DOCSLIB.ORG

Proquest Dissertations

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Proquest Dissertations INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy subm itted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6” x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. Bell & Howell Information and Learning 300 North Zeeb Road, Ann Arbor, Ml 48106-1346 USA 800-521-0600 UMI* CHARACTERIZATION OF CELL LINES RESISTANT TO TOPOISOMERASE TARGETING DRUGS AND MECHANISTIC STUDIES OF QUBVOXALINE SOLED TUMOR DRUGS - A NEW CHEMICAL CLASS OF TOPOISOMERASE U POISONS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Hanlin Gao, M.S. ★ ★ ★ ★ ★ The Ohio State University 2001 Dissertation. Committee: Approved by Dr. Robert Snapka, Advisor Dr. Steven D’Ambrosio Dr. John Hughes Advisor Dr. William Lafiise Department of Molecular Virology, Immunology and Medical Genetics UMI Number; 9999391 UMI UMI Microform 9999391 Copyright 2001 by Bell & Howell Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. Beil & Howell Information and Leaming Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT Topoisomerases are ubiquitous enzymes and play critical roles in nearly all aspects of DNA metabolism including replication, transcription, and chromosome segregation. Topoisomerases are common targets for important antineoplastic agents. Drug resistance is one of the causes o f failure of chemotherapy. To improve our understanding of the mechanism of the drug resistance to topoisomerase-targeted drugs, we selected and characterized four resistant cell lines. In the camptothecin (a topoisomerase I poison) resistant 10cRS22 cells, topoisomerase I was greatly decreased. Topoisomerase Ha is dramatically decreased and topoisomerase Up is undetectable in AMSA-r cells, the m-AMSA (a topoisomerase II poison) resistant cells These drug resistant cell lines are derived from African green monkey kidney CV-1 cells, which are a permissive host for simian virus 40 (SV40). Using these drug resistant cell lines and the SV40 DNA replication system, we have successfully identified topoisomerase lip as the cellular target of XK469, a solid tumor selective drug. Several lines of evidence showed that XK469 is a highly specific topoisomerase np poison. No specific topoisomerase Hp poison has been described previously. The unique solid tumor specificity of XK469 may be related to the pattern of topoisomerase Iip regulation during the cell cycle. We also showed that topoisomerase np knockout cells are more resistant to XK469 than topoisomerase Up normal cells. This argues strongly that topoisomerase Up is a cytotoxic target and is the major cytotoxic target of XK469. Chloroquinoxaline sulfonamide (chlorosulfaquinoxaline, CQS, NSC 339004) is active against murine and human solid tumors. Based on its structural similarity to the topoisomerase Iip-specific drug, XK469, CQS was tested and found to be both a topoisomerase Ha and a topoisomerase lip poison. Topoisomerase II poisoning by CQS is essentially undetectable in assays using the common protein dénaturant sodium dodecyl sulfate, but easily detectable with strong chaotropic protein dénaturants. The finding that detection of topoisomerase poisoning can be so dependent on the protein dénaturant used in the assay has implications for drug discovery efforts and for our understanding of topoisomerase poisons. Topoisomerase poisons stimulate DNA cleavage in a sequence-selective manner. We identified the sequence selectivity of XK469 and CQS by DNA cleavage assay, which is considered direct evidence for a topoisomerase poison. By using this assay, we also showed that ICRF-193, that was believed to be a topoisomerase II catalytic inhibitor, is also a topoisomerase II poison with selectivity for the topoisomerase np isozyme with the requirement for choatropic protein dénaturants in the topoisomerase poison assays. Ill Dedicated to my wife Bing Mu IV ACKNOWLEDGMENTS I would like to thank my advisor. Dr. Robert M. Snapka, for his intellectual support, encouragement, and guidance along with deep sensitivity, generosity and patience. 1 would also like to thank to my committee members. Dr. Steven D’Ambrosio, Dr. John Hughes and Dr. William Lafuse for their very helpful suggestions and comments. I am grateful to Mrs. Edie Yamasaki for her valuable help, encouragement and a lot more in both scientific and personal matters. I also want to thank to Dr. Kuan- chun Huang (Alex), Dr. Sun Ho Woo, Dr. Qianzheng Zhu and Dr. Shujun Liu for their direct or indirect contribution to these studies and valuable discussion. Thanks are also expressed to the members of Radiobiology Division including Ruth D’Ambrosio, Dr. Altaf Wani, Gulzar Wani, Debbi Marcus and Manzoor Wani. I thank Dr. Kenneth Chan for providing XK469 and CQS, Dr Mark Muller and Chris Furbee (TopoGen) for kDNA, topoisomerase I, lia enzymes and antibodies. Dr. Linus Shen (Abbott Laboratories, Abbott Park, IL) for topoisomerase Ha, Dr. Caroline Austin (University of Newcastle, UK) and Dr. Armi H. Andersen ( University of Aarhus, Denmark) for topoisomerase 11(3, and Dr Daniel Sullivan (University of South Florida, Tampa) for topoisomerase Up antibody. Finally, I would like to thank my wife, Bing Mu, for her understanding and support. I also would like to thank my parents and parents-in-law for their support. Without all their helps I could not finish this degree at the Ohio State University. VI VITA September 3, 1966 Bom. — Heilongjiang, China 1990 B.S., Medicine Neimenggumeng Medical University, China 1993 M.S., Immunology Beijing Medical University 1993-1996 Researcher and lecturer Department of Biochemistry and Molecular Biology Beijing Medical University, China 1996-2000 Graduate student Molecular Virology, immunology and Medical Genetics The Ohio State University PUBLICATIONS 1. Hanlin Gao, Huang Kuan-Chun, Edith F. Yamasaki Kenenth K. Chan ,Lubna Chohan, Robert M. Snapka. XK469, A Selective Topoisomerase II p Poison. Proc. Natl. Acad. Soi. U.S.A. 1999;96:12168-73. 2. Hanlin Gao, Edith F. Yamasaki, Kenneth K. Chan, Linus Sen and Robert M. Snapka. Chloroquinoxaline Sulfonamide is a Topoisomerase H cc/p Poison. Cancer Research 2000; 60: 5937-5940 vu FIELDS OF STUDY Major Field: Molecular Virology, Immunology and Medical Genetics. Minor Field: Biochemistry V lll TABLE OF CONTENTS Page Abstract............................................................................................................................. ii Dedication .........................................................................................................................iv Acknowledgments ............................................................................................................v Vita.................................................................................................................................... vi List of Tables ....................................................................................................................xi List of Figures .................................................................................................................. xi Chapters: 1. Introduction 1.1 Topoisomerase .................................................................................................. 1 1.2 Topoisomerase poisons and inhibitors...........................................................11 1.3 Resistance to topoisomerase-targeted drugs ................................................. 15 1.4 Simian virus 40 (SV40), a model system for mechanistic study of topoisomerase targeted drugs ......................................................... 18 2. Characterization of cell lines resistant to camptothecin, m-AMSA and proflavine ........................................................................................................... 26 IX 2.1 Introduction .................................................................................................... 26 2.2 Materials and methods ...................................................................................29 2.3 Results............................................................................................................ 42 2.4 discussion ........................................................................................................48 3. XK469, a novel topoisomerase np poison .................................................................99
Load more

Recommended publications
  • Selective DNA-Pkcs Inhibition Extends the Therapeutic Index of Localized Radiotherapy and Chemotherapy
    Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy Catherine E. Willoughby, … , Anderson J. Ryan, Stephen R. Wedge J Clin Invest. 2019. https://doi.org/10.1172/JCI127483. Research Article Oncology Therapeutics Graphical abstract Find the latest version: https://jci.me/127483/pdf The Journal of Clinical Investigation RESEARCH ARTICLE Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy Catherine E. Willoughby,1 Yanyan Jiang,2 Huw D. Thomas,1 Elaine Willmore,1 Suzanne Kyle,1 Anita Wittner,1 Nicole Phillips,1 Yan Zhao,1 Susan J. Tudhope,1 Lisa Prendergast,1 Gesa Junge,1 Luiza Madia Lourenco,2 M. Raymond V. Finlay,3 Paul Turner,3 Joanne M. Munck,4 Roger J. Griffin,5 Tommy Rennison,5 James Pickles,5 Celine Cano,5 David R. Newell,1 Helen L. Reeves,1,6 Anderson J. Ryan,2 and Stephen R. Wedge1 1Cancer Research UK Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. 2Cancer Research UK and UK Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom. 3Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom. 4Astex Pharmaceuticals, Cambridge, United Kingdom. 5Cancer Research UK Newcastle Drug Discovery Unit, Chemistry, School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom. 6Hepatopancreatobiliary Multidisciplinary Team, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom. Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors.
    [Show full text]
  • Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies
    Review Biomol Ther 19(4), 398-410 (2011) Epstein-Barr Virus-Associated Classical Hodgkin Lymphoma and Its Therapeutic Strategies Im-Soon Lee* Department of Biological Sciences and Center for Biotechnology Research in UBITA (CBRU), Konkuk University, Seoul 143-701, Republic of Korea Abstract Over the past few decades, our understanding of the epidemiology and immunopathogenesis of Hodgkin lymphoma (HL) has made enormous advances. Consequently, the treatment of HL has changed signifi cantly, rendering this disease of the most cur- able human cancers. To date, about 80% of patients achieve long-term disease-free survival. However, therapeutic challenges still remain, particularly regarding the salvage strategies for relapsed and refractory disease, which need further identifi cation of better prognostic markers and novel therapeutic schemes. Although the precise molecular mechanism by which Epstein-Barr virus (EBV) contributes to the generation of malignant cells present in HL still remains unknown, current increasing data on the role of EBV in the pathobiology of HL have encouraged people to start developing novel and specifi c therapeutic strategies for EBV- associated HL. This review will provide an overview of therapeutic approaches for acute EBV infection and the classical form of HL (cHL), especially focusing on EBV-associated HL cases. Key Words: Classical Hodgkin lymphoma, EBV, Hodgkin and Reed-Sternberg cells INTRODUCTION and Cole, 1980), and EBV DNA/RNA can be detected in HL tissues (Brink et al., 1997), suggesting that as a primary event Lymphoma is a type of cancer involving cells of the im- in the development of this disease, EBV infection may play a mune system, and has two major categories: Hodgkin lym- very crucial role in the pathogenesis of HL.
    [Show full text]
  • Anti-Neoplastic Effects of Topoisomerase Inhibitors in Canine Mammary Carcinoma, Melanoma, and Osteosarcoma Cell Title Lines
    Anti-neoplastic effects of topoisomerase inhibitors in canine mammary carcinoma, melanoma, and osteosarcoma cell Title lines Ong, Siew Mei; Yamamoto, Hiroki; Saeki, Kohei; Tanaka, Yuiko; Yoshitake, Ryohei; Nishimura, Ryohei; Nakagawa, Author(s) Takayuki Citation Japanese Journal of Veterinary Research, 65(1), 17-28 Issue Date 2017-02 DOI 10.14943/jjvr.65.1.17 Doc URL http://hdl.handle.net/2115/64788 Type bulletin (article) File Information 65-1_017-028.pdf Instructions for use Hokkaido University Collection of Scholarly and Academic Papers : HUSCAP Japanese Journal of Veterinary Research 65(1): 17-28, 2017 REGULAR PAPER Experimental Research Anti-neoplastic effects of topoisomerase inhibitors in canine mammary carcinoma, melanoma, and osteosarcoma cell lines Siew Mei Ong1,†), Hiroki Yamamoto1,†), Kohei Saeki1), Yuiko Tanaka1), Ryohei Yoshitake1), Ryohei Nishimura1) and Takayuki Nakagawa1,＊) 1) Laboratory of Veterinary Surgery, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan Received for publication, November 29, 2016; accepted, December 27, 2016 Abstract Numerous topoisomerase inhibitors with proven efficacy have been used extensively to treat various human neoplasms. However, among these, only doxorubicin has been used and studied extensively in veterinary oncology. The current study was performed to evaluate the responsiveness of canine osteosarcoma (cOSA), mammary gland tumour (cMGT), and malignant melanoma (cMM) cell lines to several topoisomerase inhibitors. In addition, the correlation between the sensitivity to treatment and multi-drug resistant (MDR) factors was investigated. cOSA cell lines exhibited higher sensitivity than cMGT and cMM cell lines to all the topoisomerase inhibitors tested in vitro; this was associated with the levels of multi-drug resistance protein 1 (MDR1) gene expression in the cOSA cell lines.
    [Show full text]
  • CLINICAL and PHARMACOLOGICAL STUDIES on the TOPOISOMERASE I INHIBITOR TOPOTECAN Cover Design: G.L.M
    CLINICAL AND PHARMACOLOGICAL STUDIES ON THE TOPOISOMERASE I INHIBITOR TOPOTECAN Cover design: G.L.M. Obbens Lay-out: A.A.C. Treuren-den Braber Printed by: Copynomie Erasmus Multicopy Facility Management B.V. Burg. Oudlaan 50 3062 PA Rotterdam The Netherlands phone: 010-4082898 fax: 010-4528183 ISBN: 9090091718 Copyright: G.J. Creemers. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanically, by photocopying, by recording or otherwise without the prior permission of the author. Clinical and pharmacological studies on the topoisomerase I inhibitor topotecan Klinisch en farmacologisch onderzoek met de topoisomerase I rammer topotecan. PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof. dr. P.W.C. Akkermans M.A. en volgens besluit van het college voor promoties. De open bare verdediging zal plaatsvinden op woensdag 13 maart 1996 om 13.45 uur door Gerardus Johannes Marie Creemers geboren te Eindhoven PROMOTIECOMMISSIE Promotor: Prof. dr. G. Stoter Copromotor: Dr. J. Verweij Overige leden: Prof. dr. D.O. Von Hoff Prof. dr. J.H. Beijnen Prof. dr. J.W. Oosterhuis Prof. dr. A. Hagenbeek "Aileen wat niet ophoudt pijn te doen, blijft in de herinnering" Contents Chapter 1 Introduction to the thesis. 1 Chapter 2 Review: The topoisomerase I inhibitors topotecan and irinotecan. 5 Cancer Treatment Reviews 1994: 20; 73·96. Chapter 3 Topotecan in colorectal cancer: A phase II study of the EORTe clinical trials group. 47 Annals of oncology 1995: 6; 844·846.
    [Show full text]
  • Differential Effects of the Poly (ADP-Ribose)Polymerase (PARP
    British Journal of Cancer (2001) 84(1), 106–112 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2000.1555, available online at http://www.idealibrary.com on http://www.bjcancer.com Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro KJ Bowman*, DR Newell, AH Calvert and NJ Curtin Cancer Research Unit, University of Newcastle upon Tyne Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK Summary The potent novel poly(ADP-ribose) polymerase (PARP) inhibitor, NU1025, enhances the cytotoxicity of DNA-methylating agents and ionizing radiation by inhibiting DNA repair. We report here an investigation of the role of PARP in the cellular responses to inhibitors of topoisomerase I and II using NU1025. The cytotoxicity of the topoisomerase I inhibitor, camptothecin, was increased 2.6-fold in L1210 cells by co-incubation with NU1025. Camptothecin-induced DNA strand breaks were also increased 2.5-fold by NU1025 and exposure to camptothecin-activated PARP. In contrast, NU1025 did not increase the DNA strand breakage or cytotoxicity caused by the topoisomerase II inhibitor etoposide. Exposure to etoposide did not activate PARP even at concentrations that caused significant levels of apoptosis. Taken together, these data suggest that potentiation of camptothecin cytotoxicity by NU1025 is a direct result of increased DNA strand breakage, and that activation of PARP by camptothecin-induced DNA damage contributes to its repair and consequently cell survival. However, in L1210 cells at least, it would appear that PARP is not involved in the cellular response to etoposide-mediated DNA damage.
    [Show full text]
  • Perspectiva New Perspectives on the Treatment Of
    New Perspectives on the Treatment of Differentiated Thyroid Cancer perspectiva ABSTRACT Even though differentiated thyroid carcinoma is a slow growing and usu- ally curable disease, recurrence occurs in 20–40% and cellular dedifferen- SABRINA MENDES COELHO tiation in up to 5% of cases. Conventional chemotherapy and radiotherapy DENISE PIRES DE CARVALHO have just a modest effect on advanced thyroid cancer. Therefore, dediffer- entiated thyroid cancer represents a therapeutic dilemma and a critical MÁRIO VAISMAN area of research. Targeted therapy, a new generation of anticancer treat- ment, is planned to interfere with a specific molecular target, typically a protein that is believed to have a critical role in tumor growth or progres- sion. Since many of the tumor-initiation events have already been identi- Serviço de Endocrinologia do fied in thyroid carcinogenesis, targeted therapy is a promising therapeutic Hospital Universitário Clementino tool for advanced thyroid cancer. Several new drugs are currently being Fraga Filho (SMC & MV) e Labo- tested in in vitro and in vivo studies and some of them are already being ratório de Fisiologia Endócrina used in clinical trials, like small molecule tyrosine kinase inhibitors. In this da Universidade Federal do Rio review, we discuss the bases of targeted therapies, the principal drugs de Janeiro (DPC), Rio de already tested and also options of redifferentiation therapy for thyroid car- Janeiro, RJ. cinoma. (Arq Bras Endocrinol Metab 2007;51/4:612-624) Keywords: Thyroid cancer; Redifferentiation therapy; Targeted therapy; Tyrosine kinase inhibitors RESUMO Novas Perspectivas no Tratamento do Carcinoma Diferenciado da Tireóide. Apesar de o carcinoma diferenciado da tireóide ser considerado uma doença de curso indolente e geralmente curável, recorrência tumoral ocorre em aproximadamente 20 a 40% e desdiferenciação celular, em até 5% dos casos.
    [Show full text]
  • Cancer Resistance to Treatment and Antiresistance Tools Offered By
    Casals et al. Cancer Nano (2017) 8:7 DOI 10.1186/s12645-017-0030-4 REVIEW Open Access Cancer resistance to treatment and antiresistance tools ofered by multimodal multifunctional nanoparticles Eudald Casals1†, Muriel F. Gusta1†, Macarena Cobaleda‑Siles1, Ana Garcia‑Sanz1 and Victor F. Puntes1,2,3* *Correspondence: [email protected] Abstract †Eudald Casals and Muriel F. Chemotherapeutic agents have limited efcacy and resistance to them limits today Gusta contributed equally to this work and will limit tomorrow our capabilities of cure. Resistance to treatment with antican‑ 1 Vall d’Hebron Research cer drugs results from a variety of factors including individual variations in patients and Institute (VHIR), Passeig somatic cell genetic diferences in tumours. In front of this, multimodality has appeared Vall d’Hebron 119‑129, 08035 Barcelona, Spain as a promising strategy to overcome resistance. In this context, the use of nanoparticle- Full list of author information based platforms enables many possibilities to address cancer resistance mechanisms. is available at the end of the Nanoparticles can act as carriers and substrates for diferent ligands and biologically article active molecules, antennas for imaging, thermal and radiotherapy and, at the same time, they can be efectors by themselves. This enables their use in multimodal thera‑ pies to overcome the wall of resistance where conventional medicine crash as ageing of the population advance. In this work, we review the cancer resistance mechanisms and the advantages of inorganic nanomaterials to enable multimodality against them. In addition, we comment on the need of a profound understanding of what happens to the nanoparticle-based platforms in the biological environment for those possibili‑ ties to become a reality.
    [Show full text]
  • De Novo Genome Assembly of Camptotheca Acuminata, a Natural Source of the Anti-Cancer Compound Camptothecin Dongyan Zhao1, John
    Manuscript Click here to download Manuscript Camptotheca_Ms_v15_GigaSci.docx 1 2 3 4 1 De novo genome assembly of Camptotheca acuminata, a natural source of the anti-cancer 5 6 7 2 compound camptothecin 8 9 10 3 Dongyan Zhao1, John P. Hamilton1, Gina M. Pham1, Emily Crisovan1, Krystle Wiegert-Rininger1, 11 12 13 4 Brieanne Vaillancourt1, Dean DellaPenna2, and C. Robin Buell1* 14 15 16 5 1Department of Plant Biology, Michigan State University, East Lansing, MI 48824 USA 17 18 19 20 6 2Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI 21 22 23 7 48824 USA 24 25 26 8 Email addresses: Dongyan Zhao <[email protected]>, John P. Hamilton <[email protected]>, 27 28 29 9 Gina M. Pham <[email protected]>, Emily Crisovan <[email protected]>, Krystle Wiegert- 30 31 10 Rininger <[email protected]>, Brieanne Vaillancourt <[email protected]>, Dean Dellapenna 32 33 34 11 <[email protected]>, C Robin Buell <[email protected]> 35 36 37 12 *Correspondence should be addressed to: C. Robin Buell, [email protected] 38 39 40 41 13 42 43 44 14 Manuscript type: Data note 45 46 47 48 15 49 50 51 16 Note: Reviewers can access the genome sequence and annotation using the following 52 53 54 17 temporary URL: http://datadryad.org/review?doi=doi:10.5061/dryad.nc8qr. 55 56 57 58 59 60 61 62 63 1 64 65 1 2 3 4 18 Abstract 5 6 7 8 19 Background: Camptotheca acuminata is one of a limited number of species that produce 9 10 20 camptothecin, a pentacyclic quinoline alkaloid with anti-cancer activity due to its ability to 11 12 13 21 inhibit DNA topoisomerase.
    [Show full text]
  • Chemical Biology of Natural Indolocarbazole Products: 30 Years Since the Discovery of Staurosporine
    The Journal of Antibiotics (2009) 62, 17–26 & 2009 Japan Antibiotics Research Association All rights reserved 0021-8820/09 $32.00 www.nature.com/ja REVIEW ARTICLE Chemical biology of natural indolocarbazole products: 30 years since the discovery of staurosporine Hirofumi Nakano and Satoshi O¯ mura Staurosporine was discovered at the Kitasato Institute in 1977 while screening for microbial alkaloids using chemical detection methods. It was during the same era that protein kinase C was discovered and oncogene v-src was shown to have protein kinase activity. Staurosporine was first isolated from a culture of Actinomyces that originated in a soil sample collected in Mizusawa City, Japan. Thereafter, indolocarbazole compounds have been isolated from a variety of organisms. The biosynthesis of staurosporine and related indolocarbazoles was finally elucidated during the past decade through genetic and biochemical studies. Subsequently, several novel indolocarbazoles have been produced using combinatorial biosynthesis. In 1986, 9 years since its discovery, staurosporine and related indolocarbazoles were shown to be nanomolar inhibitors of protein kinases. They can thus be viewed as forerunners of today’s crop of novel anticancer drugs. The finding led many pharmaceutical companies to search for selective protein kinase inhibitors by screening natural products and through chemical synthesis. In the 1990s, imatinib, a Bcr-Abl tyrosine kinase inhibitor, was synthesized and, following human clinical trials for chronic myelogenous leukemia, it was approved for use in the USA in 2001. In 1992, mammalian topoisomerases were shown to be targets for indolocarbazoles. This opened up new possibilities in that indolocarbazole compounds could selectively interact with ATP- binding sites of not only protein kinases but also other proteins that had slight differences in ATP-binding sites.
    [Show full text]
  • B Number Gene Name Mrna Intensity Mrna
    sample) total list predicted B number Gene name assignment mRNA present mRNA intensity Gene description Protein detected - Membrane protein membrane sample detected (total list) Proteins detected - Functional category # of tryptic peptides # of tryptic peptides # of tryptic peptides detected (membrane b0002 thrA 13624 P 39 P 18 P(m) 2 aspartokinase I, homoserine dehydrogenase I Metabolism of small molecules b0003 thrB 6781 P 9 P 3 0 homoserine kinase Metabolism of small molecules b0004 thrC 15039 P 18 P 10 0 threonine synthase Metabolism of small molecules b0008 talB 20561 P 20 P 13 0 transaldolase B Metabolism of small molecules chaperone Hsp70; DNA biosynthesis; autoregulated heat shock b0014 dnaK 13283 P 32 P 23 0 proteins Cell processes b0015 dnaJ 4492 P 13 P 4 P(m) 1 chaperone with DnaK; heat shock protein Cell processes b0029 lytB 1331 P 16 P 2 0 control of stringent response; involved in penicillin tolerance Global functions b0032 carA 9312 P 14 P 8 0 carbamoyl-phosphate synthetase, glutamine (small) subunit Metabolism of small molecules b0033 carB 7656 P 48 P 17 0 carbamoyl-phosphate synthase large subunit Metabolism of small molecules b0048 folA 1588 P 7 P 1 0 dihydrofolate reductase type I; trimethoprim resistance Metabolism of small molecules peptidyl-prolyl cis-trans isomerase (PPIase), involved in maturation of b0053 surA 3825 P 19 P 4 P(m) 1 GenProt outer membrane proteins (1st module) Cell processes b0054 imp 2737 P 42 P 5 P(m) 5 GenProt organic solvent tolerance Cell processes b0071 leuD 4770 P 10 P 9 0 isopropylmalate
    [Show full text]
  • The Influence of Cell Cycle Regulation on Chemotherapy
    International Journal of Molecular Sciences Review The Influence of Cell Cycle Regulation on Chemotherapy Ying Sun 1, Yang Liu 1, Xiaoli Ma 2 and Hao Hu 1,* 1 Institute of Biomedical Materials and Engineering, College of Materials Science and Engineering, Qingdao University, Qingdao 266071, China; [email protected] (Y.S.); [email protected] (Y.L.) 2 Qingdao Institute of Measurement Technology, Qingdao 266000, China; [email protected] * Correspondence: [email protected] Abstract: Cell cycle regulation is orchestrated by a complex network of interactions between proteins, enzymes, cytokines, and cell cycle signaling pathways, and is vital for cell proliferation, growth, and repair. The occurrence, development, and metastasis of tumors are closely related to the cell cycle. Cell cycle regulation can be synergistic with chemotherapy in two aspects: inhibition or promotion. The sensitivity of tumor cells to chemotherapeutic drugs can be improved with the cooperation of cell cycle regulation strategies. This review presented the mechanism of the commonly used chemotherapeutic drugs and the effect of the cell cycle on tumorigenesis and development, and the interaction between chemotherapy and cell cycle regulation in cancer treatment was briefly introduced. The current collaborative strategies of chemotherapy and cell cycle regulation are discussed in detail. Finally, we outline the challenges and perspectives about the improvement of combination strategies for cancer therapy. Keywords: chemotherapy; cell cycle regulation; drug delivery systems; combination chemotherapy; cancer therapy Citation: Sun, Y.; Liu, Y.; Ma, X.; Hu, H. The Influence of Cell Cycle Regulation on Chemotherapy. Int. J. 1. Introduction Mol. Sci. 2021, 22, 6923. https:// Chemotherapy is currently one of the main methods of tumor treatment [1].
    [Show full text]
  • Predicting Suitable Habitats of Camptotheca Acuminata Considering Both Climatic and Soil Variables
    Article Predicting Suitable Habitats of Camptotheca acuminata Considering Both Climatic and Soil Variables Lei Feng 1,2, Jiejie Sun 1,3, Yuanbao Shi 1,2, Guibin Wang 1,2,* and Tongli Wang 4,* 1 Co-Innovation Centre for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China; [email protected] (L.F.); [email protected] (J.S.); [email protected] (Y.S.) 2 College of Forestry, Nanjing Forestry University, Nanjing 210037, China 3 College of Biology and the Environment, Nanjing Forestry University, Nanjing 210037, China 4 Department of Forest and Conservation Sciences, Faculty of Forestry, University of British Columbia, Vancouver, BC V6T 1Z4, Canada * Correspondence: [email protected] (G.W.); [email protected] (T.W.); Tel.:+86-1377-052-1738 (G.W.); +1-604-822-1845 (T.W.) Received: 19 June 2020; Accepted: 14 August 2020; Published: 17 August 2020 Abstract: Camptotheca acuminata is considered a natural medicinal plant with antitumor activity. The assessment of climate change impact on its suitable habitats is important for cultivation and conservation. In this study, we applied a novel approach to build ecological niche models with both climate and soil variables while the confounding effects between the variables in the two categories were avoided. We found that the degree-days below zero and mean annual precipitation were the most important climatic factors, while the basic soil saturation, soil gravel volume percentage, and clay content were the main soil factors, determining the suitable habitats of C. acuminata. We found that suitable habitats of this species would moderately increase in future climates under both the RCP4.5 and RCP8.5 climate change scenarios for the 2020s, 2050s, and 2080s.
    [Show full text]