psammaplin-a and Breast-Neoplasms

Psammaplin A (PsA) is a natural product isolated from marine sponges, which has been demonstrated to have anticancer activity against several human cancer cell lines via the induction of cell cycle arrest and apoptosis. New drugs that are less toxic and more effective against multidrug-resistant cancers are urgently needed.. We tested cell proliferation, cell cycle progression and autophagic cell death pathway in doxorubicin-resistant MCF-7 (MCF-7/adr) human breast cancer cells. The potency of PsA was further determined using an in vivo xenograft model.. PsA significantly inhibited MCF-7/adr cells proliferation in a concentration-dependent manner, with accumulation of cells in G2/M phase of the cell cycle. PsA significantly decreased SIRT1 enzyme activity and reduced expression of SIRT1 protein in the cultured cells with greater potency than sirtinol or salermide. Acetylation of p53, a putative target of SIRT1, increased significantly following PsA treatment. In addition, PsA markedly increased the expression levels of autophagy-related proteins. In support of this, it was found that PsA significantly increased the expression of damage-regulated autophagy modulator (DRAM), a p53-induced protein.. The results of this study suggest that PsA is sufficient to overcome multidrug-resistant cancer via SIRT1-mediated autophagy in MCF-7/adr breast cancer cells, indicating that PsA has therapeutic potential for clinical use.

Topics: Acetylation; Animals; Antibiotics, Antineoplastic; Autophagy; Breast Neoplasms; Cell Division; Cell Line, Tumor; Disulfides; Doxorubicin; Drug Resistance, Neoplasm; Female; G2 Phase; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Membrane Proteins; Mice; Mice, Nude; Neoplasm Transplantation; Sirtuin 1; Tumor Suppressor Protein p53; Tyrosine; Xenograft Model Antitumor Assays

Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor (NHR) family, are ligand-activated transcription factors. Ligands (agonists) of PPARgamma have been shown to inhibit growth, promote terminal differentiation, and induce apoptosis in human breast tumor cells. A cell-based reporter assay was developed to examine extracts of terrestrial and marine organisms for the ability to activate PPARgamma. Bioassay-guided fractionation and isolation of an active extract from Pseudoceratina rhax yielded the known histone deacetylase (HDAC) inhibitor psammaplin A (1). Compound 1 activates PPARgamma in a MCF-7 cell-based reporter assay and induces apoptosis in human breast tumor cells in vitro. Molecular modeling studies suggest that 1 may interact with binding sites within the PPARgamma ligand-binding pocket. Therefore, in addition to its known effects on HDAC-mediated processes, activation of PPARgamma-regulated gene expression may play a role in the ability of 1 to induce apoptosis.

Topics: Animals; Apoptosis; Breast Neoplasms; Disulfides; Dose-Response Relationship, Drug; Female; Histone Deacetylase Inhibitors; Humans; Micronesia; Porifera; PPAR gamma; Tyrosine