Molecular Characterization and Enhancement of Anticancer Activity of Caffeic Acid Phenethyl Ester by γ Cyclodextrin

Abstract

Caffeic Acid Phenethyl Ester (CAPE) is a key component in New Zealand propolis, known for a variety of health promoting and therapeutic potentials. We investigated the molecular mechanism of anticancer and anti-metastasis activities of CAPE. cDNA array performed on the control and CAPE-treated breast cancer cells revealed activation of DNA damage signaling involving upregulation of GADD45α and p53 tumor suppressor proteins. Molecular docking analysis revealed that CAPE is capable of disrupting mortalin-p53 complexes. We provide experimental evidence and demonstrate that CAPE induced disruption of mortalin-p53 complexes led to nuclear translocation and activation of p53 resulting in growth arrest in cancer cells. Furthermore, CAPE-treated cells exhibited downregulation of mortalin and several other key regulators of cell migration accountable for its anti-metastasis activity. Of note, we found that whereas CAPE was unstable in the culture medium (as it gets degraded into caffeic acid by secreted esterases), its complex with gamma cyclodextrin (γCD) showed high efficacy in anti-tumor and anti-metastasis assays in vitro and in vivo (when administered through either intraperitoneal or oral route). The data proposes that CAPE-γCD complex is a potent anti-cancer and anti-metastasis reagent.

FA-97, a New Synthetic Caffeic Acid Phenethyl Ester Derivative, Ameliorates DSS-Induced Colitis Against Oxidative Stress by Activating Nrf2/HO-1 Pathway

“…As a phenolic constituent derived from honeybee propolis, CAPE possesses great anti-inflammatory activities and can suppress the proinflammatory cytokines production and enhance epithelial barrier function, which could be a potential therapeutic agent for IBD (17,18). However, the unstable chemical property, low water solubility and the poor bioavailability of CAPE limit its efficacy (19)(20)(21). Therefore, in order to enhance the water solubility, chemical stability and pharmacological activity of CAPE, FA-97 was newly synthesized by introducing a D-glucose into CAPE to construct a glucosidic bond (Figure 1).…”

“…It has been widely reported that CAPE possesses no known side effects (17) and could be a potential therapeutic agent for IBD by suppressing pro-inflammatory cytokines production and enhancing epithelial barrier function (18). However, the CAPE molecule can be decomposed easily in biological systems on account of its ester bond (α-β unsaturated carbonyl) and the catechol groups (19).…”

Anticancer activity of the supercritical extract of Brazilian green propolis and its active component, artepillin�C: Bioinformatics and experimental analyses of its mechanisms of action

“…Besides these, over 150 constituents, including flavonoids, phenolic acids, esters, terpenoids, steroids, amino acids and cinnamic acid derivatives have been identified (3), and are hence considered as popular pharmacological research material (4). A broad spectrum of biological activities identified in propolis include antitumor (5)(6)(7)(8)(9)(10)(11)(12), anti-inflammatory (13)(14)(15), anti-bacterial (16)(17)(18), anti-viral (16,19,20) and anti-fungal (16) activities. Propolis is used in cosmetic products, such as body lotions, ointments, face creams and in functional food in various forms, such as tablets, capsules, toothpaste and mouthwash preparations (21).…”

“…CAPE and ARC have been reported to differ in their bioavailability profile that in turn is determined by the stability of the compounds to the digestive enzymes and absorption through the intestinal lining. CAPE alone becomes degraded by secreted esterases (12); however, when combined with γ cyclodextrin (γCD) it is protected and has improved activity in in vitro and in vivo antitumor assays (12). On the other hand, ARC has been reported to possess extremely low absorption efficiency and bioavailability.…”

Propolis or Caffeic Acid Phenethyl Ester (Cape) Inhibits Growth and Viability in Multiple Oral Cancer Cell Lines.

“…Although this initial pilot study did not seek to determine the mechanisms of action, previous reports of the anti-oxidant, anti-mitogenic, and anticarcinogenic properties of CAPE suggest that some of the mechanisms responsible for these effects include the inhibition of NFkB, lipid peroxidation, protein tyrosine kinase, ornithine decarboxylase, and matrix metalloproteinase (MMP)-9 catalytic activity. [21][22][23] Other studies have revealed that enhanced expression and activation of the tumor suppressor p53 and activation of pro-apoptotic Bax and caspase-3 may also be induced by CAPE administration. 24,25 These results must also be viewed in context of the limitations that were intrinsic to this type of pilot study.…”