phenoxodiol and Prostatic-Neoplasms

Topics: Apoptosis; Benzopyrans; Cell Cycle; Cell Differentiation; Cell Division; Drug Evaluation, Preclinical; Flavonoids; Humans; Isoflavones; Male; Phenols; Prostatic Neoplasms

Phenoxodiol is a novel isoflavone currently being studied in clinical trials for the treatment of cancer. This study reports the pharmacokinetics of phenoxodiol in patients with cancer.. The pharmacokinetics of phenoxodiol was studied following a single intravenous (iv) bolus dose and during a continuous intravenous infusion. Three men with prostate cancer and 3 women with breast cancer received IV bolus phenoxodiol (5 mg/kg) and plasma was sampled for free and total phenoxodiol levels. On a separate occasion 5 of the same patients received a continuous intravenous infusion of phenoxodiol (2 mg/kg/h) and plasma was again sampled for free and total phenoxodiol levels. Phenoxodiol was measured using gradient HPLC with ultraviolet detection.. Following bolus injection, free and total phenoxodiol appeared to follow first order pharmacokinetics. The elimination half-lives for free and total phenoxodiol were 0.67 ± 0.53 h and 3.19 ± 1.93 h, respectively, while the total plasma clearance rates were 2.48 ± 2.33 L/h and 0.15 ± 0.08 L/h, respectively. The respective apparent volumes of distribution were 1.55 ± 0.69 L/kg and 0.64 ± 0.51 L/kg. During continuous intravenous infusion, free phenoxodiol accumulated rapidly to reach a mean concentration at steady state of 0.79 ± 0.14 μg/ml after 0.87 ± 0.18 h. The apparent accumulation half-life of free phenoxodiol was 0.17 ± 0.04 h while the plasma clearance during continuous infusion was 1.29 ± 0.23 L/h.. Phenoxodiol has a short plasma half-life, particularly in the free form, leading to a rapid attainment of steady state levels during continuous intravenous infusion.. Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000334000.

Topics: Adolescent; Adult; Aged; Australia; Breast Neoplasms; Female; Half-Life; Humans; Infusions, Intravenous; Isoflavones; Male; Middle Aged; New Zealand; Prostatic Neoplasms; Young Adult

Phenoxodiol is an isoflavone derivative that has been shown to elicit cytotoxic effects against a broad range of human cancers. We examined the effect of phenoxodiol on cell death pathways on the prostate cell lines LNCaP, DU145 and PC3, representative of different stages of prostate cancer, and its effects on cell death pathways in these cell lines. Cell proliferation assays demonstrated a significant reduction in the rate of cell proliferation after 48 h exposure to phenoxodiol (10 and 30 μM). FACS analysis and 3'-end labelling indicated that all three prostate cancer cell lines underwent substantial levels of cell death 48 h after treatment. Mitochondrial membrane depolarization, indicative of early-stage cell death signalling, using JC-1 detection, was also apparent in all cell lines after exposure to phenoxodiol in the absence of caspase-3 activation. Caspase inhibition assays indicated that phenoxodiol operates through a caspase-independent cell death pathway. These data demonstrate that phenoxodiol elicits anti-cancer effects in prostate cancer cell lines representative of early and later stages of development through an as-yet-unknown cell death mechanism. These data warrant the further investigation of phenoxodiol as a potential treatment for prostate cancer.

Topics: Apoptosis; Blotting, Western; Caspase 3; Cell Line, Tumor; Cell Proliferation; DNA Primers; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Isoflavones; Male; Mitochondrial Membranes; Prostatic Neoplasms; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Time Factors

Phenoxodiol, a synthetic analog of Genistein, is being assessed in several clinical studies against a range of cancer types and was shown to have a good efficacy and safety profile. In this study we tested the effects of Phenoxodiol against prostate cancer cell lines.. Cell-cycle analysis, plasmatic membrane damage, clonogenic assay, comet assay, and Western blot methodologies were employed to assess the effects of Phenoxodiol on prostate cancer cell lines. An in vivo model confirmed the potential therapeutic efficacy of Phenoxodiol when administered orally to tumor bearing mice.. Phenoxodiol treatment promoted a marked inhibition of proliferation and loss of colony formation in LNCaP cells in a dose- and time-dependent manner. Similar effects were also observed in the metastatic prostate cell lines PC3 and DU145. Activation of poly(ADP ribose) polymerase 1 (PARP-1) clearly indicates the induction of DNA damage by Phenoxodiol. Oral administration of Phenoxodiol induced a considerable growth inhibition of malignant tumors generated by inoculation of LNCaP cells into Balb/c nu/nu athymic mice.. These data demonstrated that Phenoxodiol promotes apoptosis, as determined by PARP-1 degradation, via mitochondrial depolarization and G1/S cell-cycle arrest thereby confirming that it is active against androgen-dependent and independent prostate cancer cells. Although a precise target for Phenoxodiol has not been identified, these data contribute to our understanding of the mechanism by which this drug promotes cell death in prostate cancer cells, and warrants the continued clinical development of Phenoxodiol as a therapeutic for the treatment of metastatic prostate cancer.

Topics: Animals; Apoptosis; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Cell Survival; Comet Assay; DNA Damage; Humans; Isoflavones; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Hormone-Dependent; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Prostatic Neoplasms; Xenograft Model Antitumor Assays

Phenoxodiol is a novel isoflav-3-ene, currently undergoing clinical trials, that has a broad in vitro activity against a number of human cancer cell lines. Phenoxodiol alone inhibited DU145 and PC3 in a dose- and time-dependent manner with IC(50) values of 8+/-1 and 38+/-9 microM, respectively. The combination of phenoxodiol and cisplatin was synergistic in DU145, and additive in PC3, as assessed by the Chou-Talalay method. Carboplatin was also synergistic in combination with phenoxodiol in DU145 cells. The activity of the phenoxodiol and cisplatin combination was confirmed in vivo using a DU145 xenograft model in nude mice. Pharmacokinetic data from these mice suggest that the mechanism of synergy may occur through a pharmacodynamic mechanism. An intracellular cisplatin accumulation assay showed a 35% (P<0.05) increase in the uptake of cisplatin when it was combined in a ratio of 1 microM:5 microM phenoxodiol, resulting in a 300% (P<0.05) increase in DNA adducts. Taken together, our results suggest that phenoxodiol has interesting properties that make combination therapy with cisplatin or carboplatin appealing.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Synergism; Drug Therapy, Combination; Humans; Isoflavones; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Prostatic Neoplasms; Transplantation, Heterologous

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. 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. Only with Capsibiol-T (50 microM) was growth of LNCaP cells in coculture inhibited comparable with monoculture. Pretreatment with Capsibiol-T followed by the treatment with Taxol had an additive effect on reduction of viability of LNCaP cells in monoculture. In contrast, an antagonistic effect of cisplatin was observed following capsaicin pretreatment.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Bone Neoplasms; Capsaicin; Catechin; Cell Survival; Cisplatin; Humans; Isoflavones; Male; Osteoblasts; Paclitaxel; Plant Extracts; Prostatic Neoplasms; Tumor Cells, Cultured