Abstract
In this work two acetylene alcohols, compound 1 and compound 2, which were isolated and identified from the sponge Cribrochalina vasculum, and which showed anti-tumor effects were further studied with respect to targets and action mechanisms. Gene expression analyses suggested insulin like growth factor receptor (IGF-1R) signaling to be instrumental in controlling anti-tumor efficacy of these compounds in non-small cell lung cancer (NSCLC). Indeed compounds 1 and 2 inhibited phosphorylation of IGF-1Rβ as well as reduced its target signaling molecules IRS-1 and PDK1 allowing inhibition of pro-survival signaling. In silico docking indicated that compound 1 binds to the kinase domain of IGF-1R at the same binding site as the well known tyrosine kinase inhibitor AG1024. Indeed, cellular thermal shift assay (CETSA) confirmed that C. vasculum compound 1 binds to IGF-1R but not to the membrane localized tyrosine kinase receptor EGFR. Importantly, we demonstrate that compound 1 causes IGF-1Rβ but not Insulin Receptor degradation specifically in tumor cells with no effects seen in normal diploid fibroblasts. Thus, these compounds hold potential as novel therapeutic agents targeting IGF-1R signaling for anti-tumor treatment.
Highlights
Marine organisms, in particular sponges (Porifera), constitute a rich source of pharmaceutical compounds and for the last 50 years it has remained the dominant phylum from which natural products with anti-tumor activity have been discovered [1, 2]
These results suggested that growth factor receptors could be targets of these C. vasculum compounds in tumor cells
This comparison showed that about 60% of the upregulated genes in the signature of IGF-1 treated breast cancer (BC) cells were down regulated in our compoundregulated gene expression data of non-small cell lung cancer (NSCLC) cells
Summary
In particular sponges (Porifera), constitute a rich source of pharmaceutical compounds and for the last 50 years it has remained the dominant phylum from which natural products with anti-tumor activity have been discovered [1, 2]. Pharmaceutical interest in sponges arose with the discovery of nucleoside analogue spongouridine from the marine sponge Cryptotethia crypta [3, 4]. This nucleoside analogue was used to construct cytarabine which today is one of the most commonly used anti-leukemia drugs [5, 6]. Another example is eribulin, a truncated synthetic version made from halichondrin B identified in the sponge Halichondria okadai. A recent example of a marine-derived drug is PM060184, a polyketide amide, that was isolated from the sponge Lithoplocamia lithistoides in 2006 and rapidly proceeded into phase I clinical trial [9, 10]
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