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Simon Green - One of the best experts on this subject based on the ideXlab platform.
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Cancer Therapy: Clinical Pharmacodynamic Effects of Seliciclib, an Orally Administered Cell Cycle Modulator, in Undifferentiated Nasopharyngeal Cancer
2010Co-Authors: Wen Son Hsieh, Simon Green, Judy Chiao, B.-k. Peh, Difeng Dong, Donny Soh, Chun-ying Cui, Ross Soo, Thomas Loh, Yoke-fong LaiAbstract:Purpose: Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature of undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects of Seliciclib, a cyclin-dependent kinase (CDK) inhibitor, were studied in patients with nasopharyngeal carcinoma. Experimental Design: Patients with treatment-naI«ve locally advanced nasopharyngeal carcinoma received Seliciclib at 800 mg or 400 mg twice daily on days1 to 3 and 8 to12. Paired tumor samples obtained at baseline and on day 13 were assessed by light microscopy, immunohistochemistry, and transcriptional profiling using real-time PCR low-density array consisting of a panel of 380 genes related to cell cycle inhibition, apoptosis, signal transduction, and cell proliferation. Results: At 800 mg bd, one patient experienced grade 3 liver toxicity and another had grade 2 vomiting; no significant toxicities were experienced in 13 patients treated at 400 mg bd. Seven of fourteen evaluable patients had clinical evidence of tumor reduction. Some of these responses were associated with increased tumor apoptosis, necrosis, and decreases in plasma EBV DNA posttreatment. Reduced protein expression of Mcl-1, cyclin D1, phosphorylated retinoblastom
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Phase I evaluation of Seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies
European Journal of Cancer, 2010Co-Authors: Christophe Le Tourneau, Sheelagh Frame, S. Faivre, Valérie Laurence, Catherine Delbaldo, Karina Vera, Véronique Girre, Judy Chiao, Sian Armour, Simon GreenAbstract:Abstract Aim Phase I study of Seliciclib (CYC202, R-roscovitine), an inhibitor of cyclin-dependent kinases 2, 7 and 9, causing cell cycle changes and apoptosis in cancer cells. Patients and methods This phase I trial aimed at defining the toxicity profile, the maximum tolerated dose (MTD), the recommended phase II dose (RD) and the main pharmacokinetic and pharmacodynamic parameters of oral Seliciclib. Three schedules were evaluated: Seliciclib given twice daily for 5 consecutive days every 3 weeks (schedule A), for 10 consecutive days followed by 2 weeks off (schedule B) and for 3 d every 2 weeks (schedule C). Results Fifty-six patients received a total of 218 cycles of Seliciclib. Dose-Limiting Toxicities (DLT) consisting of nausea, vomiting, asthenia and hypokalaemia occurred at 1600 mg bid for schedule A and in schedule C, DLT of hypokalaemia and asthenia occurred at 1800 mg bid. The evaluation of longer treatment duration in schedule B was discontinued because of unacceptable toxicity at lower doses. Other adverse events included transient serum creatinine increases and liver dysfunctions. Pharmacokinetic data showed that exposure to Seliciclib and its carboxylate metabolite increased with increasing dose. Soluble cytokeratin 18 fragments allowed monitoring of Seliciclib-induced cell death in the blood of patients treated with Seliciclib at doses above 800 mg/d. One partial response in a patient with hepatocellular carcinoma and sustained tumour stabilisations were observed. Conclusions The MTD and RD for Seliciclib are 1250 mg bid for 5 d every 3 weeks and 1600 mg bid for 3 d every 2 weeks, respectively.
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Therapeutic efficacy of Seliciclib in combination with ionizing radiation for human nasopharyngeal carcinoma.
Clinical Cancer Research, 2009Co-Authors: Angela B.y. Hui, Sheelagh Frame, Simon Green, Shijun Yue, Wei Shi, Nehad M. Alajez, Emma Ito, Brian O'sullivan, Fei-fei LiuAbstract:Purpose: Seliciclib is a small-molecule cyclin-dependent kinase inhibitor, which has been reported to induce apoptosis and cell cycle arrest in EBV-negative nasopharyngeal carcinoma cell lines. Because most nasopharyngeal carcinoma patients harbor EBV, we proceeded to evaluate the cytotoxic effects of Seliciclib in EBV-positive nasopharyngeal carcinoma models. Experimental Design: Cytotoxicity of Seliciclib was investigated in the EBV-positive cell line C666-1 and the C666-1 and C15 xenograft models. Caspase activities and cell cycle analyses were measured by flow cytometry. Efficacy of combined treatment of Seliciclib with radiation therapy was also evaluated. Results: Seliciclib caused significant cytotoxicity in the C666-1 cells in a time- and dose-dependent manner, with accumulation of cells in both sub-G 1 and G 2 -M phases, indicative of apoptosis and cell cycle arrest, respectively. Caspase-2, -3, -8, and -9 activities were all increased, with caspase-3 being the most significantly activated at 48 h after treatment. These cells also showed a reduction of Mcl-1 mRNA and protein levels. Combined treatment of Seliciclib with radiation therapy showed a synergistic interaction with enhanced cytotoxicity in C666-1 cells and delayed repair of double-strand DNA breaks. For in vivo models, significant delays in tumor growth were observed for both C666-1 and C15 tumors, which were associated with enhanced apoptosis as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and immunohistochemistry analyses. Conclusions: Seliciclib enhanced the antitumor efficacy of radiation therapy in EBV-positive nasopharyngeal carcinoma, characterized by G 2 -M arrest, and apoptosis, associated with an induction in caspase activity. This process is mediated by reduction in Mcl-1 expression and by attenuation of double-strand DNA break repair.
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abstract 3863 derivatives of Seliciclib with improved potency both in vitro and in vivo as novel cyclin dependent kinase cdk inhibitors
Cancer Research, 2009Co-Authors: Simon Green, Edward Mcdonald, Sheelagh Frame, Paul Workman, David E. Maccallum, Morag Hogben, Sian Anderson, Gavin Wood, S M Wilson, Daniella ZhelevaAbstract:Seliciclib (CYC202, R-roscovitine) is a tri-substituted purine inhibitor of CDKs 2, 7 and 9 that is currently in Phase II clinical development in patients with advanced NSCLC and Nasopharyngeal Cancer. In vivo Seliciclib is rapidly metabolised to an inactive carboxylate. A project was initiated to identify derivatives of Seliciclib that had a different metabolic profile and improved potency. A series of tri-substituted purines were synthesised and screened in kinase assays to confirm that they had a similar CDK inhibitor profile. The more potent compounds were then analysed in a screening cascade to demonstrate that they had a similar cellular mode-of-action profile to Seliciclib. This included evaluation of the compound effects on 1) cell cycle profile; 2) gene expression changes and 3) phosphorylation status of known CDK substrates. All the compounds analysed behaved very similarly to Seliciclib but with up to a 40-fold improvement in cellular potency. Four compounds were selected for more in-depth studies including in vitro ADME & specificity assays, and in vivo pharmacokinetic & xenograft models. Compared to Seliciclib significantly improved efficacy has been obtained with once a day oral dosing. Based on the superior pharmaceutical properties and in vivo efficacy one molecule was selected for further development. Results from these ongoing studies will be presented. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3863.
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Pharmacodynamic Effects of Seliciclib, an Orally Administered Cell Cycle Modulator, in Undifferentiated Nasopharyngeal Cancer
Clinical Cancer Research, 2009Co-Authors: Wen Son Hsieh, Simon Green, Judy H. Chiao, B.-k. Peh, Ross A. Soo, T. Loh, Difeng Dong, Donny Soh, Limsoon Wong, Chun-ying CuiAbstract:Purpose: Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature of undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects of Seliciclib, a cyclin-dependent kinase (CDK) inhibitor, were studied in patients with nasopharyngeal carcinoma. Experimental Design: Patients with treatment-naive locally advanced nasopharyngeal carcinoma received Seliciclib at 800 mg or 400 mg twice daily on days 1 to 3 and 8 to 12. Paired tumor samples obtained at baseline and on day 13 were assessed by light microscopy, immunohistochemistry, and transcriptional profiling using real-time PCR low-density array consisting of a panel of 380 genes related to cell cycle inhibition, apoptosis, signal transduction, and cell proliferation. Results: At 800 mg bd, one patient experienced grade 3 liver toxicity and another had grade 2 vomiting; no significant toxicities were experienced in 13 patients treated at 400 mg bd. Seven of fourteen evaluable patients had clinical evidence of tumor reduction. Some of these responses were associated with increased tumor apoptosis, necrosis, and decreases in plasma EBV DNA posttreatment. Reduced protein expression of Mcl-1, cyclin D1, phosphorylated retinoblastoma protein pRB (T821), and significant transcriptional down-regulation of genes related to cellular proliferation and survival were shown in some patients posttreatment, indicative of cell cycle modulation by Seliciclib, more specifically inhibition of cdk2/cyclin E, cdk7/cyclin H, and cdk9/cyclin T. Conclusions: Brief treatment with this regimen of Seliciclib in patients with nasopharyngeal carcinoma is tolerable at 400 mg bd and associated with tumor pharmacodynamic changes consistent with cdk inhibition, and warrants further efficacy studies in this tumor.
Sheelagh Frame - One of the best experts on this subject based on the ideXlab platform.
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fadraciclib cyc065 a novel cdk inhibitor targets key pro survival and oncogenic pathways in cancer
PLOS ONE, 2020Co-Authors: Sheelagh Frame, Chiara Saladino, Craig Mackay, Butrus Atrash, Peter Sheldrake, Edward Mcdonald, Paul Workman, David Blake, Paul A Clarke, Daniella ZhelevaAbstract:Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of Seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to Seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546).
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Targeting the rheumatoid arthritis synovial fibroblast via cyclin dependent kinase inhibition: An early phase trial.
Medicine, 2020Co-Authors: Stefan Siebert, Sheelagh Frame, Arthur G. Pratt, Deborah D. Stocken, Miranda Morton, Amy Cranston, Michael Cole, Christopher D. Buckley, Andrew FilerAbstract:INTRODUCTION Targeted biologic therapies demonstrate similar efficacies in rheumatoid arthritis despite distinct mechanisms of action. They also exhibit a ceiling effect, with 10% to 20% of patients achieving remission in clinical trials. None of these therapies target synovial fibroblasts, which drive and maintain synovitis. Seliciclib (R-roscovitine) is an orally available cyclin-dependent kinase inhibitor that suppresses fibroblast proliferation, and is efficacious in preclinical arthritis models. We aim to determine the toxicity and preliminary efficacy of Seliciclib in combination with biologic therapies, to inform its potential as an adjunctive therapy in rheumatoid arthritis. METHODS AND ANALYSIS TRAFIC is a non-commercial, multi-center, rolling phase Ib/IIa trial investigating the safety, tolerability, and efficacy of Seliciclib in patients with moderate to severe rheumatoid arthritis receiving biologic therapies. All participants receive Seliciclib with no control arm. The primary objective of part 1 (phase Ib) is to determine the maximum tolerated dose and safety of Seliciclib over 4 weeks of dosing. Part 1 uses a restricted 1-stage Bayesian continual reassessment method based on a target dose-limiting toxicity probability of 35%. Part 2 (phase IIa) assesses the potential efficacy of Seliciclib, and is designed as a single arm, single stage early phase trial based on a Fleming-A'Hern design using the maximum tolerated dose recommended from part 1. The primary response outcome after 12 weeks of therapy is a composite of clinical, histological and magnetic resonance imaging scores. Secondary outcomes include adverse events, pharmacodynamic and pharmacokinetic parameters, autoantibodies, and fatigue. ETHICS AND DISSEMINATION The study has been reviewed and approved by the North East - Tyne & Wear South Research Ethics Committee (reference 14/NE/1075) and the Medicines and Healthcare Products Regulatory Agency (MHRA), United Kingdom. Results will be disseminated through publication in relevant peer-reviewed journals and presentation at national and international conferences. TRIALS REGISTRATION ISRCTN, ISRCTN36667085. Registered on September 26, 2014; http://www.isrctn.com/ISRCTN36667085Current protocol version: Protocol version 11.0 (March 21, 2019).
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ab0356 targeting the rheumatoid arthritis synovial fibroblast via cyclin dependent kinase inhibition trafic a phase 1b study to determine the maximum tolerated dose of Seliciclib for repurposing in rheumatoid arthritis
Annals of the Rheumatic Diseases, 2020Co-Authors: Arthur G. Pratt, Stefan Siebert, Deborah D. Stocken, Miranda Morton, Amy Cranston, Michael Cole, Stephen Kelly, J. Walker, Muddassir Shaikh, Sheelagh FrameAbstract:Background: Current rheumatoid arthritis (RA) therapeutics target immune inflammation and are subject to ceiling effects, with non-response observed in a third of recipients together with low remission rates. Synovial fibroblasts (SFs) are stromal cells not yet targeted in RA, whose hyperplastic and proliferative properties drive inflammation and tissue destruction. Seliciclib (R-roscovitine) is an orally available cyclin-dependent kinase (CDK) inhibitor that suppresses SF proliferation and ameliorates inflammatory arthritis in rodents. Objectives: To determine the maximum tolerated dose (MTD) of Seliciclib in patients with active RA despite anti-TNF, with or without background conventional disease modifying anti-rheumatic drugs (cDMARDs). Safety and pharmacokinetics (PK) were also evaluated. Methods: A restricted, one-stage Bayesian continual reassessment method (CRM) determined MTD based on a target dose-limiting toxicity (DLT) probability of 35%. RA patients (DAS28 ≥3.2) were recruited sequentially to cohorts of 3 subjects each. Cohort 1 received 400mg Seliciclib daily for 4 consecutive days each week for 4 weeks, added to existing therapy. Each subsequent cohort received a dose determined by the toxicity-based CRM algorithm, calculated upon conclusion of the previous cohort. Safety was assessed through adverse event (AE) monitoring. Associations with relevant PK parameters were sought. Results: 15 anti-TNF recipients were enrolled, 10 of whom were also taking cDMARDs (median DAS28 4.9). Application of the CRM algorithm prompted one dose increment during the study (to 600mg for cohort 2), but reversion to 400mg for subsequent cohorts (Figure 1A). After treatment of 5 cohorts, 400mg was determined the MTD, with a DLT probability of 0.35 (CI 0.18-0.52; Figure 1B). 6 patients experienced DLTs, of which two were classified as serious AEs (SAEs) in keeping with the safety profile of Seliciclib; these are summarised in Table 1. Of 43/65 total AEs reported at any dose that did not contribute to a DLT, 26 were possibly, probably or definitely related to Seliciclib; 19 of these 26 were mild, 7 moderate and none severe. The most frequent AE was mild nausea. No relationship of safety and/or tolerability with concomitant cDMARD use or PK was seen. Conclusion: The MTD of Seliciclib has been defined for RA. No unexpected safety concerns were identified to preclude ongoing evaluation in patients, which focuses on clinical, radiological and biological indicators of efficacy. Disclosure of Interests: Arthur Pratt Grant/research support from: Pfizer, GlaxoSmithKlein, Stefan Siebert Grant/research support from: BMS, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB, Consultant of: AbbVie, Boehringer Ingelheim, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Celgene, Janssen, Novartis, Michael Cole: None declared, Deborah Stocken: None declared, Stephen Kelly: None declared, Muddassir Shaikh: None declared, Amy Cranston: None declared, Miranda Morton: None declared, Jennifer Walker: None declared, Sheelagh Frame Employee of: Cyclacel Ltd., Wan-fai Ng: None declared, Chris Buckley Consultant of: Janssen, Pfizer, GSK, Galapagos, Gillead, Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Andrew Filer: None declared, John D Isaacs Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck, Pfizer, Roche
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Phase I study of sequential sapacitabine and Seliciclib in patients with advanced solid tumors.
Journal of Clinical Oncology, 2012Co-Authors: Geoffrey I. Shapiro, Sheelagh Frame, Sara M. Tolaney, James M. Cleary, Leena Gandhi, Eunice L. Kwak, Jeffrey W. Clark, Andrew Wolanski, Scott J. Rodig, Judy ChiaoAbstract:3053 Background: Sapacitabine is an orally administered nucleoside analogue; the active metabolite CNDAC generates ss DNA breaks that are converted to ds DNA breaks (DSB) during subsequent replication, resulting in cell death if unrepaired. CNDAC-induced DSB repair is dependent on homologous recombination (HR). Seliciclib is a potent orally bioavailable inhibitor of CDK2, 7 and 9, and sensitizes cells to CNDAC by decreasing DSB repair via compromise of HR protein activation and transcriptional inhibition of HR components. This phase I study evaluates sequential sapacitabine and Seliciclib. Methods: Dose escalation was conducted in patients with incurable solid tumors and adequate organ function with sapacitabine b.i.d. x 7 consecutive days (d1-7), Seliciclib b.i.d. x 3 consecutive days (d8-10) followed by 11 days of rest. At least 3 patients were evaluated per dose level. MTD was the highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained...
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phase i study of sequential sapacitabine and Seliciclib in patients with advanced solid tumors
Journal of Clinical Oncology, 2012Co-Authors: Geoffrey I. Shapiro, Sheelagh Frame, Sara M. Tolaney, James M. Cleary, Leena Gandhi, Eunice L. Kwak, Jeffrey W. Clark, Andrew Wolanski, Scott J. Rodig, Judy H. ChiaoAbstract:3053 Background: Sapacitabine is an orally administered nucleoside analogue; the active metabolite CNDAC generates ss DNA breaks that are converted to ds DNA breaks (DSB) during subsequent replicat...
Y Shen - One of the best experts on this subject based on the ideXlab platform.
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‘Seed’ analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-X_L inhibitor ABT-737
Oncogene, 2007Co-Authors: X Lin, S Morgan-lappe, X Huang, D M Zakula, L A Vernetti, S W Fesik, Y ShenAbstract:ABT-737 is a subnanomolar inhibitor of the antiapoptotic proteins Bcl-2, Bcl-X_L and Bcl-w. Although ABT-737 triggers extensive cell death in many small-cell lung carcinoma (SCLC) cell lines, some of the SCLC cell lines and the majority of the cancer cell lines derived from other solid tumors were found to be resistant to ABT-737. To better understand the mechanism of resistance to ABT-737, we screened a short interfering RNA library consisting of short interfering RNA against 4000 ‘druggable’ targets in an SCLC-derived cell line, NCI-H196. By comparing the knockdowns with phenotypes, all of the three top ‘hits’ from the screen were found to result from off-target gene silencing. Interestingly, the three off-target siRNAs were found to knock down an antiapoptotic Bcl-2 family protein Mcl-1 owing to the complementation between their seed regions with the 3′ untranslated region (3′ UTR) of Mcl-1. Furthermore, reducing the level of Mcl-1 using siRNAs or the small-molecule compounds Bay43-9006 and Seliciclib was sufficient to overcome the resistance to ABT-737 in the resistant SCLC cell line and cancer cell lines derived from other solid tumors. These results provide further evidence that Mcl-1 is the major factor that causes resistance to ABT-737 in cancer cells derived from diverse solid tumors, and the combination of Mcl-1 downregulating agents with ABT-737 could be potent therapeutic regimens for patient with ABT-737-resistant SCLC and many other types of solid tumors.
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“Seed” analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small molecule Bcl-2/Bcl-XL inhibitor, ABT-737
Cancer Research, 2007Co-Authors: X Lin, S Morgan-lappe, X Huang, D M Zakula, L A Vernetti, S W Fesik, Y ShenAbstract:5160 ABT-737 is a subnanomolar inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-XL, and Bcl-w. Although ABT-737 triggers extensive cell death in many small-cell lung carcinoma (SCLC) cell lines, some of the SCLC cell lines and the majority of cancer cell lines derived from other solid tumors were found to be resistant to ABT-737. To better understand the mechanism of resistance to ABT-737, we screened an siRNA library consisting of siRNAs against 4000 “druggable” targets in a SCLC-derived cell line, NCI-H196. By comparing the knockdowns with phenotypes, all of the three top “hits” from the screen were found to result from off-target gene silencing. Interestingly, the three off-target siRNAs were found to knockdown an anti-apoptotic Bcl-2 family protein Mcl-1 due to the complementation between their seed regions with the 3’ UTR of Mcl-1. Furthermore, reducing the level of Mcl-1 using siRNAs or the small molecule compounds Bay43-9006 and Seliciclib was sufficient to overcome the resistance to ABT-737 in the resistant SCLC cell line and cancer cell lines derived from other solid tumors. These results provide further evidence that Mcl-1 is the major factor that causes resistance to ABT-737 in cancer cells derived from diverse solid tumors, and the combination of Mcl-1 down-regulating agents with ABT-737 could be potent therapeutic regimens for patient with ABT-737-resistant SCLC and many other types of solid tumors.
Helen M. Coley - One of the best experts on this subject based on the ideXlab platform.
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the cyclin dependent kinase inhibitor p57 kip2 is epigenetically regulated in carboplatin resistance and results in collateral sensitivity to the cdk inhibitor Seliciclib in ovarian cancer
British Journal of Cancer, 2012Co-Authors: Helen M. Coley, Nur Arnida Mohammed Safuwan, Pritlata Chivers, E Papacharalbous, T Giannopoulos, K Madhuri, D P Lovell, Simon Butlermanuel, Tim CrookAbstract:Carboplatin remains a first-line agent in the management of epithelial ovarian cancer (EOC). Unfortunately, platinum-resistant disease ultimately occurs in most patients. Using a novel EOC cell line with acquired resistance to carboplatin: PEO1CarbR, genome-wide micro-array profiling identified the cyclin-dependent kinase inhibitor p57(Kip2) as specifically downregulated in carboplatin resistance. Presently, we describe confirmation of these preliminary data with a variety of approaches.
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The cyclin-dependent kinase inhibitor p57(Kip2) is epigenetically regulated in carboplatin resistance and results in collateral sensitivity to the CDK inhibitor Seliciclib in ovarian cancer.
British Journal of Cancer, 2012Co-Authors: Helen M. Coley, Nur Arnida Mohammed Safuwan, Pritlata Chivers, E Papacharalbous, T Giannopoulos, Simon Butler-manuel, K Madhuri, D P Lovell, Tim CrookAbstract:The cyclin-dependent kinase inhibitor p57 Kip2 is epigenetically regulated in carboplatin resistance and results in collateral sensitivity to the CDK inhibitor Seliciclib in ovarian cancer
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The effects of the CDK inhibitor Seliciclib alone or in combination with cisplatin in human uterine sarcoma cell lines.
Gynecologic Oncology, 2007Co-Authors: Helen M. Coley, Christine Shotton, Maria I. Kokkinos, Hilary ThomasAbstract:Abstract Objectives. Inhibition of cyclin-dependent-kinases (CDKs) represents an interesting approach in cancer therapy. We have explored this in cell lines of human uterine sarcoma-tumours associated with poor survival, chemo-unresponsiveness and deregulation of cell cycle components. We studied the effects of the CDK inhibitor Seliciclib (CYC202, R-roscovitine) when used alone or in combination with cisplatin. Methods. Cell lines used: SK-UT-1, SK-UT-1b and SK-LMS-1, the cytotoxicity of Seliciclib and cisplatin was measured by the MTT assay. In combination with cisplatin the effects of Seliciclib were examined by isobologram analysis. CDK2 levels were examined at mRNA and protein level by immunoblotting and PCR. We also looked at the effects of Seliciclib on p53-dependent response of cells to Seliciclib using immunoblotting. The effects of combination treatment were analysed using annexin V and PI staining by flow cytometric analysis. Results. IC 50 values for Seliciclib were 10.5, 7.1 and 25.7 μM, for SK-UT-1, SK-UT-1b and SK-LMS-1 respectively, P53 in the SK-UT-1b (wild-type) and SK-LMS-1 lines (mutant) showed a wild-type response with induction seen with Seliciclib treatment for 24 and 48 h. Seliciclib caused a decrease in CDK2 mRNA and protein over 72 h. A combination of cisplatin and Seliciclib was synergistic in all three cell lines. Effects of combination treatment were an enhancement in apoptosis as judged by the emergence of a sub-G 1 population in cell cycle analysis and a sub-G 1 population with PI staining. Conclusions. Our data demonstrate the effectiveness of Seliciclib as a single agent and when used in combination with cisplatin where the effects are synergistic.
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Seliciclib (CYC202; r-Roscovitine) in Combination with Cytotoxic Agents in Human Uterine Sarcoma Cell Lines
Anticancer research, 2007Co-Authors: Helen M. Coley, Christine Shotton, Hilary ThomasAbstract:Background: Inhibition of cyclin-dependent kinases (CDKs) has recently emerged as an interesting approach to treat human malignancies. This was explored in human leiomyo- sarcoma (LMS) lines, which represent a tumour associated with poor survival, chemo-unresponsiveness and deregulation of cell cycle components. Materials and Methods: Using isobologram analysis with MTT chemosensitivity testing, the effects of the CDK inhibitor Seliciclib (CYC202, R-roscovitine) when used alone or in combination with paclitaxel was studied in uterine cancer cell lines. Apoptotic endpoints were also examined via Annexin V assay using flow cytometry and Western blotting. Results: Overall Seliciclib combined with paclitaxel proved synergistic for all cell lines. This was concomitant with an enhanced apoptotic effect and downregulation of the IAP survivin. Conclusion: Our data support the use of Seliciclib as part of combination therapy for uterine cancer. Human uterine sarcomas, including leiomyosarcoma (LMS) and mixed mesodermal tumours (MMT), are amongst the most chemorefractory types of cancers with high rates of local recurrence and distant metastasis. For example, for patients with uterine LMS the 5-year survival rate is 15-25% (1). Amongst the chemotherapeutic agents with reported activity in uterine sarcomas, taxanes and ifosfamide have been used as combination therapy (2, 3), although response rates overall are disappointingly low. Thus, there is an urgent need for the introduction of new therapies for uterine sarcomas. Deregulated cyclins and cyclin-dependent kinases (CDK) conferring a selective growth advantage is a common feature of human cancer, including LMS (4). These observations have formed the rationale for large drug development programs that have been designed to target the cell cycle as an approach to treat cancer. Seliciclib (CYC202), the r-enantiomer of the cell cycle inhibitory agent roscovitine has been developed as a potent CDK2 inhibitor and is currently in phase II clinical trials. Preclinical studies involving other CDK inhibitors, such as flavopiridol have demonstrated their interaction with a number of different cytotoxic agents in a synergistic manner (5). We have explored this approach by examining the effects of Seliciclib combined with paclitaxel in three human uterine sarcoma cell line models in terms of any synergy and effects on apoptosis.
Wen Son Hsieh - One of the best experts on this subject based on the ideXlab platform.
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Cancer Therapy: Clinical Pharmacodynamic Effects of Seliciclib, an Orally Administered Cell Cycle Modulator, in Undifferentiated Nasopharyngeal Cancer
2010Co-Authors: Wen Son Hsieh, Simon Green, Judy Chiao, B.-k. Peh, Difeng Dong, Donny Soh, Chun-ying Cui, Ross Soo, Thomas Loh, Yoke-fong LaiAbstract:Purpose: Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature of undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects of Seliciclib, a cyclin-dependent kinase (CDK) inhibitor, were studied in patients with nasopharyngeal carcinoma. Experimental Design: Patients with treatment-naI«ve locally advanced nasopharyngeal carcinoma received Seliciclib at 800 mg or 400 mg twice daily on days1 to 3 and 8 to12. Paired tumor samples obtained at baseline and on day 13 were assessed by light microscopy, immunohistochemistry, and transcriptional profiling using real-time PCR low-density array consisting of a panel of 380 genes related to cell cycle inhibition, apoptosis, signal transduction, and cell proliferation. Results: At 800 mg bd, one patient experienced grade 3 liver toxicity and another had grade 2 vomiting; no significant toxicities were experienced in 13 patients treated at 400 mg bd. Seven of fourteen evaluable patients had clinical evidence of tumor reduction. Some of these responses were associated with increased tumor apoptosis, necrosis, and decreases in plasma EBV DNA posttreatment. Reduced protein expression of Mcl-1, cyclin D1, phosphorylated retinoblastom
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Pharmacodynamic Effects of Seliciclib, an Orally Administered Cell Cycle Modulator, in Undifferentiated Nasopharyngeal Cancer
Clinical Cancer Research, 2009Co-Authors: Wen Son Hsieh, Simon Green, Judy H. Chiao, B.-k. Peh, Ross A. Soo, T. Loh, Difeng Dong, Donny Soh, Limsoon Wong, Chun-ying CuiAbstract:Purpose: Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature of undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects of Seliciclib, a cyclin-dependent kinase (CDK) inhibitor, were studied in patients with nasopharyngeal carcinoma. Experimental Design: Patients with treatment-naive locally advanced nasopharyngeal carcinoma received Seliciclib at 800 mg or 400 mg twice daily on days 1 to 3 and 8 to 12. Paired tumor samples obtained at baseline and on day 13 were assessed by light microscopy, immunohistochemistry, and transcriptional profiling using real-time PCR low-density array consisting of a panel of 380 genes related to cell cycle inhibition, apoptosis, signal transduction, and cell proliferation. Results: At 800 mg bd, one patient experienced grade 3 liver toxicity and another had grade 2 vomiting; no significant toxicities were experienced in 13 patients treated at 400 mg bd. Seven of fourteen evaluable patients had clinical evidence of tumor reduction. Some of these responses were associated with increased tumor apoptosis, necrosis, and decreases in plasma EBV DNA posttreatment. Reduced protein expression of Mcl-1, cyclin D1, phosphorylated retinoblastoma protein pRB (T821), and significant transcriptional down-regulation of genes related to cellular proliferation and survival were shown in some patients posttreatment, indicative of cell cycle modulation by Seliciclib, more specifically inhibition of cdk2/cyclin E, cdk7/cyclin H, and cdk9/cyclin T. Conclusions: Brief treatment with this regimen of Seliciclib in patients with nasopharyngeal carcinoma is tolerable at 400 mg bd and associated with tumor pharmacodynamic changes consistent with cdk inhibition, and warrants further efficacy studies in this tumor.
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Seliciclib r roscovitine induces apoptosis in undifferentiated nasopharyngeal cancer npc in vivo and in vitro
Journal of Clinical Oncology, 2005Co-Authors: Boon Cher Goh, Simon Green, B.-k. Peh, C.-y. Cui, Ross A. Soo, T. Loh, Wen Son Hsieh, Y.-f. Lai, Manuel Saltotellez, B. MowAbstract:3145 Cyclin dependent kinase (CDK) inhibition mimics tumor suppressor protein function and induces cell cycle arrest and apoptosis in cancer cell lines. Seliciclib, an orally administered inhibitor...
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Seliciclib (R-roscovitine) induces apoptosis in undifferentiated nasopharyngeal cancer (NPC) in vivo and in vitro
Journal of Clinical Oncology, 2005Co-Authors: Boon Cher Goh, Simon Green, B.-k. Peh, C.-y. Cui, Ross A. Soo, T. Loh, Wen Son Hsieh, Y.-f. Lai, Manuel Salto-tellez, B. MowAbstract:3145 Cyclin dependent kinase (CDK) inhibition mimics tumor suppressor protein function and induces cell cycle arrest and apoptosis in cancer cell lines. Seliciclib, an orally administered inhibitor of CDKs (including 2, 7 and 9), induces apoptosis in several human tumor cell lines through inhibition of anti-apoptotic proteins like Mcl-1, survivin and XIAP. It may also block the cell cycle via inhibition of Rb phosphorylation. Cell cycle dysregulation, with deactivation of p27 and p16 are frequently found in undifferentiated NPC. Loss of p16 leads to Rb phosphorylation and uncontrolled proliferation. Therefore, we sought to evaluate the cellular and molecular effects of Seliciclib in NPC in vitro and in vivo. 4 undifferentiated NPC cell lines (CEN-1, CNE-2, HK-1, HONE-1) were exposed to varying concentrations of Seliciclib for up to 72 hours and subjected to MTT assay, western blot, and flow cytometric cell cycle analysis. Patients with locally advanced NPC were treated with Seliciclib: 800mg bid (level 1)...