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Current Oncology Reports Mar 2006Phenoxodiol, a synthetic analog of the plant isoflavone genistein, represents a new generation of oncology drugs acting as multiple signal transduction regulators.... (Review)
Review
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
PubMed: 16507219
DOI: 10.1007/s11912-006-0044-2 -
Expert Opinion on Pharmacotherapy Apr 2009Phenoxodiol is a synthetic derivative of the naturally occurring plant isoflavone genistein. The observation that an inverse relationship exists between dietary intake... (Review)
Review
BACKGROUND
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.
OBJECTIVE
This article reviews the mechanisms of action of phenoxodiol and the completed and ongoing clinical studies evaluating this drug.
RESULTS/CONCLUSIONS
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
PubMed: 19364253
DOI: 10.1517/14656560902837980 -
Current Opinion in Investigational... Jun 2006Epithelial ovarian cancer is the fourth leading cause of cancer-related deaths in women and is the most lethal of the gynecological malignancies. Thle high mortality... (Review)
Review
Epithelial ovarian cancer is the fourth leading cause of cancer-related deaths in women and is the most lethal of the gynecological malignancies. Thle high mortality rate arises from difficulties in the early detection of the disease and the widespread development of chemoresistance. Phenoxodiol, a novel isoflavone derivative, has demonstrated antitumor activity. In addition, it has been shown to induce cell death in chemoresistant epithelial ovarian cancer cells. Moreover, suboptimal exposure of these cells to phenoxodiol lowered the IC50 value of numerous chemotherapeutic agents. In this review, the current understanding of the mechanism of action of phenoxodiol, its potential clinical application for the treatment of ovarian cancer and the concept of chemosensitization are discussed.
Topics: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Caspases; Cells, Cultured; Clinical Trials as Topic; Death Domain Receptor Signaling Adaptor Proteins; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; Humans; Isoflavones; Ovarian Neoplasms; Randomized Controlled Trials as Topic; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
PubMed: 16784025
DOI: No ID Found -
Expert Opinion on Investigational Drugs Apr 2009Flavonoids, in particular the isoflavones, are naturally occurring compounds found in soy and textured vegetables that have antiproliferative effects on a variety of... (Review)
Review
Flavonoids, in particular the isoflavones, are naturally occurring compounds found in soy and textured vegetables that have antiproliferative effects on a variety of cancer types. Phenoxodiol is a derivative of the isoflavone genisten that is 5-20 times more potent than genisten. Triphendiol is a derivative of phenoxodiol that has superior anticancer activity against pancreatic and bile duct cancers. This review will focus on the mechanisms of action and activity of two isoflavone derivatives, phenoxodiol and triphendiol, in various tumor types, especially pancreaticobiliary cancers. Triphendiol induces apoptosis in pancreatic cell lines by both caspase-mediated and caspase-independent mechanisms. The addition of triphendiol to gemcitabine is synergistic in in vitro and in vivo models of pancreatic cancer and represents a novel combination of drugs for pancreatic cancer patients.
Topics: Animals; Antineoplastic Agents; Biliary Tract Neoplasms; Biological Products; Flavonoids; Humans; Isoflavones; Pancreatic Neoplasms
PubMed: 19278301
DOI: 10.1517/13543780902762835 -
Journal of Microbiology and... May 2022Glycosyltransferase (GT)-specific degenerate PCR screening followed by in silico sequence analyses of the target clone was used to isolate a member of family1...
Glycosyltransferase (GT)-specific degenerate PCR screening followed by in silico sequence analyses of the target clone was used to isolate a member of family1 GT-encoding genes from the established fosmid libraries of soil actinomycetes ATCC 27932. A recombinant MeUGT1 was heterologously expressed as a His-tagged protein in , and its enzymatic reaction with semi-synthetic phenoxodiol isoflavene (as a glycosyl acceptor) and uridine diphosphate-glucose (as a glycosyl donor) created two different glycol-attached products, thus revealing that MeUGT1 functions as an isoflavonoid glycosyltransferase with regional flexibility. Chromatographic separation of product glycosides followed by the instrumental analyses, clearly confirmed these previously unprecedented glycosides as phenoxodiol-4'-α--glucoside and phenoxodiol-7-α--glucoside, respectively. The antioxidant activities of the above glycosides are almost the same as that of parental phenoxodiol, whereas their anti-proliferative activities are all superior to that of cisplatin (the most common platinum chemotherapy drug) against two human carcinoma cells, ovarian SKOV-3 and prostate DU-145. In addition, they are more water-soluble than their parental aglycone, as well as remaining intractable to the simulated in vitro digestion test, hence demonstrating the pharmacological potential for the enhanced bio-accessibility of phenoxodiol glycosides. This is the first report on the microbial enzymatic biosynthesis of phenoxodiol glucosides.
Topics: Escherichia coli; Glucosides; Glycosides; Glycosylation; Glycosyltransferases; Humans; Isoflavones; Male; Micromonospora
PubMed: 35131959
DOI: 10.4014/jmb.2111.11032 -
Cell Biochemistry and Biophysics Nov 2014Gallbladder cancer is the most common and aggressive type of biliary tract cancer with poor prognosis due to both its inability to be detected at an early stage and its...
Gallbladder cancer is the most common and aggressive type of biliary tract cancer with poor prognosis due to both its inability to be detected at an early stage and its poor sensitivity to conventional therapies. Gemcitabine has been more and more widely used for the treatment of gallbladder cancer; however, the response rate is not satisfactory. Phenoxodiol is an isoflavone analog with antitumor activity against a variety of cancers. In our current work, we examined the effect of phenoxodiol on gallbladder cancer cells and to determine whether phenoxodiol can enhance the antitumor activity of gemcitabine in gallbladder cancer. The combined treatment of phenoxodiol and gemcitabine was more effective at inhibiting cell proliferation than either chemotherapeutic agent treatment alone. Meanwhile, phenoxodiol arrests cell cycle progression in the G0-G1 phase. In addition, phenoxodiol and gemcitabine inhibit the phosphorylation of PI3K/Akt-signaling pathway as well as modulate the expression of apoptosis-relevant molecules. Furthermore, the antitumor effect of combination treatment with phenoxodiol and gemcitabine on gallbladder cancer was evaluated using a murine gallbladder cancer xenograft model and the results suggested that phenoxodiol enhanced the in vivo antitumor activity of gemcitabine. Taken together, our study suggested that the combination treatment with phenoxodiol and gemcitabine might offer optimal therapeutic benefits for patients with gallbladder cancer.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Deoxycytidine; Drug Synergism; Female; G1 Phase Cell Cycle Checkpoints; Gallbladder Neoplasms; Humans; Isoflavones; Mice; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Resting Phase, Cell Cycle; Signal Transduction; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays; Gemcitabine
PubMed: 24902539
DOI: 10.1007/s12013-014-0061-y -
Future Oncology (London, England) Aug 2008A major limitation in the treatment of cancers is the prevalence of chemoresistant tumors. Chemotherapy agents induce cell death by activating apoptosis. However, most... (Review)
Review
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
PubMed: 18684059
DOI: 10.2217/14796694.4.4.475 -
Enzyme and Microbial Technology Nov 2022Isoflavonoids are of great interest due to their human health-promoting properties, which have resulted in studies on exploiting these phytochemicals as hotspots in...
Isoflavonoids are of great interest due to their human health-promoting properties, which have resulted in studies on exploiting these phytochemicals as hotspots in diverse bio -industries. Biocatalytic glycosylation of isoflavonoid aglycones to glycosides has attracted marked interests because it enable the biosynthesis of isoflavonoid glycosides with high selectivity under mild conditions, and also provide an environmentally friendly option for the chemical synthesis. Thus, these inspired us to exploit new flexible and effective glycosyltransferases from microbes for making glycosides attractive compounds that are in high demand in several industries. Most recently, we have reported the functional characterization of a bacterial-origin recombinant glycosyltransferase (MeUGT1). Herein, more detailed kinetic characteristics of this biocatalyst, using a number of glycosyl donor substrates, were examined for further investigation of its biocatalytic applicability, enabling it feasible to biosynthesize new glycosides; phenoxodiol-4'-O-α-glucuronide, phenoxodiol-4'-O-α-(2''-N-acetyl)glucosaminide, phenoxodiol-4'-O-α-galactoside, phenoxodiol-4'-O-α-(2''-N-acetyl)galactosaminide and phenoxodiol-4'-O-α-(2''-deoxy)glucoside. The thorough kinetic analyses revealed that while the recombinant enzyme can utilize, albeit with different substrate preference and catalytic efficiency, a total five different nucleotide sugars as glycosyl donors, exhibiting its promiscuity towards glycosyl donors. This is the first report that a recombinant glycosyltransferase MeUGT1 that can regio-specifically glycosylate C4'-hydroxyl function of semi-synthetic phenoxodiol isoflavene to biosynthesize a series of unnatural phenoxodiol-4'-O-α-glycosides.
Topics: Glycosides; Glycosylation; Glycosyltransferases; Humans; Isoflavones
PubMed: 35998478
DOI: 10.1016/j.enzmictec.2022.110113 -
Frontiers in Bioengineering and... 2019Phenoxodiol, an isoflavene anti-tumor agent, was conjugated on the polysaccharide dextran using immobilized laccase as biocatalyst. The success of the enzymatic...
Phenoxodiol, an isoflavene anti-tumor agent, was conjugated on the polysaccharide dextran using immobilized laccase as biocatalyst. The success of the enzymatic conjugation was determined by UV-vis spectrophotometry and its functionalization degree was assessed by H NMR and was found to be 3.25 mg phenoxodiol/g of conjugate. An accelerated stability test showed that the resultant conjugate was nine times more stable than the free phenoxodiol when tested for its residual anti-oxidant activity with the Folin-Ciocalteu assay. The anti-proliferative activity of the conjugate was evaluated against neuroblastoma SKN-BE(2)C, triple-negative breast cancer MDA-MB-231, and glioblastoma U87 cancer cells. The conjugate was shown to be generally more potent than phenoxodiol against all three cell types tested. Additionally, the cytotoxicity and anti-angiogenic activity of the conjugate were also evaluated against non-malignant human lung fibroblast MRC-5 and human microvascular endothelial cells HMEC-1, respectively. The conjugate was found to be 1.5 times less toxic than phenoxodiol while mostly retaining 62% of its anti-angiogenic activity in the conjugate form. This study provides further evidence that the conjugation of natural product-derived drugs onto polysaccharide molecules such as dextran can lead to better stability and enhanced biological activity of the conjugate compared to the free drug alone.
PubMed: 31440502
DOI: 10.3389/fbioe.2019.00183 -
The Prostate Aug 2010Phenoxodiol, 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...
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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
PubMed: 20564423
DOI: 10.1002/pros.21156