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Cancer Research Jul 2011The benzyl styryl sulfone, ON 01910.Na, is a novel anticancer agent that inhibits mitotic progression and induces apoptosis in most cancer cell lines. We examined the...
The benzyl styryl sulfone, ON 01910.Na, is a novel anticancer agent that inhibits mitotic progression and induces apoptosis in most cancer cell lines. We examined the effect of ON 01910.Na on DNA damage-signaling molecules upstream of Cdc25C (Chk1, Chk2, and H2AX), as well as on Ran GTPase-activating protein 1 conjugated to small ubiquitin-related modifier 1 (RanGAP1·SUMO1), a mitosis coordinator. Prostate cancer, lymphoma, and leukemic cells were incubated with the drug for 4, 16, or 24 hours. Cell lysates were resolved on SDS-PAGE and analyzed by Western blot. Camptothecin and doxorubicin treatment caused activation/phosphorylation of DNA damage-responsive molecules by 4 hours, whereas ON 01910.Na did not do so. ON 01910.Na caused hyperphosphorylation of RanGAP1·SUMO1 within 4 hours that was sustained for more than 24 hours. Mild phosphorylation of Chk2 was observed only after 24-hour exposure, indicating that DNA damage response was not an initial effect of ON 01910.Na. MOLT-3 cells, synchronized by double-thymidine block, when released into a medium containing ON 01910.Na, accumulated mitotic cell number with a peak from 10 to 14 hours and remained near plateau for 20 hours, which corresponded with the time of RanGAP phosphorylation. ON 01910.Na had minimal effects on tubulin polymerization. These findings imply that ON 01910.Na neither induces DNA damage directly nor acts as a tubulin toxin. Its biological activity appears to rely on prolonged phosphorylation/hyperphosphorylation of RanGAP1·SUMO1. M-phase arrest and the consequent induction of apoptosis that follows could possibly be attributed to it. ON 01910.Na may act as an inhibitor of a RanGAP1·SUMO1 phosphatase or a stimulant of a new kinase. RanGAP1·SUMO1 appears to be a new target pathway for cancer chemotherapy.
Topics: Camptothecin; Cell Cycle; Cell Line, Tumor; DNA Damage; Doxorubicin; GTPase-Activating Proteins; Glycine; Humans; Mitosis; Phosphorylation; Polymerization; Precursor Cell Lymphoblastic Leukemia-Lymphoma; SUMO-1 Protein; Signal Transduction; Sulfones; Tubulin
PubMed: 21646468
DOI: 10.1158/0008-5472.CAN-10-1603 -
Archives of Gynecology and Obstetrics May 2011Ovarian cancer is a difficult to treat cancer entity with a high relapse rate. After initial surgery and chemotherapy, only a few options for therapeutic treatment... (Review)
Review
INTRODUCTION
Ovarian cancer is a difficult to treat cancer entity with a high relapse rate. After initial surgery and chemotherapy, only a few options for therapeutic treatment remain in case of cancer recurrence. New treatment options with improved efficacies to circumvent acquired or pre-existing drug resistance are needed.
MATERIALS
This survey focuses on new prospective drugs for ovarian cancer treatment that either cause direct damage to the nuclear DNA or inhibit chromosome segregation by acting as mitotic spindle inhibitors.
RESULTS
Among a plethora of currently tested and proposed new drugs for ovarian cancer treatment, only a few appear to meet the criteria of sufficient and reliable efficacy with tolerable toxicity. These include the naturally occurring DNA-alkylating alkaloid trabectedin, the nitrogen mustard prodrug canfosfamide, and the synthetic kinase inhibitor ON-01910. The latter inhibits mitotic spindle formation without a direct tubulin interaction, avoiding adverse neurotoxic reactions common to the taxanes. Further, epothilones and oxaliplatin, already approved drugs for other cancer entities, show promising activity against ovarian cancer; they are even of interest as a first-line treatment option.
DISCUSSION
Although the current focus and interest of modern cancer drug design tends to be more specific and targeted therapies, including therapeutic antibodies and specific small molecules to inhibit growth-, apoptosis-, and angiogenesis-regulating signalling cascades, the main target for ovarian cancer treatment appears to remain its basic, though uncontrolled working proliferation machinery. This includes the current gold standard for ovarian cancer chemotherapy, carboplatin, and taxanes, as well as the few remaining alternatives, such as topotecan, doxorubicin, and gemcitabine, which all rely on their ability to bind to or to modify the DNA or the chromosome-separating spindle apparatus. Thus, the genomic integrity and replication machinery of ovarian cancer cells prove to represent an established, and obviously still effective target to be tackled for ovarian cancer treatment.
Topics: Antineoplastic Agents, Alkylating; Cell Division; DNA; Drugs, Investigational; Female; Humans; Microtubules; Ovarian Neoplasms
PubMed: 21082186
DOI: 10.1007/s00404-010-1757-x -
Drug Metabolism and Disposition: the... Sep 2010Sodium (E)-{N-[2-methyloxy-5-(2',4',6'-trimethoxy-styrylsulfonyl) methylenephenyl]amino}acetate (C(21)H(24)NNaO(8)S, ON 01910.Na) is a novel, synthetic benzyl styryl...
Sodium (E)-{N-[2-methyloxy-5-(2',4',6'-trimethoxy-styrylsulfonyl) methylenephenyl]amino}acetate (C(21)H(24)NNaO(8)S, ON 01910.Na) is a novel, synthetic benzyl styryl sulfone, currently in phase I clinical trials in cancer patients. Our objective was to use electrospray mass spectrometry to determine, in intact complexes, the number of drug molecules bound to albumin and selected enzymes. Native and recombinant albumin incubated with the drug, at various molar ratios, revealed simultaneous and discontinuous progression of drug binding, yielding intact albumin-drug complexes containing up to 22 drug molecules. Comparable complex protein-drug patterns were obtained for several enzymes, e.g., carbonic anhydrase. Intact albumin-ON 01910 complexes were also found in all patient samples. The drug-binding profiles were comparable, but not identical, for increasing sampling times and different doses (400-1700 mg/m(2)). We concluded that the techniques developed are capable of detecting the simultaneous formation of intact protein-drug complexes and of determining the number of drug molecules bound to proteins. The results enhance our hypothesis that drug binding may lead to conformational changes in proteins that, in turn, account for the exclusion of specific binding complexes and may influence protein behavior and activity. Application of these techniques reveals new insights about the nature of the antineoplastic drug ON 01910 in patient plasma, and the information obtained may have significance in understanding drug delivery to tumors.
Topics: Albumins; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Enzymes; Glycine; Humans; In Vitro Techniques; Protein Binding; Sulfones
PubMed: 20501913
DOI: 10.1124/dmd.110.033001 -
Molecular Cancer Therapeutics Feb 2010This work aimed to discover targets for combination treatment with gemcitabine in pancreatic cancer. We selected 11 tumors from our live collection of freshly generated...
This work aimed to discover targets for combination treatment with gemcitabine in pancreatic cancer. We selected 11 tumors from our live collection of freshly generated pancreatic cancer xenografts with known degrees of varying gemcitabine sensitivity. We briefly (6 h) exposed fine-needle aspiration material to control vehicle or gemcitabine (1 mumol/L) and compared the gene expression of the treated and untreated samples using a reverse transcription-PCR-based, customized low-density array with 45 target genes of therapeutic interest. The gene expression of the untreated sample (which can be considered a baseline/static readout) was not predictive of gemcitabine efficacy in these tumors. Altogether, the only gene that differentiated sensitive versus resistant cases was polo-like kinase 1 (Plk1), showing >50% downregulation in sensitive cases and no change in the resistant cases. Inhibition of Plk1 by either small interfering RNA gene knockdown or with the Plk1 pathway modulator (ON 01910.Na) synergized with gemcitabine in gemcitabine-refractory in vitro models providing mechanistic proof of concept. In vivo experiments in gemcitabine-resistant xenografts showed synergistic activity decreasing cell proliferation and tumor regressions. A quantitative gene expression-based vulnerability assay identified Plk1 as a relevant target dictating the susceptibility of pancreatic cancer to gemcitabine. Dynamic interrogation of cancer has the potential to provide key information about mechanisms of resistance and to enhance individualization of treatment.
Topics: Animals; Antineoplastic Agents; Biopsy, Fine-Needle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Drug Resistance, Neoplasm; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Treatment Outcome; Gemcitabine; Polo-Like Kinase 1
PubMed: 20103597
DOI: 10.1158/1535-7163.MCT-09-0693 -
The Oncologist Jun 2009Polo-like kinases (PLKs) are a group of highly conserved serine/threonine protein kinases that play a key role in processes such as cell division and checkpoint... (Review)
Review
Polo-like kinases (PLKs) are a group of highly conserved serine/threonine protein kinases that play a key role in processes such as cell division and checkpoint regulation of mitosis. About 80% of human tumors, of various origins, express high levels of PLK transcripts. However, PLK mRNA is mostly absent in surrounding healthy tissues. Overexpression of PLK is associated with a poor prognosis in several tumor types and a lower overall survival rate. The overexpression of PLKs in human tumors, but not in healthy nondividing cells, makes them an attractive, selective target for cancer drug development. PLK inhibitors interfere with different stages of mitosis, such as centrosome maturation, spindle formation, chromosome separation, and cytokinesis. They induce mitotic chaos and severely perturb cell cycle progression, eventually leading to cancer cell death. Several PLK inhibitors are in development and are undergoing evaluations as potential cancer treatments. This review includes an overview of PLK inhibitors in early clinical development (i.e., BI 2536, BI 6727, GSK461364, ON 019190.Na, and HMN-214) and in advanced preclinical development (i.e., ZK-thiazolidinone, NMS-1, CYC-800, DAP-81, and LC-445). If proof of principle is confirmed in large studies, PLK inhibitors will offer a new targeted antitumor therapy for cancer patients.
Topics: Aniline Compounds; Animals; Cell Cycle Proteins; Clinical Trials as Topic; Cyclic N-Oxides; Drug Evaluation, Preclinical; Glycine; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pteridines; Pyridines; Sulfonamides; Sulfones; Thiazolidines; Polo-Like Kinase 1
PubMed: 19474163
DOI: 10.1634/theoncologist.2009-0010 -
Cancer Chemotherapy and Pharmacology Dec 2009ON 01910.Na is a novel targeted anti-cancer agent under clinical investigation in Phase I and II trials. The purpose of this research was to evaluate the pharmacokinetic...
PURPOSE
ON 01910.Na is a novel targeted anti-cancer agent under clinical investigation in Phase I and II trials. The purpose of this research was to evaluate the pharmacokinetic profile of ON 01910.Na across several species, and to evaluate the effects of protein binding and duration of exposure on its in vitro cytotoxic activity.
METHODS
Data were collated from several preclinical investigations, where the plasma disposition and tissue distribution of ON 01910.Na were assessed after administration (10-150 mg/kg, IP or IV) to several species (mouse, rat, and dog). Plasma protein binding was assessed using ultrafiltration. Cytotoxic activity of ON 01910.Na was determined in DU145 cells, and activity was correlated to unbound drug concentration and the duration of exposure.
RESULTS
ON 01910.Na exhibits extensive plasma protein binding and the compound displays rapid elimination from the circulation in all three animal species (t(1/2) range 0.404-0.870 h). Tissue distribution studies in mice revealed highest drug accumulation in the liver, followed by the kidneys. ON 01910.Na is not extensively metabolized in vivo and urinary excretion is predominant at higher doses. ON 01910.Na cytotoxicity in DU145 cells was adversely affected by protein binding in the incubation medium. Drug cytotoxicity was greatly enhanced upon extending the duration of exposure at reduced drug concentrations.
CONCLUSIONS
Due to the short half-life and rapid clearance of the drug, administration of ON 01910.Na by continuous IV infusion is a likely treatment option for cancer patients.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Female; Glycine; Half-Life; Humans; Infusions, Intravenous; Kidney; Liver; Male; Mice; Prostatic Neoplasms; Protein Binding; Rats; Species Specificity; Sulfones; Tissue Distribution
PubMed: 19466411
DOI: 10.1007/s00280-009-1022-9 -
Oncogene Mar 2009Mantle cell lymphoma (MCL) is characterized by the uncontrolled overexpression of cyclin D1. Styryl sulfonyl compounds have shown potent antitumor activity against MCL...
Mantle cell lymphoma (MCL) is characterized by the uncontrolled overexpression of cyclin D1. Styryl sulfonyl compounds have shown potent antitumor activity against MCL by inducing cell-cycle arrest and apoptosis. However, the exact molecular mechanism by which these compounds function is yet to be elucidated. Here, we show that the prototypical styryl sulfonyl compound ON 01910.Na decreased cyclin D1 and c-Myc protein levels in MCL cells, whereas mRNA levels of cyclin D1 were minimally affected. Notably, ON 01910.Na suppressed eukaryotic translation initiation factor 4E (eIF4E)-mediated cyclin D1 mRNA translation, decreased levels of phosphorylated Akt, mammalian target of Rapamycin (mTOR) and eIF4E-binding protein (eIF4E-BP), lowered the cap site binding activity of eIF4E and directly inhibited activity of phosphatidylinositol-3 kinase (PI-3K). Analysis of apoptotic signaling pathways revealed that ON 01910.Na induced the release of cytochrome c from mitochondria, altered expression of Bcl-2 family of proteins and stimulated activation of caspases. Taken together, styryl sulfonyls can cause a rapid decrease of cyclin D1 by blocking cyclin D1 mRNA translation through inhibition of the PI-3K/Akt/mTOR/eIF4E-BP signaling pathway and triggering a cytochrome c-dependent apoptotic pathway in MCL cells.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cyclin D1; Eukaryotic Initiation Factor-4E; Extracellular Signal-Regulated MAP Kinases; Forkhead Box Protein O1; Forkhead Transcription Factors; Glycine; Humans; Lymphoma, Mantle-Cell; Mitogen-Activated Protein Kinase Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Biosynthesis; Protein Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Signal Transduction; Sulfones; TOR Serine-Threonine Kinases; p38 Mitogen-Activated Protein Kinases; raf Kinases
PubMed: 19198627
DOI: 10.1038/onc.2008.502 -
Oncogene Jan 2009The pupose of this study was to evaluate the activity of ON 01910.Na, a mitotic inhibitor, in in vitro and in vivo models of pancreatic cancer and to discover biomarkers...
The pupose of this study was to evaluate the activity of ON 01910.Na, a mitotic inhibitor, in in vitro and in vivo models of pancreatic cancer and to discover biomarkers predictive of efficacy. Successive in vitro and in vivo models were used; these included cell line-derived and patient-derived tumors from our PancXenoBank, a live collection of freshly generated pancreatic cancer xenografts. ON 01910.Na showed equivalent activity to gemcitabine against pancreatic cancer cell lines in vitro. The activity of the agent correlated with suppression of phospho-CDC25C and cyclin B1. These markers were optimized for a fine-needle aspirate ex vivo rapid assay. Cyclin B1 mRNA evaluation yielded the most optimal combination of accuracy and reproducibility. Next, nine patient-derived tumors from the PancXenoBank were profiled using the assay developed in cell lines and treated with ON01910.Na for 28 days. Two cases were cataloged as potential responders and seven as resistants. There was a correlation between the ex vivo assay and sensitivity to the tested agent, as the two cases prospectively identified as sensitive met prespecified criteria for response. Of the seven tumors of predictive resistant, only one was found to be sensitive to ON 01910.Na. In addition, there was a good correlation between cyclin B1 downregulation ex vivo and changes in cyclin B1 protein post-treatment. The novel mitotic inhibitor, ON 01910.Na, showed activity in preclinical model of pancreatic cancer. A rapid assay was rationally developed that not only identified cases sensitive to ON 01910.Na, but also anticipated the pharmacodynamic events occurring after in vivo exposure.
Topics: Animals; Antimetabolites, Antineoplastic; Biopsy, Fine-Needle; Cell Line, Tumor; Cyclin B; Cyclin B1; Deoxycytidine; Drug Resistance, Neoplasm; Female; Glycine; Humans; Mice; Mice, Nude; Pancreatic Neoplasms; Predictive Value of Tests; Sulfones; Xenograft Model Antitumor Assays; cdc25 Phosphatases; Gemcitabine
PubMed: 19029951
DOI: 10.1038/onc.2008.424 -
Journal of Clinical Oncology : Official... Dec 2008We conducted a first-in-man (to our knowledge) phase I study to determine the dose-limiting toxicities (DLTs), characterize the pharmacokinetic profile, and document any...
PURPOSE
We conducted a first-in-man (to our knowledge) phase I study to determine the dose-limiting toxicities (DLTs), characterize the pharmacokinetic profile, and document any antitumor activity of ON 01910.Na, a new chemical entity that arrests cancer cells in G(2)/M by modulating mitotic regulatory pathways including polo-like kinase 1 (Plk1).
PATIENTS AND METHODS
Patients had solid tumors refractory to standard therapy. ON 01910.Na was administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 in 28-day cycles. The starting dose was 80 mg, and an accelerated titration schedule (single-patient cohorts) was used for escalation. Pharmacokinetics were studied on days 1 and 15 of cycle 1.
RESULTS
Twenty patients (11 women and nine men; age 46 to 73 years) were enrolled onto the study. Dose levels of 80, 160, 320, 480, 800, 1,280, 2,080, and 3,120 mg were evaluated in single-patient cohorts. A DLT and additional grade 2 toxicities made the 4,370-mg dose (n = 6) not tolerable, and the next lower dose cohort (3,120 mg) was expanded to six assessable patients. Toxicities were skeletal, abdominal, and tumor pain; nausea; urge to defecate; and fatigue. Hematologic toxicity was infrequent and mild. ON 01910.Na pharmacokinetics were characterized by a rapid distribution phase (distribution half-life, 1 hour) and a relatively slow elimination phase (elimination half-life, 27 hours). A refractory ovarian cancer patient had an objective response after four cycles and remained progression free for 24 months.
CONCLUSION
ON 01910.Na showed a distinct but moderate toxicity pattern. The recommended phase II dose of ON 01910.Na with this schedule of administration is 3,120 mg. Single-agent activity was documented in an ovarian cancer patient.
Topics: Aged; Antineoplastic Agents; Cell Cycle Proteins; Cell Division; Dose-Response Relationship, Drug; Female; G2 Phase; Gene Expression Regulation, Neoplastic; Glycine; Humans; Male; Middle Aged; Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Sulfones; Time Factors; Treatment Outcome; Polo-Like Kinase 1
PubMed: 18955447
DOI: 10.1200/JCO.2008.17.9788 -
Journal of Chromatography. B,... Sep 2007A reverse-phase high performance liquid chromatographic method with tandem mass spectrometry (LC-MS/MS) was developed and validated for the quantitation of ON 01910.Na,...
A reverse-phase high performance liquid chromatographic method with tandem mass spectrometry (LC-MS/MS) was developed and validated for the quantitation of ON 01910.Na, a novel synthetic benzyl styryl sulfone, in human plasma. The assay involved a simple sample preparation with acetonitrile protein precipitation. ON 01910.Na and the internal standard temazepam were separated on a Waters X-Terra MS C(18) column with mobile phase of acetonitrile containing 0.1% formic acid /10mM ammonium acetate (55:45, v/v) using isocratic flow at 0.2 mL/min for 5 min. The analytes were monitored by tandem-mass spectrometry with electrospray positive ionization. Two calibration curves were generated over the range of 10-2000 ng/mL and 100-20000 ng/mL. The lower limit of quantitation (LLOQ) was 10 ng/mL for ON 01910.Na in human plasma. The accuracy and within- and between-day precisions were within the acceptance criteria for bioanalytical assays. ON 01910.Na was found stable in plasma at -70 degrees C for at least 1 year. The method was successfully applied to characterize the plasma concentration-time profiles of ON 01910.Na in the cancer patients in the Phase I study.
Topics: Chromatography, Liquid; Glycine; Humans; Mitosis; Reference Standards; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Sulfones; Tandem Mass Spectrometry
PubMed: 17588831
DOI: 10.1016/j.jchromb.2007.05.047