC circulating tumor cell lines (CTCs). This compound exhibited high activity against SCLC cell lines (mean IC50 0.89 µM), as well as SCLC CTCs as single cells and in the form of tumorospheres (mean IC50 0.57 µM). NSCLC lines showed a mean IC50 of 1.15 µM for fascaplysin. Analysis of signal transduction mediators point to an ATM-triggered signaling cascade provoked by drug-induced DNA damage. Fascaplysin reveals at least an additive cytotoxic effect with cisplatin, which is the mainstay of lung cancer chemotherapy. In conclusion, fascaplysin shows high activity against lung cancer cell lines and spheroids of SCLC CTCs which are linked to the dismal prognosis of this tumor type. Derivatives of fascaplysin may constitute valuable new agents for the treatment of lung cancer.
Highlights
Among malignant diseases, lung cancer is the leading cause of mortality [1]
Targeted therapies in the form of tyrosine kinase inhibitors (TKIs) and immunotherapy directed to checkpoint proteins have successfully changed the treatment of Non-Small Cell Lung Cancer (NSCLC); patients lacking markers for precision medicine or eventually progressing after specific regimens are referred to classical chemotherapy consisting of platinum-drug-based combinations [6]
For the NSCLC cell lines PC-9 and A549, combinations of fascaplysin and cisplatin or etoposide were tested in cytotoxicity tests
Summary
Lung cancer is the leading cause of mortality [1]. NSCLC constitutes the most common subtype with approximately 85% of cases and a 5-year survival rate ranging from. Fascaplysin-induced apoptosis was characterized by phosphorylation in HeLa cells [17]. Was antiangiogenesis, and HCT-116 colon tumors showed reduced size in the absenceAngiogenesis of drug toxicity blocked by fascaplysin byblocked the inhibition of vascularby endothelial growth (VEGF). We have previously assessed cytotoxic activity of fascaplysin against SCLC cell lines, not covered by the NCI60 cell line panel, a tumor tumor entity entity that that accounts accounts for aa significant significant fraction fraction of of lung lung cancer cancer deaths deaths [20]. CTClines cell lines derived fromsamples the blood distinct with extended disease [7]. Western blot arrays and the NCI-H526 SCLC and the A549 NSCLC cell line, respectively. Phosphoprotein Western blot arrays and the NCI-H526 SCLC and the A549 NSCLC cell line, Mar. Drugs 2018, 16, 383 respectively
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