Investigation of the effects of drugs effective on PI3K-AKT signaling pathway in colorectal cancer alone and in combination

Amaç. Bu çalışma kolorektal kanser tedavisinde etkili madde ve/veya olası maddekombinasyonlarını belirlemek için tasarlanmıştır. Bu nedenle kolorektal kanserin patofizyolojikmekanizmalarında önemli bir rol oynadığı bilinen PI3K/Akt yolağını hedef alan NVPBEZ-235,API-1, LY 294002 ve PP242nin tek ve kombinasyon halinde anti-proliferatif etkileri araştırıldı.Daha önce bu kanser tipinde çalışılmayan NVPBEZ-235, API-1 ve PP242nin anti-proliferatifetkilerinin olup olmadığı araştırıldı. Ayrıca bu etkileri kolorektal kanser üzerinde anti-proliferatifbir etkiye sahip olduğu bilinen LY 294002 ile karşılaştırıldı. Yöntem. DLD-1 hücre hattıkolorektal hücre olarak kullanıldı. Gerçek zamanlı hücre analizi (XCELLigence sistemi) kolorektalhücre çoğalmasında ajanların etkilerini belirlemek için kullanıldı. Bulgular. Maddeler tek başınauygulandığı zaman NVPBEZ-235, dual PI3K/mTOR inhibitörü NVP-BEZ en güçlü sitotoksiketkiye ve PI3K inhibitörü LY294002 en düşük sitotoksisiteye sahipti. Kombinasyonların hiçbiri,tek başına uygulamaları ile karşılaştırıldığında daha üstün değildi. Sonuç. Bu çalışma PI3K/Aktyolağı hedef alındığında, kombine tedavi yerine daha yüksek afinitesi ve etkinliği olan tek birmadde ile hedefe yönelik spesifik tedavinin daha uygun olacağını göstermektedir. Ayrıca özelliklePI3K/Akt yolağını etkileyen maddeler arasında NVP-BEZ hedefe yönelik tedavide gelenekseltedaviler için bir alternatif olabilir.

Kolorektal kanserde PI3K-AKT sinyal yolağı üzerinden etki gösteren ilaçların tek başlarına ve kombinasyonlarının etkilerinin araştırılması

Aim. This study was designed to determine the agent and/or possible agent combinations that maybe effective in the treatment of colorectal cancer. For this reason the single and combinedantiproliferative effects of NVPBEZ-235, API-1, LY 294002 and PP242 which target PI3K/AKTpathway well known to have an important role in pathophysiological mechanisms of colorectalcancer were investigated. We investigated whether NVPBEZ-235, API-1 and PP242 haveantiproliferative effects which have not been studied on this cancer type and also compared theeffects with LY294002 known to have antiproliferative effect on colorectal cancer. Method. DLD- 1 cell line was used as colorectal cells. Real time cell analysis (xCELLigence system) was used todetermine the effects of the agents in colorectal cell proliferation. Results. When the agents wereapplied alone, PI3K/mTOR dual inhibitor NVP-BEZ had the strongest cytotoxic effect and PI3Kinhibitor LY294002 had the lowest cytotoxic effect. None of the combinations were not superiorcompared to alone applications. Conclusion. This study indicates that when PI3K/AKT pathway istargeted, instead of combined treatment, targeted specific treatment with a single agent havinghigher affinity and effectiveness would be more appropriate. Also among the agents effectingPI3K/AKT pathway especially, NVP-BEZ for targeted therapy can be alternative to conventionaltreatments.

PDF

___

1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011; 61: 212-36.
2. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996; 87: 159-70.
3. Bachman KE, Argani P, Samuels Y. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 2004; 3: 772-5.
4. Hahn WC, Weinberg RA. Rules for making human tumor cells. New Engl J Med 2002; 347: 1593-603.
5. Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 2008; 27: 5511-26.
6. Huang XF, Chen JZ. Obesity, the PI3K/Akt signal pathway and colon cancer. Obes Rev 2009; 10: 610-6.
7. Zhao L, Class I. PI3K in oncogenic cellular transformation. Oncogene 2008; 27: 5486-96.
8. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296:1655-7.
9. Itoh N, Semba S, Ito M. Phosphorylation of Akt/PKB is required for suppression of cancer cell apoptosis and tumor progression in human colorectal carcinoma. Cancer 2002; 94(12): 3127-34.
10. Khaleghpour K, Li Y, Banville D, Yu Z, Shen SH. Involvement of the PI 3- kinase signaling pathway in progression of colon adenocarcinoma. Carcinogenesis 2004; 25: 241-8.
11. Gingras AC, Raught B and Sonenberg N. mTOR signaling to translation. Curr Topics Microbiol Immunol 2004; 15: 147-59.
12. Wullschleger S, Loewith R, Hall MN. TOR signalling in growth and metabolism. Cell 2006; 124: 471-84.
13. Johnson SM, Gulhati P, Rampy BA. Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer. J Am Coll Surg 2010; 210: 767-76.
14. Semba S, Itoh N, Ito M, Harada M, Yamakawa M. The in vitro and in vivo effects of 2-(4-morpholinyl)-8-phenyl-chromone (LY294002), a specific inhibitor of phosphatidylinositol 3'-kinase, in human colon cancer cells. Clin Cancer Res 2002; 8: 1957-63.
15. Mallawaaratchy DM, Mactier S, Kaufman KL, Blomfield K, Christopherson RI. The phosphoinositide 3-kinase inhibitor LY294002, decreases aminoacyl-tRNA synthetases, chaperones and glycolytic enzymes in human HT-29 colorectal cancer cells. J Proteomics 2012, 75: 1590-9.
16. Roche Diagnostics GmbH. Introduction of the RTCA SP Instrument. RTCA SP Instrument Operators Manuel, A. Acea Biosciences, Inc. 2008; 14-16.
17. Lieu C, Kopetz S. The SRC family of protein tyrosine kinases: A new and promising target for colorectal cancer therapy. Clin Colorectal Cancer 2010; 9: 89-94.
18. Manzano A, Perez-Segura P. Colorectal cancer chemoprevention: Is this the future of colorectal cancer prevention? Sceintific Worald Journal 2012; 327341.
19. Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 2005; 9: 59-71.
20. Raufman JP, Shant J, Guo CY, Roy S, Cheng K. Deoxycholyltaurine rescues human colon cancer cells from apoptosis by activating EGFR-dependent PI3K/Akt signaling. J Cell Physiol 2008, 215: 538-49.
21. Brugge J, Hung MC, Mills GB. A new mutational AKTivation in the PI3K pathway. Cancer Cell 2007; 12:104-7.
22. Roy HK, Olusola BF, Clemens DL. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis 2002; 23:201-5.
23. Colakoglu T, Yildirim S, Kayaselcuk F. Clinicopathological significance of PTEN loss and the phosphoinositide 3-kinase/Akt pathway in sporadic colorectal neoplasms: Is PTEN loss predictor of local recurrence? Am J Surg 2008; 195: 719-25.
24. Rychahou PG, Murillo CA, Evers BM. Targeted RNA interference of PI3K pathway components sensitizes colon cancer cells to TNF-related apoptosis- inducing ligand (TRAIL). Surgery 2005; 138: 391-7.
25. Rychahou PG, Kang J, Gulhati P. Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis. Proc Natl Acad Sci U S A 2008; 105: 20315-20.
26. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007; 12: 9-22.
27. Sarbassov DD, Ali SM, Kim DH. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 27; 14: 1296-303.
28. Jastrzebski K, Hannan KM, Tchoubrieva EB, Hannan RD, Pearson RB. Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function. Growth Factors 2007, 25: 209-26.
29. Gulhati P, Cai Q, Li J. Targeted inhibition of mTOR signaling inhibits tumorigenesis of colorectal cancer. Clin Cancer Res 2009; 15: 7207-16.
30. Koehl GE, Spitzner M, Ousingsawat J. Rapamycin inhibits oncogenic intestinal ion channels and neoplasia in APC (Min/+) mice. Oncogene 2010; 29: 1553-60.