Fatih TOK, Bedia KOÇYİĞİT KAYMAKÇIOĞLU

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Kanser tedavisinde yeni bir yaklaşım: Poli (ADP-riboz) polimeraz-1 inhibitörleri

Genetik materyal olan DNA’da iç ve dış etkenler sonucu hasar oluşabilir. Normal bir hücrede bu hasarı onarabilecek çok sayıda tamir mekanizması vardır. Bunlardan biri de PARP-1 enzimidir. PARP-1, nikotinamid adenin dinükleotidden ADP-riboz yapılarını protein akseptörüne transfer eder. Böylece tek zincir DNA kırıkları onarılır. PARP-1’in inhibisyonu durumunda ise bu tek zincir DNA kırıkları onarılamaz ve çift zincir DNA kırıkları oluşur. Sonuçta hücre nekrozise ya da apoptozise gider. Kanser tedavisinde tümörlü hücrelerin PARP-1 inhibisyonuyla öldürülmesi amaçlanmaktadır. Bu amaçla son on yıl içinde çok sayıda çalışma yapılmış olup, günümüzde faz aşamasında bulunan ve piyasaya sürülmeyi bekleyen PARP-1 inhibitörleri mevcuttur. Bu derlemede, DNA’da oluşan hasarın hangi mekanizmalarla onarıldığı, PARP enzim ailesinin genomik bütünlüğü nasıl koruduğu ve kanser tedavisinde kullanılmak üzere geliştirilmiş PARP-1 inhibitörü kimyasal bileşiklerin yapıları hakkında bilgi verilmiştir.
Anahtar Kelimeler:

Poli(ADP-riboz) polimeraz, moleküler modelleme, PARP-1 inhibitörleri, kanser tedavisi

A new approach in cancer treatment: poly (ADP-ribose) polymerase-1 inhibitors

Internal and external factors can damage DNA, the genetic material. Numerous repair mechanisms, which can repair those damages, exist in the normal cell. One of those is called PARP-1 enzyme. PARP-1 transfers ADP-ribose subunits from nicotinamide adenine nucleotide to protein acceptor. Thus, single strand DNA breaks can be repaired. If PARP-1 inhibition occurs, single strand DNA breaks cannot be repaired and double strand DNA breaks can be formed. Eventually, cells undergo necrosis or apoptosis. The aim of cancer treatment is to inhibit the PARP-1 enzyme. For this purpose, many studies have been published over the last decade and currently PARP-1 enzyme inhibitors which are in the phase studies and which are waiting to be marketed are available. In this review, information are given for the mechanisms by which DNA damage is repaired, the protection mechanism of the genomic integrity of PARP enzyme family and chemical structure of PARP-1 inhibitors which are improved to use in cancer treatment.
Keywords:

Poly(ADP-ribose) polymerase, molecular modelling, PARP-1 inhibitors, cancer treatment,

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  • Vos MD, Schreiber V, Dantzer F: The diverse roles and clinical relevance of PARPs in DNA damage repair: Current state of the art. Biochem Pharmacol. 2012; 84: 137-146.
  • Emami S: Interplay between p-53 family, their regulators, and PARPs in DNA repair. Clin Res Hepatol Gastroenterol. 2011; 35: 98-104.
  • Zhu G, Gong J, Gandhi VB, Liu X, Shi Y, Johnson EF, Donawho CK, Ellis PA, Bouska JJ, Osterling DJ, Olson AM, Park C, Luo Y, Shoemaker A, Giranda VL, Penning TD: Discovery and SAR of orally efficacious tetrahydropyridopyridazinone PARP inhibitors for the treatment of cancer. Bioorg Med Chem Lett. 2012; 20: 4635-4645.
  • Drew Y, Plummer R: PARP inhibitors in cancer therapy: Two modes of attack on the cancer cell widening the clinical applications. Drug Resist Update. 2009; 12: 153-156.
  • Plummer R: Poly(ADP-ribose) polymerase (PARP) inhibitors: From Bench to Bedside. Clin Oncol. 2014; 26: 250-256.
  • Powell C, Mikropoulos C, Kaye SB, Nutting CM, Bhide SA, Newbold K, Harrington KJ: Pre-clinical and clinical evaluation of PARP inhibitors as tumor-specific radiosensitisers. Cancer Treat Rev. 2010; 36: 566- 575.
  • Giansanti V, Dona F, Tillhon M, Scovassi AI: PARP inhibitors: New tools to protect from inflammation. Biochem Pharmacol. 2010; 80: 1869- 1877.
  • Erie DA, Weninger KR: Single molecule studies of DNA mismatch repair. DNA Repair. 2014; 20: 71-81.
  • Zhu Q, Wang X, Chu Z, He G, Dong G, Xu Y: Design, synthesis and biological evaluation of novel imidazo[4,5-c]-pyridinecarboxamide derivatives as PARP-1 inhibitors. Bioorg Med Chem Lett. 2013; 23: 1993-1996.
  • Zhou D, Chu W, Xu J, Jones LA, Peng X, Li S, Chen DL, Mach RH: Synthesis, [18F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography. Bioorg Med Chem Lett. 2014; 22: 1700-1707.
  • Ishida J, Yamamoto H, Kido Y, Kamijo K, Murano K, Miyake H, Ohkubo M, Kinoshita T, Warizaya M, Iwashita A, Mihara K, Matsuoka N, Hattori K: Discovery of potent selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling. Bioorg Med Chem Lett. 2006; 14: 1378-1390.
  • Luo X, Kraus WL: A one and a two expanding roles for poly(ADP- ribose) polymerases in metabolism. Cell Metab. 2011: 353-355.
  • Gandhi VB, Luo Y, Liu X, Shi Y, Klinghofer V, Johnson EF, Park C, Giranda VL, Penning TD, Zhu G: Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP- ribose) polymerase (PARP) for the treatment of cancer. Bioorg Med Chem Lett. 2010; 20: 1023-1026.
  • Meli E, Pangallo M, Baronti R, Chiarigu A, Cozzi A, Giampietro DEP, Moroni F: Poly (ADP-ribose) polymerase as a key player in excitotoxicity and post-ischemic brain damage. Toxicol Lett. 2003; 139: 153-162.
  • Langelier MF, Riccio AA, Pascal JM: PARP-2 and PARP-3 are selectively activated by 5’ phosphorylated DNA breaks through and allosteric regulatory mechanism shared with PARP-1. Nucleic Acids Res. 2014; 42: 7762-7775.
  • Ji Y, Tulin AV: The roles of PARP-1 in gene control and cell differentiation. Curr Opin Genet Dev. 2010; 20: 512-518.
  • Burkle A, Virag L: Poly(ADP-ribose): PARadigms and PARadoxes. Mol Aspects Med. 2013; 34: 1046-1065.
  • Weaver AN, Yang ES: Beyond DNA repair: additional functions of PARP-1 in cancer. Front Oncol. 2013;3 :290.
  • Swindall AF, Stanley JA, Yang ES: PARP-1: Friend or foe of DNA damage and repair in tumorigenesis? Cancers. 2013; 5: 943-958.
  • Kraus WL, Hottiger MO: PARP-1 and gene regulation: Progress and puzzles. Mol Aspects Med. 2013; 34: 1109-1123.
  • Furgason JM, Bahassi EM: Targetting DNA repair mechanisms in cancer. Pharmacol Therapeut. 2013; 137: 298-308.
  • Toss A, Cortesi L: Molecular mechanisms of PARP inhibitors in BRCA- related ovarian cancer. Cancer Sci Ther. 2013; 5: 409-416.
  • Glendenning J, Tutt A: PARP inhibitors-current status and the walk towards early breast cancer. The Breast. 2011; 20: S12-S19.
  • Curtin NJ, Szabo C: Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond. Mol Aspects Med. 2013; 34: 1217- 1256.
  • Curtin NY: Poly(ADP-ribose) polymerase (PARP) and PARP inhibitors. Drug Discov Today: Disease Models. 2012; 9: e51-e58.
  • Sandhu SK, Yap TA, Bono JS. Poly(ADP-ribose) polymerase inhibitors in cancer treatment: A clinical perspective. Eur J Cancer. 2010; 46: 9-20.
  • Giannini G, Battistuzzi G, Vesci L, Milazzo FM, Paolis FD, Barbarino M, Guglielmi MB, Carollo V, Gallo G, Artali R, Dallavalle S: Novel PARP-1 inhibitors based on a 2-propanoyl-3H-quinazolin-4-one scaffold. Bioorg Med Chem Lett. 2014; 24: 462-466.
  • Hannigan K, Kulkarni SS, Bdzhola VG, Golub AG, Yarmoluk SM, Talele TT: Identification of novel PARP-1 inhibitors by structure-based virtual screening. Bioorg Med Chem Lett. 2013; 23: 5790-5794.
  • Scarpelli R, Boueres JK, Cerretani M, Ferrigno F, Ontoria JM, Rowley M, Fademrecht CS, Toniatti C, Jones P: Synthesis and biological evaluation of substituted 2-phenyl-2H-indazole-7-carboxamides as potent poly(ADP-ribose) polymerase (PARP) inhibitors. Bioorg Med Chem Lett. 2010; 20: 488-492.
  • Pescatore G, Branca D, Fiore F, Kinzel O, Bufi LL, Muraglia E, Orvieto F, Rowley M, Toniatti C, Torrisi C, Jones P: Identification and SAR of novel pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as inhibitors potent poly(ADP-ribose) polymerase 1(PARP-1). Bioorg Med Chem Lett. 2010; 20: 1094-1099.
  • Wang L, Zhou X, Xiao M, Jiang N, Liu F, Zhou W, Wang X, Zheng Z, Li S: Synthesis and biological evaluation of substituted 4-(tiophen-2- ylmethyl)-2H-phythalazin-1-ones as potent PARP-1 inhibitors. Bioorg Med Chem Lett. (2014).
  • Chen J, Peng H, He J, Huan X, Miao Z, Yang C: Synthesis of isoquinolinone-based tricycles as novel poly(ADP-ribose) polymerase (PARP-1) inhibitors. Bioorg Med Chem Lett. 2014; 24: 2669-2673.
  • Pellicciari R, Camaioni E, Costantino G, Marinozzi M, Macchiarulo A, Moroni F, Natalini Benedetto: Towards new neuroprotective agents: design and synthesis of 4H-thieno[2,3-c] isoquinolin-5-one derivatives as potent PARP-1 inhibitors. Il Farmaco. 2003; 58: 851-858.
  • Liu JF, Konstantinopoulos PA, Matulonis UA: PARP inhibitors in ovarian cancer: Current status and future promise. Gynecol Oncol. 2014; 133: 362-369.
  • Cincinelli R, Musso L, Merlini L, Giannini G, Vesci L, Milazzo FM, Carenini N, Perego P, Penco S, Artali R, Zunino F, Pisano C, Dallavalle S: 7-Azaindole-1-carboxamides as a new class of PARP-1 inhibitors. Bioorg Med Chem. 2014; 22: 1089-1103.
  • Godoy JMP, Godoy MFG: Evaluation of new approach to the treatment of lymphedema resulting from breast cancer therapy. Eur J Intern Med. 2013; 24: 59-62.
  • Beauchamp MC, Knafo A, Yasmeen A, Carboni JM, Gottardis MM, Pollak MN, Gotlieb WH: BMS-536924 sensitizes human epithelial ovarian cancer cells to the PARP inhibitor, 3-aminobenzamide. Gynecol Oncol. 2009; 115: 193-198.
  • Schmid BC, Oehler MK: New perspectives in ovarian cancer treatment. Maturitas. 2014; 77: 128-136.
  • Murai J, Marchand C, Shahane SA, Sun H, Huang R, Zhang Y, Chergui A, Ji J, Doroshow JH, Jadhav A, Takeda S, Xia M, Pommier Y: Identification of novel PARP inhibitors using a cell-based TDP1 inhibitory assay in a quantitative high-throughput screening platform. DNA Repair. (2014). http://dx.doi.org/10.1016/j.dnareb.2014.03.006.
  • Reinbolt RE, Hays JL: The role of PARP inhibitors in the treatment of gynecologic malignancies. Front Oncol. 2013; 3: 1-12.
  • Koppensteiner R, Samartzis EP, Noske A, Teichman AV, Dedes I, Gwerder M, Imesch P, Ikenberg K, Moch H, Fink D, Stucki M, Dedes KJ: Effect of MRE11 loss on PARP inhibitor sensitivity in endometrial cancer in vitro. Plos One. 2014; 9: e100041.
  • Miyasaka A, Oda K, Ikeda Y, Hiraike O, Kashiyama T, Enomoto A, Hosoya N, Koso T, Fukuda T, Inaba K, Sone K, Uehara Y, Kurikava R, Nagasaka K, Matsumoto Y, Arimoto T, Nakagawa S, Kuramoto H, Miyagawa K, Yano T, Kawana K, Osuga Y, Fujii T: Anti-tumor activity of olabarib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in cultured endometrial carcinoma cells. BMC Cancer. 2014; 14: 179.
  • Leal AP, Vargas JMR, Quesada RA, Rodriguez MI, Linares JL, Almodovar MR, Oliver FJ: PARP inhibitors: New partners in the therapy of cancer and inflammatory diseases. Free Radical Bio Med. 2009; 47: 13-26.
  • Sodhi RK, Singh N, Jaggi AS: Poly(ADP-ribose) polymerase-1 (PARP-1) and its therapeutic implications. Vasc Pharmacol. 2010; 53: 77-87.
Clinical and Experimental Health Sciences-Cover
  • Yayın Aralığı: Yılda 4 Sayı
  • Başlangıç: 2011
  • Yayıncı: Marmara Üniversitesi
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Kanser tedavisinde yeni bir yaklaşım: Poli (ADP-riboz) polimeraz-1 inhibitörleri

Fatih TOK, Bedia KOÇYİĞİT KAYMAKÇIOĞLU