Abstract
Heteronemin, a marine sesterterpenoid-type natural product, possesses diverse bioactivities, especially antitumor effect. Accumulating evidence shows that heteronemin may act as a potent anticancer agent in clinical therapy. To fully understand the antitumor mechanism of heteronemin, we further explored the precise molecular targets in prostate cancer cells. Initially, 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. In addition, the results of a cell-free system assay indicated that heteronemin could act as topoisomerase II (topo II) catalytic inhibitor through the elimination of essential enzymatic activity of topoisomerase IIα expression. We found that the use of heteronemin-triggered apoptosis by 20.1–68.3%, caused disruption of 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. Moreover, our findings indicated that 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, suggesting PTP activation plays 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. Finally, heteronemin promoted autophagy and apoptosis through the inhibition of Hsp 90 and topo II as well as PTP activation in prostate cancer cells. Taken together, these multiple targets present heteronemin as an interesting candidate for its future development as an antiprostatic agent.
Highlights
Cancer is one of the leading causes of death worldwide
We investigated the cytotoxic and antitumor effects of heteronemin as well as its mechanism of action in human prostate cancer cell lines with androgen-dependent and independent types in vitro cellular and in vivo xenograft models
We found that heteronemin induced LNcap apoptosis
Summary
Cancer is one of the leading causes of death worldwide. The global estimates of cancer prevalence for 27 sites in the adult population indicated the five-year global cancer prevalence to be 28.8 million in 2008. This marine natural product demonstrated significant inhibition of viability and proliferation against a series of cancer cell lines, including leukemia, colon and breast cancer, cervica,l and renal carcinoma with IC50 less than 1 micromolar. Activation through proteasome and induced apoptotic cell death Such are interesting this marine natural product demonstrated significant inhibition of viability and proliferation against because compounds targeting hypoxic signaling in tumors or phospholipases A2 in inflammatory a series of cancer cell lines, including leukemia, colon and breast cancer, cervica,l and renal carcinoma diseases represent therapeutic agents [4,17]. We investigated the cytotoxic and antitumor effects of heteronemin as well as its mechanism of action in human prostate cancer cell lines with androgen-dependent and independent types in vitro cellular and in vivo xenograft models
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