phenoxodiol and Neoplasms

Idronoxil has been the subject of more than 50 peer-reviewed publications over the last two decades. This isoflavone is an intriguing regulator of multiple signal transduction pathways, capable of causing a range of biological effects, including cell cycle arrest, apoptosis, an ability to stimulate the immune system, and inhibition of angiogenesis. These multifaceted actions suggest that idronoxil has the potential to synergize with, or complement, a wide range of cancer therapies. Whilst clinically tested in the past, idronoxil's journey was discontinued as a result of its low bioavailability in humans when administered either intravenously or orally, though strategies to overcome this issue are currently being explored. Here, we summarize the current literature regarding the key cellular targets of idronoxil and the mechanisms by which idronoxil exerts its anticancer effects, laying a new foundation toward giving this unique molecule a second chance of contributing to the future of cancer treatment.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Humans; Isoflavones; Neoplasms; Signal Transduction

Flavonoids, secondary metabolites ubiquitously produced in the plant kingdom, are low molecular weight polyphenolic molecules. They are characterized by variable chemical structures and show a vast array of biological activities (i.e... antiviral, antiinflammatory, antitumor, antimicrobial, estrogenic, antiestrogenic, antioxidant, mutagenic and antimutagenic) targeting different pathways. Some of these compounds such as Genistein, Daidzein or its synthetic derivative Phenoxodiol as well as Luteolin and Quercetin are able to inhibit DNA topoisomerases. This review discusses that Flavonoids targeting DNA topoisomerases may lead to novel drug development with anticancer potential.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Databases, Factual; DNA Topoisomerases; Flavonoids; Humans; Isoflavones; Neoplasms

Phenoxodiol is a synthetic derivative of the naturally occurring plant isoflavone genistein. The observation that an inverse relationship exists between dietary intake of isoflavones and cancer incidence has led to the evaluation of these compounds in cancer therapy.. This article reviews the mechanisms of action of phenoxodiol and the completed and ongoing clinical studies evaluating this drug.. By altering the chemical structure of genistein, the new compound phenoxodiol showed increased anticancer activity without any increase in toxicity. In addition to its direct cytotoxic activity against different cancers, phenoxodiol sensitizes chemoresistant ovarian cancer cells to platinum and taxane drugs, as well as gemcitabine and topotecan. The US Food and Drug Administration has granted 'fast track' status to the development of phenoxodiol as chemosensitizer for platinum and taxane drugs used in the treatment of recurrent ovarian cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; DNA Topoisomerases, Type II; Humans; Isoflavones; Neoplasms

A major limitation in the treatment of cancers is the prevalence of chemoresistant tumors. Chemotherapy agents induce cell death by activating apoptosis. However, most cancer cells express high levels of antiapoptotic proteins and, hence, are chemoresistant. Phenoxodiol, a novel isoflavone derivative, has been shown to induce apoptosis both in vitro and in vivo, even in chemoresistant cancer cells. In addition, phenoxodiol has been shown to chemosensitize resistant cancer cells to commonly used chemotherapy agents, such as carboplatin and paclitaxel. This review will discuss the characterization of phenoxodiol's molecular mechanism and its current state in the clinic.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Clinical Trials as Topic; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Female; Humans; Isoflavones; Lysophospholipids; Male; Models, Biological; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Sphingosine; Topoisomerase II Inhibitors

Interference with the innate apoptotic activity is a hallmark of neoplastic transformation and tumor formation. Modulation of the apoptotic cascade has been proposed as a new approach for the treatment of cancer. In this chapter, we discuss the role of apoptosis in ovarian cancer and the use of phenoxodiol as a model for the regulation of apoptosis and potential use as chemosensitizer for chemoresistant ovarian cancer cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Chemotherapy, Adjuvant; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Isoflavones; Models, Biological; Neoplasms; X-Linked Inhibitor of Apoptosis Protein

Phenoxodiol, a synthetic analog of the plant isoflavone genistein, represents a new generation of oncology drugs acting as multiple signal transduction regulators. Phenoxodiol exerts its effect mainly by the induction of apoptosis through multiple mechanisms resulting in degradation of antiapoptotic proteins, with increased levels being linked to chemoresistance in tumor cells. Preclinical studies with this agent showed promising anticancer activity leading to a potential role in the treatment of a wide range of solid and hematologic cancers. Early clinical studies, especially in chemotherapy-resistant ovarian cancer, showed minimal toxicity with minor antitumor activity. Hormone-refractory prostate cancer is another promising area in which phenoxodiol is being actively tested. Studies are ongoing to define the optimal use of this novel anticancer agent.

Topics: Animals; Antineoplastic Agents; Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspases; Cell Line, Tumor; Clinical Trials as Topic; Cyclin-Dependent Kinase Inhibitor p21; Down-Regulation; Female; Humans; Intracellular Signaling Peptides and Proteins; Isoflavones; Lysophospholipids; Male; Neoplasms; Sphingosine; Topoisomerase II Inhibitors; X-Linked Inhibitor of Apoptosis Protein

We wished to define the maximum tolerated dose (MTD), toxicity, and pharmacokinetics of the novel isoflav-3-ene, NV06 (Phenoxodioltrade mark), a compound with a diphenolic structure related chemically and biologically to genistein and flavopiridol.. Twenty-one patients with advanced cancers were treated with weekly intravenous administration of NV06 at escalating dose levels with 1-4 patients at each dose cohort. Plasma sampling was undertaken to characterize the pharmacokinetic (PK) profile of the compound.. Toxicity was minimal, with asymptomatic Grade 3 lymphocytopenia occurring in nine patients. Nine patients developed Grade 1 nausea, six patients developed Grade 1 increases in alkaline phosphatase, and six patients developed Grade 1 increases in transaminases. Two patients experienced hypersensitivity reactions. The MTD was not reached. Most patients had progressive disease on treatment but eight completed 12 weeks and two completed 24 weeks of treatment. The best response was stable disease of 6 months duration. The plasma half-life (T1/2), clearance (Cl), and volume of distribution (VD) were 304 (+/-91) min, 82 (+/-19) ml/min and 32,663 (+/-7,199) ml, respectively, for total NV06.. NV06 is well tolerated and can be given safely as an intravenous infusion over 1-2 h at a dose of at least 30 mg/kg.

Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Half-Life; Humans; Infusions, Intravenous; Isoflavones; Lymphopenia; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms

Phenoxodiol is a multi-pathway initiator of apoptosis with broad anti-tumor activity and high specificity for tumor cells. Its biochemical effects are particularly suited to reversal of chemo-resistance, and the drug is being developed as a chemo-sensitizer of standard chemotherapeutics in solid cancers. 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.. 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). Treatment cycles continued until disease progression. Toxicity was based on standard criteria; efficacy was based on changes in tumor burden (WHO); pharmacokinetic analysis was conducted on plasma samples at specified time points during treatment cycles.. Nineteen heavily-pre-treated patients with solid tumors received a median of three cycles of treatment (range 1-13); two patients received >or= 12 cycles. No dose-limiting toxicities were encountered, with emesis and fatigue (one patient) and rash (one patient) the only significant toxicities. Stabilized disease was the best efficacy outcome, with one patient showing stable disease at 24 weeks. Pharmacokinetics suggested a linear relationship between dosage and mean steady-state plasma concentrations of phenoxodiol.. A 7-day continuous infusion of phenoxodiol given every 2 weeks is well tolerated up to a dose of 27.0 mg/kg/day.

Topics: Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Isoflavones; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Topoisomerase II Inhibitors

Mouse embryonic fibroblast (MEF) cells prepared from transgenic mice overexpressing a cancer-specific and growth-related cell surface NADH oxidase with protein disulfide-thiol interchange activity grew at rates approximately twice those of wild-type embryonic fibroblast cells. Growth of transgenic MEF cells overexpressing tNOX was inhibited by low concentrations of the green tea catechin (-)-epigallocatechin-3-gallate (EGCg) or the synthetic isoflavene phenoxodiol. Both are putative tNOX-targeted inhibitors with anti-cancer activity. With both EGCg and phenoxodiol, growth inhibition was followed after about 48 h by apoptosis. Growth of wild-type mouse fibroblast cells from the same strain was unaffected by EGCg and phenoxodiol and neither compound induced apoptosis even at concentrations 100-1,000-fold higher than those that resulted in apoptotic death in the transgenic MEF cells. The findings validate earlier reports of evidence for tNOX presence as contributing to unregulated growth of cancer cells as well as the previous identification of the tNOX protein as the molecular target for the anti-cancer activities attributed to both EGCg and phenoxodiol. The expression of tNOX emerges as both necessary and sufficient to account for the cancer cell-specific growth inhibitions by both EGCg and phenoxodiol.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Catechin; Cell Shape; Cells, Cultured; Embryo, Mammalian; Female; Fibroblasts; Isoflavones; Male; Mice; Mice, Transgenic; NADH, NADPH Oxidoreductases; Neoplasms; Oxidation-Reduction; Phenotype

Phenoxodiol (2H-1-benzopyran-7-0,1, 3-[4-hydroxyphenyl], PXD) is a synthetic analogue of the naturally-occurring plant isoflavone and anticancer agent, genistein. PXD directly induces mitotic arrest and apoptosis in most cancer cells and is currently undergoing clinical trials, as a chemotherapeutic in ovarian and prostate cancers. We show here that PXD also exhibits potent antiangiogenic properties. Thus, it inhibited endothelial cell proliferation, migration and capillary tube formation and inhibited expression of the matrix metalloproteinase MMP-2, a major matrix degrading enzyme. Importantly, we demonstrate that PXD is functional in vivo since it inhibited the extent of capillary tube invasion in an in vivo model of angiogenesis. 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. However, PXD had no effect on unstimulated endothelial cells. We also describe that PXD inhibits the lipid kinase sphingosine kinase, which recently has been implicated in endothelial cell activation and angiogenesis as well as oncogenesis. Thus, our results suggest that PXD may be an effective anticancer drug targeting the two drivers of tumour growth--the proliferation of the tumour cells themselves and the angiogenic and inflammatory stimulation of the vasculature.

Topics: Animals; Capillaries; Cell Movement; Cell Proliferation; Endothelial Cells; Female; Humans; Inflammation; Isoflavones; Mice; Neoplasms; Neovascularization, Pathologic; Phosphotransferases (Alcohol Group Acceptor); Umbilical Cord