2-Phenyl-8-(1-phenylallyl)-chromenone compounds have a pan-PPAR modulator pharmacophore.

Adiponectin is an adipocytokine with insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties. Adiponectin secretion-inducing compounds have therapeutic potential in a variety of metabolic diseases. Phenotypic screening led to the discovery that 5,7-dihydroxy-8-(1-(4-hydroxy-3-methoxyphenyl)allyl)-2-phenyl-4H-chromen-4-one (compound 1) had adiponectin secretion-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Compound 1 was originally reported to be an anti-cancer chemical isolated from natural honeybee propolis, and its adiponectin secretion-inducing activity was found in non-cytotoxic concentrations. In a target identification study, compound 1 and its potent synthetic derivative compound 5 were shown to be novel pan-peroxisome proliferator-activator receptor (PPAR) modulators. Molecular docking models with PPARs have indicated that the binding modes of chromenone compounds preferentially interacted with the hydrophobic ligand binding pocket of PPARs. In addition, chromenone compounds have been shown to result in different phenotypic outcomes in the transcriptional regulation of lipid metabolic enzymes than those of selective PPAR mono-agonists for PPARα, PPARγ, and PPARδ. In line with the pharmacology of adiponectin and PPAR pan-modulators, compounds 1 and 5 may have diverse therapeutic potentials to treat cancer and metabolic diseases.

Role of nuclear receptors in breast cancer stem cells.

The recapitulation of primary tumour heterogenity and the existence of a minor sub-population of cancer cells, capable of initiating tumour growth in xenografts on serial passages, led to the hypothesis that cancer stem cells (CSCs) exist. CSCs are present in many tumours, among which is breast cancer. Breast CSCs (BCSCs) are likely to sustain the growth of the primary tumour mass, as well as to be responsible for disease relapse and metastatic spreading. Consequently, BCSCs represent the most significant target for new drugs in breast cancer therapy. Both the hypoxic condition in BCSCs biology and pro-inflammatory cytokine network has gained increasing importance in the recent past. Breast stromal cells are crucial components of the tumours milieu and are a major source of inflammatory mediators. Recently, the anti-inflammatory role of some nuclear receptors ligands has emerged in several diseases, including breast cancer. Therefore, the use of nuclear receptors ligands may be a valid strategy to inhibit BCSCs viability and consequently breast cancer growth and disease relapse.