title: Modulation of bcl-2 and cytotoxicity by licochalcone-A, a novel estrogenic flavonoid.
abstract: Herbal therapies are commonly used by patients with cancer, despite little understanding about their clinical and biological activity. We recently demonstrated that the herbal combination PC-SPES, which contains licorice root, had potent estrogenic activity in vitro, in animals, and in patients with prostate cancer. Licochalcone-A (LA) is one flavonoid extracted from licorice root with antiparasitic and anti-tumor activity, but the effect on the human estrogen receptor and mechanism of anti-tumor activity is unknown. Recent studies demonstrated that the mechanism of cytotoxic effect by some estrogens may involve modulation of the anti-apoptotic protein bcl-2. In the present study, we determined if LA had estrogenic activity, anti-tumor activity, and modulated the apoptotic protein bcl-2 in human cell lines derived from acute leukemia, breast cancer, and prostate cancer. A yeast growth-based assay under the control of the human estrogen receptor (hER) demonstrated that LA was a phytoestrogen. A cell viability assay demonstrated that LA had anti-tumor activity in all cell lines tested and enhanced the effect of paclitaxel and vinblastine chemotherapy. LA induced apoptosis in MCF-7 and HL-60 cell lines, as demonstrated by cleavage of PARP, the substrate of ICE-like proteases. Immunoblot analysis demonstrated that LA decreased the anti-apoptotic protein bcl-2 and altered the bcl-2/bax ratio in favor of apoptosis. In contrast, the parent compound chalcone or estradiol did not decrease bc1-2 expression. Therefore, these data demonstrate that LA is a phytoestrogen with anti-tumor activity and is capable of modulating bcl-2 protein expression. The modulation of bcl-2 may be dependent on specific structural differences between LA and the parent compound chalcone and independent of LA estrogenicity.
authors.affiliation: UMDNJ-Robert Wood Johnson Medical School, Department of Medicine, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Rafi
authors.forename: R T
authors.initials: RT
authors.lastname: Rosen
authors.forename: A
authors.initials: A
authors.lastname: Vassil
authors.forename: C T
authors.initials: CT
authors.lastname: Ho
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: G
authors.initials: G
authors.lastname: Ghai
authors.forename: G
authors.initials: G
authors.lastname: Lambert
authors.forename: R S
authors.initials: RS
authors.lastname: DiPaola
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology; D047188:Chalcones; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D006801:Humans; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D014407:Tumor Cells, Cultured; D015003:Yeasts / Q000187:drug effects; D051028:bcl-2-Associated X Protein
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; D047188:Chalcones; D004968:Estrogens, Non-Steroidal; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D002599:Chalcone; C070840:licochalcone A