Majusculamide-o, a Simplified Marine Natural Product Analog, Exhibits Potent and Specific Cancer Cell Cytotoxicity

Metastatic solid tumors (e.g., ovary, pancreas, liver, lung, and brain) contribute to a high mortality rate in cancer patients with few therapeutically effective anticancer drugs available for their treatment, highlighting the need to develop agents that target solid tumors. Natural products (NPs) derived from cyanobacteria possess potent anticancer activity, yet most are hard to synthesize and modify to improve therapeutic efficacy. Here, we have efficiently synthesized a simplified analog of the marine NP majusculamide D, majusculamide o (maj-o, 1), that has remarkable potency and selective cytotoxicity towards various metastatic cancer cells. We found that maj-o (1) treatment causes apoptosis in various cancer cell lines of the ovary (OVCAR3), pancreas (PANC1), brain (U251N), and lung (H125) in a dose dependent manner with the least cytotoxic effect towards non-metastatic or primary tumors of the liver (HEPG2) and ovary (OVCAR8). 1 significantly alters gene expression signatures with more treatment time and affect pathway associated with PI3K-Akt signaling. Our finding suggests that maj-o has great potential to serve a lead compound for drug discovery of novel antineoplastics for solid tumors. OVCAR3 cells were plated in 6-well plates with 500k cells per well and treated with 638 nM (500 ng/ml) MJS-O after 24 h. Durations of treatment were either 0 h, 4 h, or 24 h, and the DMSO concentration between samples was normalized. The RNA was isolated and purified using a RNeasy Mini Kit. RNA amounts were quantified with a DS-11 Spectrophotometer (DeNovix). 1 μg of RNA per sample was shipped to the Van Andel Institute Genomics core (333 Bostwick Ave. NE, Grand Rapids, MI 49503) for RNA analysis.