DIŞA ATIM POMPA SİSTEMLERİ VE BU SİSTEMLERİN KANSER TEDAVİSİNDEKİ ETKİNLİKLERİ

Abstract

ÖZET

            Membranlar hücreleri çevresinde ayıran, lipit, proteinler ve karbonhidratlardan oluşan çift tabakalı yapılardır. Çeşitli moleküllerin hücre zarı boyunca taşınmasını sağlayan sistemler arasında hücre zarına yerleşmiş taşıyıcı proteinler bulunmaktadır.

            Kanser, kontrolsüz hücre çoğalmasıyla karakterize bir grup hastalığın genel adıdır. Ortalama ömrün uzaması gibi çeşitli etkenler ile kanser görülme sıklığı artmaktadır. Kanserin tedavisi önündeki en önemli engellerden bir tanesi, kanser hücrelerinin kemoterapötiklere karşı geliştirdikleri çoklu ilaç direncidir. Bu dirence sebep olan en önemli etkenlerden birisi ABC taşıyıcı proteinleridir. Günümüze kadar keşfedilmiş 49 üyesi bulunan bu protein süper ailesinin, in vivo şartlarda çoklu ilaç direnci ile ilişkili olduğu belirlenmiş 4 üyesi bulunmaktadır. Bunlar P-glikoprotein (MDR1), çoklu ilaç direnci ilişkili protein (MRP1), göğüs kanseri direnç proteini (BCRP) ve ABCC10’dur. Bu proteinler, kimyasal yapısı ve etki mekanizmaları bakımından birbirinden çok farklı pek çok antikanser ilacını hücre dışına atarak, kanser hücrelerinin kemoterapötiklere direnç geliştirmesine neden olmaktadır.

            Kanser hücrelerinde oluşan çoklu ilaç direncini atlatmak ve bu hücreleri antikanser ilaçlarına tekrar duyarlı hale getirmek için denenen stratejilerden birisi, antikanser ilaçların p-gp inhibitörleri ile birlikte verilmesidir. Bu amaçla 3 nesil p-gp inhibitörü geliştirilmiştir. Henüz klinik çalışmalarda başarı gösteremeyen bu inhibitörler, kanser tedavisi açısından üzerinde durulması gereken çok önemli bir alanı oluşturmaktadır.

 

ABSTRACT

Membranes, which separate the cells from their environment, are two-layered structures composed of lipits, proteins and carbohydrates. One of the systems that allow the transport of various molecules accros cell membranes are carrier proteins that are located on the cell membrane.

Cancer is the general name of a group of diseases characterized by uncontrolled cell proliferation. The incidence of cancer is increasing with various factors such as the average life span. One of the most important obstacles to cancer treatment is multidrug resistance, which cancer cells develop against chemotherapeutics. ABC carrier proteins are one of the most important factors that cause this resistance. Until today 49 members of this protein superfamily has been discovered, there are 4 members who are found to be associated with multiple drug resistance in vivo conditions. These are P-glycoprotein (MDR1), multidrug resistance-associated protein (MRP1), breast cancer resistance protein (BCRP) and ABCC10. These proteins can efflux many different anticancer drugs which are different from each other in terms of chemical structure and mechanism of action and cause cancer cells to develop resistance to chemotherapeutics.

One strategy that has been tried to overcome the multiple drug resistance that occurs in cancer cells and make these cells susceptible to anticancer drugs is the co-administration of anticancer drugs with p-gp inhibitors. Three generations of p-gp inhibitors have been developed for this purpose. These inhibitors, which have not yet been successful in clinical trials, constitute a very important area to be addressed in terms of cancer treatment.

Keywords

• ABC taşıyıcılar,çoklu ilaç direnci

References

1. Referans 1 Kumar, Abbas, Aster (Çeviri: S. Tuzlalı, M. Güllüoğlu, U. Çevikbaş) Neoplazi In: Robbins Temel Patoloji. 2014, 161-215
2. Referans 2 Kathawala R.J, Gupta P, Ashby Jr C.R, Chen Z.S, In:The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade, Drug Resistance Updates2015, 18: 1-17
3. Referans 3 Chen Z, Shi T, Zhang L, Zhu P, Deng M, Huang C, Hu T, Jiang L, Li J, In: Mammalian drug efflux transporters of the ATP-binding cassette (ABC) family in multidrug resistance: A review op the past decade, Cancer Letters 2016, 370 :153-164
4. Referans 4 Housman C, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S, In: Drug resistance in cancer: An overview, Cancer 2014, 6, 1769 1792; doi:10.3390/cancers6031769
5. Referans 5 Löscher W, Potschka H, In: Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. The American Society for Experimental NeuroTherapeutics 2005, Vol.2, 86-98
6. Referans 6. Chang G, In: Multidrug resistance ABC transportes, FEBS Letters 555, 2013, 102-105
7. Referans 7 Baker E, El-Osta A, In: MDR1, chemotherapy and chromotin remodeling, Cancer Biology & Therapy, 2004, 3:9, 819-824
8. Referans 8 Vasiliou V, Vasiliou K, Nebert D.W, Human ATP-cinding casette (ABC) transporter family. In: Henry Stewart Publications 1479-7364 Human Genomics April 2009 Vol. 3. No 3. 281-290

9. Referans 9 Hediger M, Romero M, Peng J, Rolfs A, Takanaga H, Bruford E, In: The ABC’s oh the solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins. Eur J Physiol 2004, 447: 465-468.
10. Referans 10 He L, Vasiliou K, Nebert D, In: Analysis and update of the human solute carrier (SLC) gene superfamily. Human Genomics 2009 Vol.3 No.2 195-206
11. Referans 11 Hediger M, Clemencon B, Burrier R, Bruford E, In: The ABC’s of membrane transporters in health and disease (SLC series) 2013: 34(2-3): 95-107
12. Referans 12 Piatkov İ, Caetano D, Assur Y, Lau S.L, Jones T, Boyages S. C, McLean M, In: ABCB1 and ABCC1 single-nucleotide polymorphisms in patients treated with clozapine. Pharmacogenomics and Personalized Medicine 2017: 10 235-242
13. Referans 13 Glavinas H, Krajcsi P, Cserepes J, Sarkadi B In: The role of ABC transporters in drug resistance, metabolism and toxicity. Current Drug Delivery, 2004. 1. 27-42
14. Referans 14 Rice A.J, Park A, Pinkett H.W, In: Diversity in ABC transporters: Type I, II and III importers. Crit. Rev. Biochem. Mol. Biol, 2014, 49(5):426-437
15. Referans 15 Dean M, Hamon Y, Chimini G, In: The human ATP-binding cassette (ABC) transporter superfamily. Journal of Lipid Research, 2001, Vol 42, 1007-1017
16. Referans 16 Ejendal K.F.K, Hrycyna C.A, In: Multidrug resistance and cancer: The role of the human ABC transporter ABCG2. Current Protein and Peptide Science, 2002, 3, 503-511
17. Referans 17 Durmus S, Hendrikx J.J, Schinkel A.H, In: Apical ABC transporters and cancer chemotherapeutic drug disposition. Advances in Cancer Research,2015 Vol 125
18. Referans 18 Fletcher J.I, Williams R.T, Henderson M.J, Moris M.D, Haber M, In: ABC transporters as mediators of drug resistance and contributors to cancer cell biology. Drug Resistance Updates,2016 ,26 1-9
19. Referans 19 Gottesman M.M, In: Mechanisms of cancer drug resistance. Annu. Rev. Med. 2002. 53;615-27
20. Referans 20 Abdallah H.M, Al-Abd A.M, El-Dine R.S, El-Halawani A.M, In: P-glycoprotein inhibitors of naturel origin as potential tumor chemo-sensitizers: A review. Journal of Advanced Research 2015, 6, 45-62
21. Referans 21 Nooter K, Herweijer H, In: Multidrug resistance (mdr) genes in human cancer, Br. J. Cancer (1991), 63, 663-669
22. Referans 22 Hodin S, Basset T, Jacqueroux E, Delezay O, Clotagatide A, Perek N, Mismetti P, Delavenne X, In: In-vitro comparison of the role of P-glycoprotein and breast cancer resistance protein on direct oral anticoagulants disposition.
23. Referans 23 Patel A, Wang D, Sim H, Ambudekar S.V, Chen Z, In: ABC transporter modulatory drugs from marine sources: A new approach to overcome drug resistance in cancer.
24. Referans 24 Schinkel A, Mayer U, Wagenaar E, Mol C, van Deemter L, Smit J, In: Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins, Proc. Natl. Acad. Sci. 1997, Vol. 94: 4028-4033.
25. Referans 25 Harris A, Hochhauser D, In: Mechanisms of the multidrug resistance in cancer treatment, Acta Oncologica 1992, Vol.31, No.2: 205-213