There is an emerging paradigm shift in oncology that seeks to emphasize molecularly targeted approaches for cancer prevention and therapy. Chalcones (1,3-diphenyl-2-propen-1-ones), naturally-occurring compounds with widespread distribution in spices, tea, beer, fruits and vegetables, consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α, β-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of α, β-unsaturated carbonyl moiety with cysteine residues in proteins, some lead chalcones from both natural products and synthesis have been identified in a variety of screening assays for modulating important pathways or molecular targets in cancers. These pathways and targets that are affected by chalcones include MDM2/p53, tubulin, proteasome, NF-kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-γ and β-catenin/Wnt. Compared to current cancer targeted therapeutic drugs, chalcones have the advantages of being inexpensive, easily available and less toxic; the ease of synthesis of chalcones from substituted benzaldehydes and acetophenones also makes them an attractive drug scaffold. Therefore, this review is focused on molecular targets of chalcones and their potential implications in cancer prevention and therapy.

Aberrant histone lysine methylation that is controlled by histone lysine methyltransferases (KMTs) and demethylases (KDMs) plays significant roles in carcinogenesis. Infections by tumor viruses or parasites and exposures to chemical carcinogens can modify the process of histone lysine methylation. Many KMTs and KDMs contribute to malignant transformation by regulating the expression of human telomerase reverse transcriptase (hTERT), forming a fused gene, interacting with proto-oncogenes or being up-regulated in cancer cells. In addition, histone lysine methylation participates in tumor suppressor gene inactivation during the early stages of carcinogenesis by regulating DNA methylation and/or by other DNA methylation independent mechanisms. Furthermore, recent genetic discoveries of many mutations in KMTs and KDMs in various types of cancers highlight their numerous roles in carcinogenesis and provide rare opportunities for selective and tumor-specific targeting of these enzymes. The study on global histone lysine methylation levels may also offer specific biomarkers for cancer detection, diagnosis and prognosis, as well as for genotoxic and non-genotoxic carcinogenic exposures and risk assessment. This review summarizes the role of histone lysine methylation in the process of cellular transformation and carcinogenesis, genetic alterations of KMTs and KDMs in different cancers and recent progress in discovery of small molecule inhibitors of these enzymes.

S phase kinase-associated protein 2 (Skp2) has been shown to be required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb) deficient mice. Here we have demonstrated that flavokawain A (FKA), a novel chalcone from the kava plant, selectively inhibited the growth of pRb deficient cell lines and resulted in a proteasome-dependent and ubiquitination-mediated Skp2 degradation. Degradation of Skp2 by FKA was found to be involved in a functional Cullin1, but independent of Cdh1 expression. Further studies have demonstrated that FKA docked into the ATP binding pocket of the precursor cell-expressed developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) complex, inhibited NEDD8 conjugations to both Cullin1 and Ubc12 in PC3 cells and Ubc12 NEDDylation in an in vitro assay. Finally, dietary feeding of the autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with FKA inhibited the formation of high-grade prostatic intra-epithelial neoplasia lesions (HG-PIN) and prostate adenocarcinomas, reduced the tumor burden and completely abolished distant organ metastasis. Immunohistochemistry studies revealed that dietary FKA feeding resulted in marked anti-proliferative and apoptotic effects via down-regulation of Skp2 and NEDD8 and up-regulation of p27/Kip1 in the prostate of TRAMP mice. Our findings therefore provide evidence that FKA is a promising NEDDylation inhibitor for targeting Skp2 degradation in prostate cancer prevention and treatment.

A new series of 20 brominated chalcone derivatives were designed, synthesized, and investigated for their effects against the growth of four cancer cell lines (EC109, SKNSH, HepG2, MGC803). Among them, compound 19 which given chemical name of H72, was the most potent one on gastric cancer cell lines (i.e. MGC803, HGC27, SGC7901) with IC50s ranged from 3.57 to 5.61μM. H72 exhibited less cytotoxicity to non-malignant gastric epithelial cells GES-1. H72 treatment of MGC803 and HGC27 induced generation of reactive oxygen species (ROS) leading to activation of caspase 9/3 cascade and mitochondria mediated apoptosis. H72 also up-regulated the expression of DR5, DR4 and BimEL, and down-regulated the expression of Bid, Bcl-xL, and XIAP. N-acetyl cysteine (NAC), a ROS scavenger completely blocked these effects of H72 in MGC803 cells. Intraperitoneal administration of H72 significantly inhibited the growth of MGC803 cells in vivo in a xenograft mouse model without observed toxicity. These results indicated that H72 is a lead brominated chalcone derivate and deserves further investigation for prevention and treatment of gastric cancer.

A new series of etherification chalcone derivatives were designed and synthesized through Willimison etherification and Claisen-Schmidt condensation. Among them, compound 2-c which was given chemical name of S17, has been successfully screened out as the most potent one on gastric cancer cell line(MGC803) through the investigation for their effects against the growth of five cancer cell lines (EC109, HepG2, MCF7, MGC803, SKNSH). S17 exhibited strong anti-proliferative activity on other two gastric cancer cells (HGC27 and SGC7901), but less cytotoxicity to non-malignant gastric epithelial cells GES1. S17 potently killed gastric cancer cells with causing modulation of Bcl-2 family proteins and activation of caspase 9/3 cascade. S17 also up-regulated DR5 expression and DR5 knockdown partially reversed S17-induced apoptosis, caspase activation and MMP decrease. S17 robustly induced generation of ROS with Keap/Nrf2 pathway activated and the application of ROS scavenger N-acetyl cysteine (NAC) completely blocked these effects by S17 in MGC803 cells. Intraperitoneal administration of S17 significantly inhibited the growth of MGC803 cells in vivo in a xenograft mouse model without observed toxicity. These results indicated that S17 is a leadbrominated chalcone derivate and deserves further investigation for prevention and treatment of gastric cancer.