Novel chemotherapeutic agent, FND-4b, activates AMPK and inhibits colorectal cancer cell proliferation


Autoři: Heather F. Sinner aff001;  Jeremy Johnson aff003;  Piotr G. Rychahou aff001;  David S. Watt aff004;  Yekaterina Y. Zaytseva aff002;  Chunming Liu aff002;  B. Mark Evers aff001
Působiště autorů: Department of Surgery, University of Kentucky, Lexington, Kentucky, United States of America aff001;  Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States of America aff002;  Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, United States of America aff003;  Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America aff004;  Center for Molecular Medicine, Organic Synthesis Core, University of Kentucky, Lexington, Kentucky, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224253

Souhrn

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the US with the majority of deaths due to metastatic disease. Current chemotherapeutic regimens involve highly toxic agents, which limits their utility; therefore, more effective and less toxic agents are required to see a reduction in CRC mortality. Novel fluorinated N,N’-diarylureas (FND) were developed and characterized by our group as potent activators of adenosine monophosphate-activated kinase (AMPK) that inhibit cell cycle progression. The purpose of this study was to determine the effect of a lead FND compound, FND-4b, either alone or combined with PI-103 (a dual PI3K/mTOR inhibitor) or SN-38 (active metabolite of irinotecan) on cell cycle arrest and apoptosis of CRC cell lines (both commercially-available and novel lines established from our patient population). Treatment with FND-4b for 24h resulted in a marked induction of phosphorylated AMPK expression and a concomitant reduction in markers of cell proliferation, such as cyclin D1, in all CRC cell lines. Apoptosis was also notably increased in CRC cells treated with FND-4b. Regardless of the genetic profile of the CRC cells, FND-4b treatment alone resulted in decreased cell proliferation. Moreover, the combination of FND-4b with PI-103 resulted in increased cell death in all cell lines, while the combination of FND-4b with SN-38 resulted in increased cell death in select cell lines. Our findings identify FND-4b, which activates AMPK at micromolar concentrations, as a novel and effective inhibitor of CRC growth either alone or in combination with PI-103 and SN-38.

Klíčová slova:

Apoptosis – Cancer treatment – Cell cycle and cell division – Cell cycle inhibitors – Cell proliferation – Colorectal cancer – Drug therapy – HT29 cells


Zdroje

1. Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177–93. Epub 2017/03/02. doi: 10.3322/caac.21395 28248415.

2. Gill S, Blackstock AW, Goldberg RM. Colorectal cancer. Mayo Clin Proc. 2007;82(1):114–29. Epub 2007/02/09. doi: 10.4065/82.1.114 17285793.

3. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386–422. Epub 2016/07/07. doi: 10.1093/annonc/mdw235 27380959.

4. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205(2):275–92. Epub 2005/01/11. doi: 10.1002/path.1706 15641020.

5. Luo Z, Zang M, Guo W. AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol. 2010;6(3):457–70. Epub 2010/03/13. doi: 10.2217/fon.09.174 20222801.

6. Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9(8):563–75. Epub 2009/07/25. doi: 10.1038/nrc2676 19629071.

7. Faubert B, Vincent EE, Poffenberger MC, Jones RG. The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator. Cancer Lett. 2015;356(2 Pt A):165–70. Epub 2014/02/04. doi: 10.1016/j.canlet.2014.01.018 24486219.

8. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304–5. Epub 2005/04/26. doi: 10.1136/bmj.38415.708634.F7 15849206.

9. Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007;67(14):6745–52. Epub 2007/07/20. doi: 10.1158/0008-5472.CAN-06-4447 17638885.

10. Sviripa V, Zhang W, Conroy MD, Schmidt ES, Liu AX, Truong J, et al. Fluorinated N,N'-diarylureas as AMPK activators. Bioorg Med Chem Lett. 2013;23(6):1600–3. Epub 2013/02/19. doi: 10.1016/j.bmcl.2013.01.096 23414799.

11. Carr BI, Cavallini A, Lippolis C, D’Alessandro R, Messa C, Refolo MG, et al. Fluoro-Sorafenib (Regorafenib) effects on hepatoma cells: growth inhibition, quiescence, and recovery. J Cell Physiol. 2013;228(2):292–7. Epub 2012/07/11. doi: 10.1002/jcp.24148 22777740.

12. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006;5(10):835–44. Epub 2006/10/04. doi: 10.1038/nrd2130 17016424.

13. Kenlan DE, Rychahou P, Sviripa VM, Weiss HL, Liu C, Watt DS, et al. Fluorinated N,N'-Diarylureas As Novel Therapeutic Agents Against Cancer Stem Cells. Mol Cancer Ther. 2017;16(5):831–7. Epub 2017/03/05. doi: 10.1158/1535-7163.MCT-15-0634 28258165.

14. Kojima K, Shimanuki M, Shikami M, Samudio IJ, Ruvolo V, Corn P, et al. The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia. 2008;22(9):1728–36. Epub 2008/06/13. doi: 10.1038/leu.2008.158 18548093.

15. Yi YW, Kang HJ, Bae EJ, Oh S, Seong YS, Bae I. beta-TrCP1 degradation is a novel action mechanism of PI3K/mTOR inhibitors in triple-negative breast cancer cells. Exp Mol Med. 2015;47:e143. Epub 2015/02/28. doi: 10.1038/emm.2014.127 25721419.

16. Lopez-Fauqued M, Gil R, Grueso J, Hernandez-Losa J, Pujol A, Moline T, et al. The dual PI3K/mTOR inhibitor PI-103 promotes immunosuppression, in vivo tumor growth and increases survival of sorafenib-treated melanoma cells. Int J Cancer. 2010;126(7):1549–61. Epub 2009/10/08. doi: 10.1002/ijc.24926 19810100.

17. Yi YW, Hong W, Kang HJ, Kim HJ, Zhao W, Wang A, et al. Inhibition of the PI3K/AKT pathway potentiates cytotoxicity of EGFR kinase inhibitors in triple-negative breast cancer cells. J Cell Mol Med. 2013;17(5):648–56. Epub 2013/04/23. doi: 10.1111/jcmm.12046 23601074.

18. Kulkarni AA, Roy B, Rao PS, Wyant GA, Mahmoud A, Ramachandran M, et al. Supramolecular nanoparticles that target phosphoinositide-3-kinase overcome insulin resistance and exert pronounced antitumor efficacy. Cancer Res. 2013;73(23):6987–97. Epub 2013/10/15. doi: 10.1158/0008-5472.CAN-12-4477 24121488.

19. Ueno M, Nonaka S, Yamazaki R, Deguchi N, Murai M. SN-38 induces cell cycle arrest and apoptosis in human testicular cancer. Eur Urol. 2002;42(4):390–7. Epub 2002/10/04. doi: 10.1016/s0302-2838(02)00321-4 12361906.

20. Berg KCG, Eide PW, Eilertsen IA, Johannessen B, Bruun J, Danielsen SA, et al. Multi-omics of 34 colorectal cancer cell lines—a resource for biomedical studies. Molecular Cancer. 2017;16(1):116. doi: 10.1186/s12943-017-0691-y 28683746

21. Arkwright RT, Deshmukh R, Adapa N, Stevens R, Zonder E, Zhang Z, et al. Lessons from Nature: Sources and Strategies for Developing AMPK Activators for Cancer Chemotherapeutics. Anticancer Agents Med Chem. 2015;15(5):657–71. Epub 2014/12/17. 25511514.

22. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009;69(19):7507–11. Epub 2009/09/16. doi: 10.1158/0008-5472.CAN-09-2994 19752085.

23. Lee KC, Lin CT, Chang SF, Chen CN, Liu JL, Huang WS. Effect of AICAR and 5-Fluorouracil on X-ray Repair, Cross-Complementing Group 1 Expression, and Consequent Cytotoxicity Regulation in Human HCT-116 Colorectal Cancer Cells. Int J Mol Sci. 2017;18(11). Epub 2017/11/09. doi: 10.3390/ijms18112363 29117108.

24. Jose C, Hebert-Chatelain E, Bellance N, Larendra A, Su M, Nouette-Gaulain K, et al. AICAR inhibits cancer cell growth and triggers cell-type distinct effects on OXPHOS biogenesis, oxidative stress and Akt activation. Biochim Biophys Acta. 2011;1807(6):707–18. Epub 2011/06/22. doi: 10.1016/j.bbabio.2010.12.002 21692240.

25. Yung MM, Chan DW, Liu VW, Yao KM, Ngan HY. Activation of AMPK inhibits cervical cancer cell growth through AKT/FOXO3a/FOXM1 signaling cascade. BMC Cancer. 2013;13:327. Epub 2013/07/04. doi: 10.1186/1471-2407-13-327 23819460.

26. Song CW, Lee H, Dings RP, Williams B, Powers J, Santos TD, et al. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Sci Rep. 2012;2:362. Epub 2012/04/14. doi: 10.1038/srep00362 22500211.

27. Chen X, Xie C, Fan XX, Jiang ZB, Wong VK, Xu JH, et al. Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid metabolism. Oncotarget. 2017;8(56):96089–102. Epub 2017/12/10. doi: 10.18632/oncotarget.21716 29221189.

28. Law BYK, Gordillo-Martinez F, Qu YQ, Zhang N, Xu SW, Coghi PS, et al. Thalidezine, a novel AMPK activator, eliminates apoptosis-resistant cancer cells through energy-mediated autophagic cell death. Oncotarget. 2017;8(18):30077–91. Epub 2017/04/14. doi: 10.18632/oncotarget.15616 28404910.

29. Valtorta S, Nicolini G, Tripodi F, Meregalli C, Cavaletti G, Avezza F, et al. A novel AMPK activator reduces glucose uptake and inhibits tumor progression in a mouse xenograft model of colorectal cancer. Invest New Drugs. 2014;32(6):1123–33. Epub 2014/08/20. doi: 10.1007/s10637-014-0148-8 25134489.

30. Li C, Liu VW, Chan DW, Yao KM, Ngan HY. LY294002 and metformin cooperatively enhance the inhibition of growth and the induction of apoptosis of ovarian cancer cells. Int J Gynecol Cancer. 2012;22(1):15–22. Epub 2011/11/15. doi: 10.1097/IGC.0b013e3182322834 22080879.

31. Maurya AK, Vinayak M. PI-103 and Quercetin Attenuate PI3K-AKT Signaling Pathway in T- Cell Lymphoma Exposed to Hydrogen Peroxide. PLoS One. 2016;11(8):e0160686. Epub 2016/08/06. doi: 10.1371/journal.pone.0160686 27494022.

32. Jang NY, Kim DH, Cho BJ, Choi EJ, Lee JS, Wu HG, et al. Radiosensitization with combined use of olaparib and PI-103 in triple-negative breast cancer. BMC Cancer. 2015;15:89. Epub 2015/04/18. doi: 10.1186/s12885-015-1090-7 25884663.

33. Jokinen E, Laurila N, Koivunen JP. Alternative dosing of dual PI3K and MEK inhibition in cancer therapy. BMC Cancer. 2012;12:612. Epub 2012/12/25. doi: 10.1186/1471-2407-12-612 23259591.

34. Network NCC. NCCN Guidelines Version 2.2018 Colon Cancer Fort Washington, PA: N ational Comprehensive Cancer Network; [cited 2018]. www.nccn.org.

35. Marsh S, Hoskins JM. Irinotecan pharmacogenomics. Pharmacogenomics. 2010;11(7):1003–10. Epub 2010/07/07. doi: 10.2217/pgs.10.95 20602618.

36. Panczyk M. Pharmacogenetics research on chemotherapy resistance in colorectal cancer over the last 20 years. World J Gastroenterol. 2014;20(29):9775–827. Epub 2014/08/12. 25110414.

37. Encarnacao JC, Pires AS, Amaral RA, Goncalves TJ, Laranjo M, Casalta-Lopes JE, et al. Butyrate, a dietary fiber derivative that improves irinotecan effect in colon cancer cells. J Nutr Biochem. 2018;56:183–92. Epub 2018/03/28. doi: 10.1016/j.jnutbio.2018.02.018 29587241.

38. Tahara M, Inoue T, Sato F, Miyakura Y, Horie H, Yasuda Y, et al. The use of Olaparib (AZD2281) potentiates SN-38 cytotoxicity in colon cancer cells by indirect inhibition of Rad51-mediated repair of DNA double-strand breaks. Mol Cancer Ther. 2014;13(5):1170–80. Epub 2014/03/01. doi: 10.1158/1535-7163.MCT-13-0683 24577941.

39. Bonetti A, Giuliani J, Muggia F. Targeted agents and oxaliplatin-containing regimens for the treatment of colon cancer. Anticancer Res. 2014;34(1):423–34. Epub 2014/01/10. 24403498.


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