Intrinsic Apoptotic Signaling and Inhibit Growth Factor Signaling Cascades in Non – Small Cell Lung Carcinoma

Marine-derived compounds have been explored and considered as possible antitumor agents. In this study, we analyzed extracts of the sponge Cribrochalina vasculum for their ability to inhibit tumor cell proliferation. Screening identified two acetylenic compounds of similar structure that showed strong tumor-specific toxicity innon–small cell lung carcinoma (NSCLC) cells and small-cell lung carcinoma cells, and lessprominent toxicity in ovarian carcinoma,while having no effect on normal cells. These acetylenic compoundswere found to cause a time-dependent increase in activation of apoptotic signaling involving cleavage of caspase-9, caspase-3, and PARP, as well as apoptotic cell morphology in NSCLC cells, but not in normal fibroblasts. Further analysis demonstrated that these compounds caused conformational change in Bak and Bax, and resulted in loss ofmitochondrial potential and cytochrome c release inNSCLCcells.Moreover, a decreasedphosphorylation of the growth factor signaling kinases Akt, mTOR, and ERK was evident and an increased phosphorylation of JNKwas observed. Thus, these acetylenic compounds holdpotential as novel therapeutic agents that should be further explored for NSCLC and other tumor malignancies. Mol Cancer Ther; 13(12); 2941–54. 2014 AACR.