Cribrochalina vasculum derived compounds demonstrate tumor specific apoptosis activation, repression of cell cycle and inhibition of growth factor signaling

Marine derived compounds have been explored and considered as possible antitumor agents (e.g. Eribulin, Trabectedin). In our project we screened hundreds of extracts from marine sponges and associated microbes for antitumor activity. The compounds from Cribrochalina vasculum are highly efficient in non small and small cell lung cancer (NSCLC, SCLC) and ovarian cancer cells while non-malignant cells remained unaffected. Deciphering action mechanism of these compounds in tumor cells revealed that induction of apoptotic signaling involving Bak/Bax and caspases activation through regulation of Ras/Raf/MAP kinase pathway and Akt signaling was instrumental (Zovko et al., 2014). Akt and MAPK kinase signaling are controlled by growth factor receptors indicating that this could be a target of compounds. In order to further study if this was the case we applied global genomic profiling of cells treated with compound. About 1300 genes were down regulated specifically in tumor cells by compound. Analysis of these gene expression alterations suggested inhibition of insulin-like growth factor receptor 1 (IGF-1R) signaling as one of the targets. Some of the candidate genes involved in this pathway have been validated on protein level and our results imply that compounds are inhibiting expression of IGF-1R and its signaling in NSCLC. Thus, C. vasculum compounds hold great tumor selective cytotoxicity and impair tumor cell growth signaling networks resulting in prominent apoptotic response. IGF-1R may be a direct or indirect target of the compounds. Further studies are aimed to confirm mechanism of action in vivo and understand their role in treatment of tumor malignancies.