Disease relevance of Haginin E

• In this study we characterize the cytotoxic effect of phenoxodiol, a synthetic anticancer drug analog of genestein, and demonstrate the mechanism of action by which phenoxodiol affects the components of the Fas apoptotic pathway on ovarian cancer cells [1].
• This phase I, single-center trial was conducted to test a continuous intravenous dosing regimen of phenoxodiol in patients with late-stage, solid tumors to determine toxicity, pharmacokinetics, and preliminary efficacy [2].
• Involvement of BH3-only proapoptotic proteins in mitochondrial-dependent Phenoxodiol-induced apoptosis of human melanoma cells [3].
• One of these compounds, phenoxodiol, is now in human clinical trials and has shown promise in patients with recurrent ovarian cancer where the cancer is refractory or resistant to standard chemotherapy, and in patients with hormone-refractory prostate cancer [4].
• An in vitro coculture model of prostate cancer cells (LNCaP) with human osteoblasts (hFOB) was utilized to define the efficacy of the tNOX inhibitors EGCg, capsaicin, Capsibiol-T and phenoxodiol against bone metastasis of prostate cancer alone and in combination with Taxol and cisplatin [5].

High impact information on Haginin E

• These data therefore indicate that phenoxodiol promotes G(1)-S arrest by the specific loss in cdk2 activity due to p53-independent p21(WAF1) induction [6].
• Analysis of in vitro purified cyclin-dependent kinase (cdk) activity showed that phenoxodiol did not inhibit cdk activity [6].
• In contrast, cellular cdk2 activity obtained from HN12 cell lines exposed to phenoxodiol for 12 hours decreased by 60%, whereas cdk6 activity remained unaltered, suggesting that the loss of cdk2 activity was specific [6].
• Moreover, clear evidence of cell death as determined by nuclear morphology and plasmatic membrane damage occur despite ZVAD, suggesting that another mechanism besides caspase-dependent apoptosis is required for clonogenic death induced by phenoxodiol [6].
• To assess the role of p21(WAF1) induction by phenoxodiol, we used HCT116 isogenic cell lines and showed that phenoxodiol induced G(1) arrest together with p21(WAF1) expression in wild-type clones [6].

Biological context of Haginin E

• This novel feature of phenoxodiol may have clinical implications, as the majority of human malignancies have aberrations in cell cycle progression regulation [6].
• Primary ovarian cancer cells, isolated from ascitic fluids of ovarian cancer patients, resistant to conventional chemotherapy, undergo apoptosis following phenoxodiol treatment [1].
• Pharmacokinetics suggested a linear relationship between dosage and mean steady-state plasma concentrations of phenoxodiol [2].
• Using a XIAP inhibitor, phenoxodiol, we demonstrate that XIAP inactivation sensitizes trophoblast cells to Fas stimulation, as evidenced by the anti-Fas mAb-induced decrease in trophoblast cell viability and increase in caspase-8, caspase-9 and caspase-3 activation [7].
• The effect of phenoxodiol on the inhibitory concentration 50% (IC50) of carboplatin, paclitaxel, and gemcitabine was determined by the CellTiter 96 Assay. The in vivo effect of combination treatments with phenoxodiol and the above-mentioned agents was determined in animal xenograft models [8].

Anatomical context of Haginin E

• To determine the mechanism of antiproliferative effects of phenoxodiol, we examined its effects in a battery of human cell lines [6].
• We show that phenoxodiol inhibits hallmarks of endothelial cell activation, namely TNF or IL-1 induced E-selectin and VCAM-1 expression and IL-8 secretion [9].
• METHODS AND RESULTS: Responses to brachial artery infusion of dehydroequol (0.1, 0.3, 1 and 3 micromol/min) in forearm resistance arteries were obtained in six healthy males [10].
• Variation in sensitivity to Phenoxodiol appeared related to events upstream of the mitochondria and the degree of conformational change in Bax [3].
• Isoflavone treatment for 24 weeks had no effect on the total area of atherosclerotic plaques in the whole aorta, but DeE reduced the plaque thickness in the aortic arch by 29%, although this did not reach statistical significance [11].

Associations of Haginin E with other chemical compounds

• In general, the LNCaP cells were more resistant to treatment with EGCg, capsaicin, phenoxodiol and Taxol when grown in coculture than when grown in monoculture [5].
• Supplementation with dihydrodaidzein (DiD), dehydroequol (DeE) (both 25 mg kg(-1) x day(-1)) and their combination (D/D; 12.5 mg kg(-1) x day(-1) for each) for 24 weeks reduced plasma high-density lipoprotein (HDL) and non-HDL cholesterol [11].
• Apoptosis was observed in Phenoxodiol-treated cells by using annexin V/propidium iodide staining and determining mitochondrial membrane potential [3].

Gene context of Haginin E

• In addition, it was demonstrated that phenoxodiol is capable of inducing apoptosis by: 1) the activation of the mitochondrial pathway through caspase-2 and Bid signaling, and 2) the proteasomal degradation of the anti-apoptotic protein XIAP [8].
• BACKGROUND: Previously, it was demonstrated that phenoxodiol induces apoptosis in epithelial ovarian carcinoma (EOC) cells and that it is capable of sensitizing these cells to Fas-mediated apoptosis [8].
• Together, these studies suggest that Phenoxodiol induces apoptosis of melanoma cells by induction of p53-dependent BH3 proteins (Bad, PUMA and Noxa) and the p53-independent Bim protein, resulting in activation of Bax and its downstream events [3].

Analytical, diagnostic and therapeutic context of Haginin E

• METHODS: Phenoxodiol given by intravenous infusion continuously for 7 days on 14-day cycles was dose-escalated on an inter-patient basis at dosages of 0.65,1.3, 3.3, 20.0, and 27.0 mg/kg/day (three to four patients per stratum) [2].
• Tumour latency was increased from 70.4 days in the control group to 92.9 (P=0.04) days and 97.8 (P=0.03) days in the groups that were fed 50 and 75 mg/kg phenoxodiol, respectively [12].

References