Current Protein & Peptide ScienceCurrent Protein & Peptide ScienceCurrent Protein & Peptide Science1389-20371875-5550Bentham Science64546510.2174/1389203724666230512144011Life SciencesResearch ArticleMechanism-based Suppression of Cancer by Targeting DNA-Replicating EnzymesAryaPreetiinfo@benthamscience.netMalhotraHiteshinfo@benthamscience.netChaudharyBenuinfo@benthamscience.netSarwaraAmritinfo@benthamscience.netGoyalRajatinfo@benthamscience.netWanChunpenginfo@benthamscience.netMishraDineshinfo@benthamscience.netGautamRupeshinfo@benthamscience.net, Guru Gobind Singh College of PharmacyMM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University)Jiangxi Key Laboratory for Postharvest Technology and Nondestructive Testing of Fruits & Vegetables, College of Agronomy, Jiangxi Agricultural University, Indore Institute of Pharmacy,Indore Institute of Pharmacy, Indore Institute of Pharmacy0101202425141111012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1389-2037/article/view/645465

The human genetic structure undergoes continuous wear and tear process due to the mere presence of extrinsic as well as intrinsic factors. In normal physiological cells, DNA damage initiates various checkpoints that may activate the repair system or induce apoptosis that helps maintain cellular integrity. While in cancerous cells, due to alterations in signaling pathways and defective checkpoints, there exists a marked deviation of error-free DNA repairing/synthesis. Currently, cancer therapy targeting the DNA damage response shows significant therapeutic potential by tailoring the therapy from non-specific to tumor-specific activity. Recently, numerous drugs that target the DNA replicating enzymes have been approved or some are under clinical trial. Drugs like PARP and PARG inhibitors showed sweeping effects against cancer cells. This review highlights the mechanistic study of different drug categories that target DNA replication and thus depicts the futuristic approach of targeted therapy.

CancerDNA damage responsePARPtopoisomerasethymidylate synthasecancer cells.Hanahan, D.; Weinberg, RA Hallmarks of cancer: The next generation. Cell., 2011, 144(5), 646-674.Vafa, O.; Wade, M.; Kern, S.; Beeche, M.; Pandita, T.K.; Hampton, G.M.; Wahl, G.M. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: A mechanism for oncogene-induced genetic instability. Mol. Cell, 2002, 9(5), 1031-1044. doi: 10.1016/S1097-2765(02)00520-8 PMID: 12049739Tubbs, A.; Nussenzweig, A. Endogenous DNA damage as a source of genomic instability in cancer. Cell, 2017, 168(4), 644-656. doi: 10.1016/j.cell.2017.01.002 PMID: 28187286Grivennikov, S.I.; Greten, F.R.; Karin, M. Immunity, inflammation, and cancer. Cell, 2010, 140(6), 883-899. doi: 10.1016/j.cell.2010.01.025 PMID: 20303878Mateo, J.; Lord, C.J.; Serra, V.; Tutt, A.; Balmaña, J.; Castroviejo-Bermejo, M.; Cruz, C.; Oaknin, A.; Kaye, S.B.; de Bono, J.S. A decade of clinical development of PARP inhibitors in perspective. Ann. Oncol., 2019, 30(9), 1437-1447. doi: 10.1093/annonc/mdz192 PMID: 31218365Jeggo, P.A.; Pearl, L.H.; Carr, A.M. DNA repair, genome stability and cancer: A historical perspective. Nat. Rev. Cancer, 2016, 16(1), 35-42. doi: 10.1038/nrc.2015.4 PMID: 26667849Chatterjee, N.; Walker, G.C. Mechanisms of DNA damage, repair, and mutagenesis. Environ. Mol. Mutagen., 2017, 58(5), 235-263. doi: 10.1002/em.22087 PMID: 28485537Langelier, M.F.; Riccio, A.A.; Pascal, J.M. PARP-2 and PARP-3 are selectively activated by 5′ phosphorylated DNA breaks through an allosteric regulatory mechanism shared with PARP-1. Nucleic Acids Res., 2014, 42(12), 7762-7775. doi: 10.1093/nar/gku474 PMID: 24928857Eustermann, S.; Wu, W.F.; Langelier, M.F.; Yang, J.C.; Easton, L.E.; Riccio, A.A.; Pascal, J.M.; Neuhaus, D. Structural basis of detection and signaling of DNA single-strand breaks by human PARP-1. Mol. Cell, 2015, 60(5), 742-754. doi: 10.1016/j.molcel.2015.10.032 PMID: 26626479Langelier, M.F.; Planck, J.L.; Roy, S.; Pascal, J.M. Structural basis for DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1. Science, 2012, 336(6082), 728-732. doi: 10.1126/science.1216338 PMID: 22582261Bétermier, M.; Bertrand, P.; Lopez, B.S. Is non-homologous end-joining really an inherently error-prone process? PLoS Genet., 2014, 10(1), e1004086. doi: 10.1371/journal.pgen.1004086 PMID: 24453986Jiang, X.; Li, X.; Li, W.; Bai, H.; Zhang, Z. PARP inhibitors in ovarian cancer: Sensitivity prediction and resistance mechanisms. J. Cell. Mol. Med., 2019, 23(4), 2303-2313. doi: 10.1111/jcmm.14133 PMID: 30672100Champoux, J.J. DNA topoisomerases: Structure, function, and mechanism. Annu. Rev. Biochem., 2001, 70(1), 369-413. doi: 10.1146/annurev.biochem.70.1.369 PMID: 11395412Wang, J.C. Cellular roles of DNA topoisomerases: A molecular perspective. Nat. Rev. Mol. Cell Biol., 2002, 3(6), 430-440. doi: 10.1038/nrm831 PMID: 12042765Corbett, K.D.; Berger, J.M. Structure, molecular mechanisms, and evolutionary relationships in DNA topoisomerases. Annu. Rev. Biophys. Biomol. Struct., 2004, 33(1), 95-118. doi: 10.1146/annurev.biophys.33.110502.140357 PMID: 15139806Nitiss, J.L. DNA topoisomerase II and its growing repertoire of biological functions. Nat. Rev. Cancer, 2009, 9(5), 327-337. doi: 10.1038/nrc2608 PMID: 19377505Vos, S.M.; Tretter, E.M.; Schmidt, B.H.; Berger, J.M. All tangled up: How cells direct, manage and exploit topoisomerase function. Nat. Rev. Mol. Cell Biol., 2011, 12(12), 827-841. doi: 10.1038/nrm3228 PMID: 22108601Chen, S.H.; Chan, N.L.; Hsieh, T. New mechanistic and functional insights into DNA topoisomerases. Annu. Rev. Biochem., 2013, 82(1), 139-170. doi: 10.1146/annurev-biochem-061809-100002 PMID: 23495937Pommier, Y.; Sun, Y.; Huang, S.N.; Nitiss, J.L. Roles of eukaryotic topoisomerases in transcription, replication and genomic stability. Nat. Rev. Mol. Cell Biol., 2016, 17(11), 703-721. doi: 10.1038/nrm.2016.111 PMID: 27649880Krishnakumar, R.; Kraus, W.L. The PARP side of the nucleus: Molecular actions, physiological outcomes, and clinical targets. Mol. Cell, 2010, 39(1), 8-24. doi: 10.1016/j.molcel.2010.06.017 PMID: 20603072Hu, Y.; Petit, S.A.; Ficarro, S.B.; Toomire, K.J.; Xie, A.; Lim, E.; Cao, S.A.; Park, E.; Eck, M.J.; Scully, R.; Brown, M.; Marto, J.A.; Livingston, D.M. PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination-mediated DNA repair. Cancer Discov., 2014, 4(12), 1430-1447. doi: 10.1158/2159-8290.CD-13-0891 PMID: 25252691Zhao, W.; Hu, H.; Mo, Q.; Guan, Y.; Li, Y.; Du, Y.; Li, L. Function and mechanism of combined PARP-1 and BRCA genes in regulating the radiosensitivity of breast cancer cells. Int. J. Clin. Exp. Pathol., 2019, 12(10), 3915-3920. PMID: 31933782Hanzlikova, H.; Gittens, W.; Krejcikova, K.; Zeng, Z.; Caldecott, K.W. Overlapping roles for PARP1 and PARP2 in the recruitment of endogenous XRCC1 and PNKP into oxidized chromatin. Nucleic Acids Res., 2017, 45(5), 2546-2557. PMID: 27965414Gogola, E.; Duarte, A.A.; de Ruiter, J.R.; Wiegant, W.W.; Schmid, J.A.; de Bruijn, R.; James, D.I.; Guerrero, L.S.; Vis, D.J.; Annunziato, S.; van den Broek, B.; Barazas, M.; Kersbergen, A.; van de Ven, M.; Tarsounas, M.; Ogilvie, D.J.; van Vugt, M.; Wessels, L.F.A.; Bartkova, J.; Gromova, I.; Andújar-Sánchez, M.; Bartek, J.; Lopes, M.; van Attikum, H.; Borst, P.; Jonkers, J.; Rottenberg, S. Selective loss of PARG restores PARylation and counteracts parp inhibitor-mediated synthetic lethality. Cancer Cell, 2018, 33(6), 1078-1093. doi: 10.1016/j.ccell.2018.05.008 PMID: 29894693Heeke, A.L.; Pishvaian, M.J.; Lynce, F.; Xiu, J.; Brody, J.R.; Chen, W.J.; Baker, T.M.; Marshall, J.L.; Isaacs, C. Prevalence of homologous recombination–related gene mutations across multiple cancer types. JCO Precis. Oncol., 2018, 2018(2), 1-13. doi: 10.1200/PO.17.00286 PMID: 30234181Wang, D.; Li, C.; Zhang, Y.; Wang, M.; Jiang, N.; Xiang, L.; Li, T.; Roberts, T.M.; Zhao, J.J.; Cheng, H.; Liu, P. Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes. Gynecol. Oncol., 2016, 142(3), 548-556. doi: 10.1016/j.ygyno.2016.07.092 PMID: 27426307Fong, P.C.; Boss, D.S.; Yap, T.A.; Tutt, A.; Wu, P.; Mergui-Roelvink, M.; Mortimer, P.; Swaisland, H.; Lau, A.; O’Connor, M.J.; Ashworth, A.; Carmichael, J.; Kaye, S.B.; Schellens, J.H.M.; de Bono, J.S. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med., 2009, 361(2), 123-134. doi: 10.1056/NEJMoa0900212 PMID: 19553641Coleman, R.L.; Fleming, G.F.; Brady, M.F.; Swisher, E.M.; Steffensen, K.D.; Friedlander, M.; Okamoto, A.; Moore, K.N.; Efrat Ben-Baruch, N.; Werner, T.L.; Cloven, N.G.; Oaknin, A.; DiSilvestro, P.A.; Morgan, M.A.; Nam, J.H.; Leath, C.A., III; Nicum, S.; Hagemann, A.R.; Littell, R.D.; Cella, D.; Baron-Hay, S.; Garcia-Donas, J.; Mizuno, M.; Bell-McGuinn, K.; Sullivan, D.M.; Bach, B.A.; Bhattacharya, S.; Ratajczak, C.K.; Ansell, P.J.; Dinh, M.H.; Aghajanian, C.; Bookman, M.A. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N. Engl. J. Med., 2019, 381(25), 2403-2415. doi: 10.1056/NEJMoa1909707 PMID: 31562800Tuli, R.; Shiao, S.L.; Nissen, N.; Tighiouart, M.; Kim, S.; Osipov, A.; Bryant, M.; Ristow, L.; Placencio-Hickok, V.; Hoffman, D.; Rokhsar, S.; Scher, K.; Klempner, S.J.; Noe, P.; Davis, M.J.; Wachsman, A.; Lo, S.; Jamil, L.; Sandler, H.; Piantadosi, S.; Hendifar, A. A phase 1 study of veliparib, a PARP-1/2 inhibitor, with gemcitabine and radiotherapy in locally advanced pancreatic cancer. EBioMedicine, 2019, 40, 375-381. doi: 10.1016/j.ebiom.2018.12.060 PMID: 30635165Dockery, L.E.; Tew, W.P.; Ding, K.; Moore, K.N. Tolerance and toxicity of the PARP inhibitor olaparib in older women with epithelial ovarian cancer. Gynecol. Oncol., 2017, 147(3), 509-513. doi: 10.1016/j.ygyno.2017.10.007 PMID: 29037805Okayama, H.; Edson, C.M.; Fukushima, M.; Ueda, K.; Hayaishi, O. Purification and properties of poly(adenosine diphosphate ribose) synthetase. J. Biol. Chem., 1977, 252(20), 7000-7005. doi: 10.1016/S0021-9258(19)66926-7 PMID: 198398Benjamin, R.C.; Gill, D.M. Poly(ADP-ribose) synthesis in vitro programmed by damaged DNA. A comparison of DNA molecules containing different types of strand breaks. J. Biol. Chem., 1980, 255(21), 10502-10508. doi: 10.1016/S0021-9258(19)70491-8 PMID: 6253477Ray, C.A.; Nussenzweig, A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat. Rev. Mol. Cell Biol., 2017, 18(10), 610-621. doi: 10.1038/nrm.2017.53 PMID: 28676700Nitiss, J.L. Investigating the biological functions of DNA topoisomerases in eukaryotic cells. Biochim. Biophys. Acta Gene Struct. Expr., 1998, 1400(1-3), 63-81. doi: 10.1016/S0167-4781(98)00128-6 PMID: 9748506Pandey, A.; Makhija, P.; Prakash, G.C.; Anil, B.G. PARG inhibitors’ success: A long way to go! Curr. Enzym. Inhib., 2014, 10(2), 81-93. doi: 10.2174/1573408010666141126220225Stewart, L.; Redinbo, M.R.; Qiu, X.; Hol, W.G.J.; Champoux, J.J. A model for the mechanism of human topoisomerase. iScience, 1998, 279(5356), 1534-1541. doi: 10.1126/science.279.5356.1534 PMID: 9488652Berger, J.M.; Gamblin, S.J.; Harrison, S.C.; Wang, J.C. Structure and mechanism of DNA topoisomerase II. Nature, 1996, 379(6562), 225-232. doi: 10.1038/379225a0 PMID: 8538787Bates, A.D.; Maxwell, A. DNA supercoiling. In: DNA Topology; Rickwood, D., Ed.; IRL-Press Inc.: New York, 1993; pp. 17-45.Okoro, C.O.; Fatoki, T.H. Fatoki TH. A mini review of novel topoisomerase ii inhibitors as future anticancer agents. Int. J. Mol. Sci., 2023, 24(3), 2532. doi: 10.3390/ijms24032532 PMID: 36768852Hsiang, Y.H.; Liu, L.F. Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res., 1988, 48(7), 1722-1726. PMID: 2832051Muggia, F.M.; Creaven, P.J.; Hansen, H.H.; Cohen, M.H.; Selawry, O.S. Phase I clinical trial of weekly and daily treatment with camptothecin (NSC-100880): Correlation with preclinical studies. Cancer Chemother. Rep., 1972, 56(4), 515-521. PMID: 5081595Masuda, N.; Fukuoka, M.; Kusunoki, Y.; Matsui, K.; Takifuji, N.; Kudoh, S.; Negoro, S.; Nishioka, M.; Nakagawa, K.; Takada, M. CPT-11: A new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J. Clin. Oncol., 1992, 10(8), 1225-1229. doi: 10.1200/JCO.1992.10.8.1225 PMID: 1321891Hertzberg, R.P.; Caranfa, M.J.; Holden, K.G.; Jakas, D.R.; Gallagher, G.; Mattern, M.R.; Mong, S.M.; Bartus, J.O.L.; Johnson, R.K.; Kingsbury, W.D. Modification of the hydroxylactone ring of camptothecin: Inibition of mammalian topoisomerase I and biological activity. J. Med. Chem., 1989, 32(3), 715-720. doi: 10.1021/jm00123a038 PMID: 2537428Rivory, L.P.; Riou, J.F.; Haaz, M.C.; Sable, S.; Vuilhorgne, M.; Commerçon, A.; Pond, S.M.; Robert, J. Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients. Cancer Res., 1996, 56(16), 3689-3694. PMID: 8706009Fukuoka, M.; Niitani, H.; Suzuki, A.; Motomiya, M.; Hasegawa, K.; Nishiwaki, Y.; Kuriyama, T.; Ariyoshi, Y.; Negoro, S.; Masuda, N. A phase II study of CPT-11, a new derivative of camptothecin, for previously untreated non-small-cell lung cancer. J. Clin. Oncol., 1992, 10(1), 16-20. doi: 10.1200/JCO.1992.10.1.16 PMID: 1309380Ottaviani, A.; Welsch, J.; Agama, K.; Pommier, Y.; Desideri, A.; Baker, B.J.; Fiorani, P. From Antarctica to cancer research: A novel human DNA topoisomerase 1B inhibitor from Antarctic sponge Dendrilla antarctica. J. Enzyme Inhib. Med. Chem., 2022, 37(1), 1404-1410. doi: 10.1080/14756366.2022.2078320 PMID: 35603503Tsunoda, T.; Tanimura, H.; Hotta, T.; Tani, M.; Iwahashi, M.; Tanaka, H.; Matsuda, K.; Yamaue, H. In vitro antitumor effect of topoisomerase-I inhibitor, CPT-11, on freshly isolated human gastric and colorectal cancer. Anticancer Res., 1999, 19(6B), 5451-5455. PMID: 10697576Frangoul, H.; Ames, M.M.; Mosher, R.B.; Reid, J.M.; Krailo, M.D.; Seibel, N.L.; Shaw, D.W.; Steinherz, P.G.; Whitlock, J.A.; Holcenberg, J.S. Phase I study of topotecan administered as a 21-day continous infusion in children with recurrent solid tumors: A report from the Children’s Cancer Group. Clin. Cancer Res., 1999, 5(12), 3956-3962. PMID: 10632325Bailly, C. Topoisomerase I poisons and suppressors as anticancer drugs. Curr. Med. Chem., 2000, 7(1), 39-58. doi: 10.2174/0929867003375489 PMID: 10637356Dahut, W.; Harold, N.; Takimoto, C.; Allegra, C.; Chen, A.; Hamilton, J.M.; Arbuck, S.; Sorensen, M.; Grollman, F.; Nakashima, H.; Lieberman, R.; Liang, M.; Corse, W.; Grem, J. Phase I and pharmacologic study of 9-aminocamptothecin given by 72-hour infusion in adult cancer patients. J. Clin. Oncol., 1996, 14(4), 1236-1244. doi: 10.1200/JCO.1996.14.4.1236 PMID: 8648379Zhou, B.N.; Johnson, R.K.; Mattern, M.R.; Wang, X.; Hecht, S.M.; Beck, H.T.; Ortiz, A.; Kingston, D.G.I. Isolation and biochemical characterization of a new topoisomerase I inhibitor from Ocotea leucoxylon. J. Nat. Prod., 2000, 63(2), 217-221. doi: 10.1021/np990442s PMID: 10691712Fleury, F.; Sukhanova, A.; Ianoul, A.; Devy, J.; Kudelina, I.; Duval, O.; Alix, A.J.P.; Jardillier, J.C.; Nabiev, I. Molecular determinants of site-specific inhibition of human DNA topoisomerase I by fagaronine and ethoxidine. Relation to DNA binding. J. Biol. Chem., 2000, 275(5), 3501-3509. doi: 10.1074/jbc.275.5.3501 PMID: 10652345Mortensen, U.H.; Stevnsner, T.; Krogh, S.; Olesen, K.; Westergaard, O.; Bonven, B.J. Distamycin inhibition of topoisomerase I-DNA interaction: A mechanistic analysis. Nucleic Acids Res., 1990, 18(8), 1983-1989. doi: 10.1093/nar/18.8.1983 PMID: 2159632Wall, M.E.; Wani, M.C. Camptothecin and taxol: Discovery to clinic--thirteenth Bruce F. Cain Memorial Award Lecture. Cancer Res., 1995, 55(4), 753-760. PMID: 7850785Hsiang, Y.H.; Hertzberg, R.; Hecht, S.; Liu, L.F. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J. Biol. Chem., 1985, 260(27), 14873-14878. doi: 10.1016/S0021-9258(17)38654-4 PMID: 2997227Eng, W.K.; Faucette, L.; Johnson, R.K.; Sternglanz, R. Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol. Pharmacol., 1988, 34(6), 755-760. PMID: 2849043Ayusawa, D.; Arai, H.; Wataya, Y.; Seno, T. A specialized form of chromosomal DNA degradation induced by thymidylate stress in mouse FM3A cells. Mutat. Res., 1988, 200(1-2), 221-230. doi: 10.1016/0027-5107(88)90086-3 PMID: 2839770Nassan, M.A.; Aldhahrani, A.; Amer, H.H.; Elhenawy, A.; Swelum, A.A.; Ali, O.M.; Zaki, Y.H. Investigation of the anticancer effect of α-aminophosphonates and arylidine derivatives of 3-Acetyl-1-aminoquinolin-2(1H)-one on the DMBA model of breast cancer in albino rats with in silico prediction of their thymidylate synthase inhibitory effect. Molecules, 2022, 27(3), 756. doi: 10.3390/molecules27030756 PMID: 35164019Grem, J.L. Fluorinated pyrimidines. In: Cancer Chemotherapy: Principles and Practice; Chabner, B.A.; Collins, J.M., Eds.; J. B. Lippincott Company: Philadelphia, 1990, pp. 180-224.Shafer, C.M.; Lindvall, M.; Bellamacina, C.; Gesner, T.G.; Yabannavar, A.; Jia, W.; Lin, S.; Walter, A. 4-(1H-Indazol-5-yl)-6-phenylpyrimidin-2(1H)-one analogs as potent CDC7 inhibitors. Bioorg. Med. Chem. Lett., 2008, 18(16), 4482-4485. doi: 10.1016/j.bmcl.2008.07.061 PMID: 18672368Salerno, D.; Hasham, M.G.; Marshall, R.; Garriga, J.; Tsygankov, A.Y.; Graña, X. Direct inhibition of CDK9 blocks HIV-1 replication without preventing T-cell activation in primary human peripheral blood lymphocytes. Gene, 2007, 405(1-2), 65-78. doi: 10.1016/j.gene.2007.09.010 PMID: 17949927Swords, R.; Mahalingam, D.; O’Dwyer, M.; Santocanale, C.; Kelly, K.; Carew, J.; Giles, F. Cdc7 kinase – A new target for drug development. Eur. J. Cancer, 2010, 46(1), 33-40. doi: 10.1016/j.ejca.2009.09.020 PMID: 19815406Montagnoli, A.; Bosotti, R.; Villa, F.; Rialland, M.; Brotherton, D.; Mercurio, C.; Berthelsen, J.; Santocanale, C. Drf1, a novel regulatory subunit for human Cdc7 kinase. EMBO J., 2002, 21(12), 3171-3181. doi: 10.1093/emboj/cdf290 PMID: 12065429Manohar, S.M.; Joshi, K.S. Promising anticancer activity of multitarget cyclin dependent kinase inhibitors against human colorectal carcinoma cells. Curr. Mol. Pharmacol., 2022, 15(7), 1024-1033. doi: 10.2174/1874467215666220124125809 PMID: 35068399