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Marine environment is the richest form of life on earth. It provided humanity with food, jewelry, and medicine. Marine sponges represent a rich source of potent therapeutics with thousands of biologically active compounds isolated from these magnificent creatures. One interesting example of the isolated class of secondary metabolites is heteronemin, which was isolated from the marine sponge Hyrtios sp. It is a marine sesterterpenoid-type natural product that exhibited potent cytotoxic activity against several cancer cell lines including prostate cancer cell lines. The importance of finding new therapeutic entities against prostate cancer encouraged us to evaluate the cytotoxic activity of heteronemin and its mechanism of action. Heteronemin exhibited potent cytotoxic effect against LNcap and PC3 prostate cancer cells with IC50 1.4 and 2.7 μM after 24 h, respectively. In the xenograft animal model, the tumor size was significantly suppressed to about 51.9% in the heteronemin-treated group in comparison with the control group with no significant difference in the mice body weights. Heteronemin inhibited topoisomerase II (topo II) as demonstrated by the cell-free system assay. Heteronemin induced apoptosis by 20.1–68.3%, disrupted mitochondrial membrane potential (MMP) by 66.9–99.1% and promoted calcium release by 1.8-, 2.0-, and 2.1-fold compared with the control group in a dose-dependent manner, as demonstrated by annexin-V/PI, rhodamine 123 and Fluo-3 staining assays, respectively. The pretreatment of LNcap cells with an inhibitor of protein tyrosine phosphatase (PTPi) diminished growth inhibition, oxidative and Endoplasmic Reticulum (ER) stress, as well as activation of Chop/Hsp70 induced by heteronemin, indicating that PTP activation played a crucial rule in the cytotoxic activity of heteronemin. Using molecular docking analysis, heteronemin exhibited more binding affinity to the N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. It promoted autophagy and apoptosis through the inhibition of Hsp 90 and topo II as well as PTP activation in prostate cancer cells. These multiple targets render heteronemin as an interesting candidate which can be further developed into an antiprostatic agent.
