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Kolorektal Kanserde Rapamisin ve Vemurafenib’in Apoptotik Etkilerinin Karşılaştırılması

Year 2023, Volume: 49 Issue: 3, 331 - 336, 31.12.2023

Hilal Nakkaş Tuba Özdemir Sancı Beyza Ecem Öz Bedir Emine Terzi

https://doi.org/10.32708/uutfd.1376556

Abstract

Kolorektal kanser (KRK), dünyada en sık görülen üçüncü kanser türüdür. KRK’de ilk tedavi seçeneği cerrahi ve kemoterapidir. Ancak, kullanılan ilaçlara karşı gelişen direnç, uygulanan kemoterapinin başarısız olmasına yol açmaktadır. Son yıllarda yeni teröpatik ajan arayışları, KRK gelişimi ve ilerlemesinde rol oynayan farklı moleküler mekanizmalar üzerinde yoğunlaşmaktadır. mTOR ve MAPK sinyal yolaklarının KRK gelişiminde anahtar rol oynadığı bilinmektedir. Bu çalışmada, KRK hücrelerinde mTOR yolağı inhibitörü Rapamisin (RAPA) ve MAPK yolağı inhibitörü Vemurafenib (VMF)’in apoptoz üzerine olan etkilerinin karşılaştırılması amaçlanmıştır. Çalışmamızda, insan KRK hücrelerinde üretilen HT29 hücre hattı kültüre edilmiştir. RAPA ve VMF’nin HT29 KRK hücreleri üzerindeki uygun dozunun belirlenmesi için WST-1 testi ve apoptotik etkilerinin belirlenmesi amacıyla da akım sitometrisi yöntemi kullanılmıştır. İstatistiksel anlamlılık düzeyi p≤0.05 olarak kabul edilmiştir. Elde ettiğimiz verilere göre, HT29 hücrelerine uygulanacak olan RAPA ve VMF dozu 24. saatte sırasıyla 46,97 μM ve 35,84 μM olarak bulunmuştur. HT29 hücrelerinde RAPA’nın apoptotik süreç üzerinde VMF’den daha etkin olduğu bulunmuştur (RAPA için; p<0.0001, VMF için; p<0.01). Sonuç olarak, çalışmamızda RAPA ve VMF’nin HT29 kolorektal kanser hücrelerinin canlılığını azalttığı ve apoptozu kaspaz 3/7 yolu ile indüklediği görülmüştür.

Keywords

Kolorektal kanser mTOR MAPK Rapamisin Vemurafenib

References

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  • 2. Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 2019 Dec;16(12):713-732. doi: 10.1038/s41575-019-0189-8.
  • 3. Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, Bray F. Cancer statistics for the year 2020: An overview. Int J Cancer. 2021 Apr 5.
  • 4. Hossain MS, Karuniawati H, Jairoun AA, Urbi Z, Ooi J, John A, Lim YC, Kibria KMK, Mohiuddin AKM, Ming LC, Goh KW, Hadi MA. Colorectal Cancer: A Review of Carcinogenesis, Global Epidemiology, Current Challenges, Risk Factors, Preventive and Treatment Strategies. Cancers (Basel). 2022 Mar 29;14(7):1732. doi: 10.3390/cancers14071732
  • 5. Mármol I, Sánchez-de-Diego C, Pradilla Dieste A, Cerrada E, Rodriguez Yoldi MJ. Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer. Int J Mol Sci. 2017 Jan 19;18(1):197. doi: 10.3390/ijms18010197.
  • 6. Karl J, Wild N, Tacke M, Andres H, Garczarek U, Rollinger W, et.al. Improved diagnosis of colorectal cancer using a combination of fecal occult blood and novel fecal protein markers. Clin Gastroenterol Hepatol. 2008 Oct;6(10):1122-8.
  • 7. Messersmith WA. NCCN Guidelines Updates: Management of Metastatic Colorectal Cancer. J Natl Compr Canc Netw. 2019 May 1;17(5.5):599-601. doi: 10.6004/jnccn.2019.5014.
  • 8. Farooqi AA, de la Roche M, Djamgoz MBA, Siddik ZH. Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights. Semin Cancer Biol. 2019 Oct;58:65-79.
  • 9. Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer. 2019 Feb 19;18(1):26. doi: 10.1186/s12943-019-0954-x.
  • 10. Afzal O, Altamimi ASA, Mubeen B, Alzarea SI, Almalki WH, Al-Qahtani SD, Atiya EM, Al-Abbasi FA, Ali F, Ullah I, Nadeem MS, Kazmi I. mTOR as a Potential Target for the Treatment of Microbial Infections, Inflammatory Bowel Diseases, and Colorectal Cancer. Int J Mol Sci. 2022 Oct 18;23(20):12470. doi: 10.3390/ijms232012470.
  • 11. Hua H, Kong Q, Zhang H, Wang J, Luo T, Jiang Y. Targeting mTOR for cancer therapy. J Hematol Oncol. 2019 Jul 5;12(1):71. doi: 10.1186/s13045-019-0754-1.
  • 12. Caputo F, Santini C, Bardasi C, Cerma K, Casadei-Gardini A, Spallanzani A, Andrikou K, Cascinu S, Gelsomino F. BRAF-Mutated Colorectal Cancer: Clinical and Molecular Insights. Int J Mol Sci. 2019 Oct 28;20(21):5369. doi: 10.3390/ijms20215369.
  • 13. Hertzman Johansson C, Egyhazi Brage S. BRAF inhibitors in cancer therapy. Pharmacology & Therapeutics, 2014, 142(2):176-82.
  • 14. Roskoski R. Properties of FDA-approved small molecule protein kinase inhibitors. Pharmacological Research, 2019, 144:19-50.
  • 15. Zaman A, Wu W, Bivona TG. Targeting Oncogenic BRAF: Past, Present, and Future, Cancers (Basel), 2019, 11(8):1197.
  • 16. Stefani C, Miricescu D, Stanescu-Spinu II, Nica RI, Greabu M, Totan AR, Jinga M. Growth Factors, PI3K/AKT/mTOR and MAPK Signaling Pathways in Colorectal Cancer Pathogenesis: Where Are We Now? Int J Mol Sci. 2021 Sep 23;22(19):10260. doi: 10.3390/ijms221910260.
  • 17. Kikuchi K, Hoshino D. Sensitization of HT29 colorectal cancer cells to vemurafenib in three-dimensional collagen cultures. Cell Biol Int. 2020 Feb;44(2):621-629. doi: 10.1002/cbin.11262.
  • 18. Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020 Mar 20;5(1):22. doi: 10.1038/s41392-020-0116-z.
  • 19. Tiwari A, Saraf S, Verma A, Panda PK, Jain SK. Novel targeting approaches and signaling pathways of colorectal cancer: An insight. World J Gastroenterol. 2018 Oct 21;24(39):4428-4435. doi: 10.3748/wjg.v24.i39.4428.
  • 20. Li J, Kim SG, Blenis J. Rapamycin: one drug, many effects. Cell Metab. 2014 Mar 4;19(3):373-9. doi: 10.1016/j.cmet.2014.01.001.
  • 21. Alayev A, Berger SM, Kramer MY, Schwartz NS, Holz MK. The combination of rapamycin and resveratrol blocks autophagy and induces apoptosis in breast cancer cells. J Cell Biochem. 2015 Mar;116(3):450-7.
  • 22. Dai ZJ, Gao J, Ma XB, Kang HF, Wang BF, Lu WF, et.al. Antitumor effects of rapamycin in pancreatic cancer cells by inducing apoptosis and autophagy. Int J Mol Sci. 2012 Dec 21;14(1):273-85.
  • 23. Shafer A, Zhou C, Gehrig PA, Boggess JF, Bae-Jump VL. Rapamycin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and induction of apoptosis. Int J Cancer. 2010 Mar 1;126(5):1144-54.
  • 24. Eng CP, Sehgal SN, Vézina C. Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo). 1984 Oct;37(10):1231-7. doi: 10.7164/antibiotics.37.1231.
  • 25. Li S, Yang G, Zhu X, Cheng L, Sun Y, Zhao Z. Combination of rapamycin and garlic-derived S-allylmercaptocysteine induces colon cancer cell apoptosis and suppresses tumor growth in xenograft nude mice through autophagy/p62/Nrf2 pathway. Oncol Rep. 2017 Sep;38(3):1637-1644.
  • 26. Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, Hirth P. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov. 2012 Nov;11(11):873-86. doi: 10.1038/nrd3847.
  • 27. Kopetz S, Desai J, Chan E, Hecht JR, O'Dwyer PJ, Maru D, Morris V, Janku F, Dasari A, Chung W, Issa JP, Gibbs P, James B, Powis G, Nolop KB, Bhattacharya S, Saltz L. Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer. J Clin Oncol. 2015 Dec 1;33(34):4032-8. doi: 10.1200/JCO.2015.63.2497.
  • 28. Hu M, Yu Z, Mei P, Li J, Luo D, Zhang H, Zhou M, Liang F, Chen R. Lycorine Induces autophagy-associated apoptosis by targeting MEK2 and enhances vemurafenib activity in colorectal cancer. Aging (Albany NY). 2020 Jan 3;12(1):138-155. doi: 10.18632/aging.102606.
  • 29. Hong DS, Morris VK, El Osta B, Sorokin AV, Janku F, Fu S, et.al. Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation. Cancer Discov. 2016 Dec;6(12):1352-1365.
  • 30. Zhi J, Li Z, Lv J, Feng B, Yang D, Xue L, et.al. Effects of PHA-665752 and vemurafenib combination treatment on in vitro and murine xenograft growth of human colorectal cancer cells with BRAFV600E mutations. Oncol Lett. 2018 Mar;15(3):3904-3910.

Comparison of Apoptotic Effects of Rapamycin and Vemurafenib in Colorectal Cancer

Year 2023, Volume: 49 Issue: 3, 331 - 336, 31.12.2023

Hilal Nakkaş Tuba Özdemir Sancı Beyza Ecem Öz Bedir Emine Terzi

https://doi.org/10.32708/uutfd.1376556

Abstract

The third most prevalent cancer in the world is colorectal cancer (CRC). Chemotherapy and surgery are the primary CRC treatments. Patients with CRC develop resistance to the chemotherapy treatments, which leads to the chemotherapy's failure. Due to this, various molecular processes that contribute to the development and progression of CRC have come into attention recently. mTOR and MAPK signaling pathways are crucial for the growth of CRC and mTOR pathway inhibitor RAPA and the MAPK pathway inhibitor VMF affected the apoptosis of CRC cells. Human CRC cells HT29 were cultured. The WST-1 test was used to identify the optimum dose of RAPA and VMF on HT29 CRC cells. To determine the apoptotic effects of RAPA and VMF on HT29 cells, flow cytometry was performed. Statistical significance level was accepted as p≤0.05. According to the data we obtained, the dose of RAPA and VMF to be applied to HT29 cells was found to be 46.97 μM and 35.84 μM, respectively, at the 24th hour. RAPA was found to have a greater impact on apoptosis in HT29 cells than VMF (p<0.0001 for RAPA, p<0.01 for VMF). In summary, our study found that RAPA and VMF decreased the viability of HT29 colorectal cancer cells and caused apoptosis via the caspase 3/7 pathway.

Keywords

Colorectal cancer mTOR MAPK Rapamycin Vemurafenib

References

  • 1. Katsaounou K, Nicolaou E, Vogazianos P, Brown C, Stavrou M, Teloni S, Hatzis P, Agapiou A, Fragkou E, Tsiaoussis G, Potamitis G, Zaravinos A, Andreou C, Antoniades A, Shiammas C, Apidianakis Y. Colon Cancer: From Epidemiology to Prevention. Metabolites. 2022 May 30;12(6):499
  • 2. Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 2019 Dec;16(12):713-732. doi: 10.1038/s41575-019-0189-8.
  • 3. Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, Bray F. Cancer statistics for the year 2020: An overview. Int J Cancer. 2021 Apr 5.
  • 4. Hossain MS, Karuniawati H, Jairoun AA, Urbi Z, Ooi J, John A, Lim YC, Kibria KMK, Mohiuddin AKM, Ming LC, Goh KW, Hadi MA. Colorectal Cancer: A Review of Carcinogenesis, Global Epidemiology, Current Challenges, Risk Factors, Preventive and Treatment Strategies. Cancers (Basel). 2022 Mar 29;14(7):1732. doi: 10.3390/cancers14071732
  • 5. Mármol I, Sánchez-de-Diego C, Pradilla Dieste A, Cerrada E, Rodriguez Yoldi MJ. Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer. Int J Mol Sci. 2017 Jan 19;18(1):197. doi: 10.3390/ijms18010197.
  • 6. Karl J, Wild N, Tacke M, Andres H, Garczarek U, Rollinger W, et.al. Improved diagnosis of colorectal cancer using a combination of fecal occult blood and novel fecal protein markers. Clin Gastroenterol Hepatol. 2008 Oct;6(10):1122-8.
  • 7. Messersmith WA. NCCN Guidelines Updates: Management of Metastatic Colorectal Cancer. J Natl Compr Canc Netw. 2019 May 1;17(5.5):599-601. doi: 10.6004/jnccn.2019.5014.
  • 8. Farooqi AA, de la Roche M, Djamgoz MBA, Siddik ZH. Overview of the oncogenic signaling pathways in colorectal cancer: Mechanistic insights. Semin Cancer Biol. 2019 Oct;58:65-79.
  • 9. Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer. 2019 Feb 19;18(1):26. doi: 10.1186/s12943-019-0954-x.
  • 10. Afzal O, Altamimi ASA, Mubeen B, Alzarea SI, Almalki WH, Al-Qahtani SD, Atiya EM, Al-Abbasi FA, Ali F, Ullah I, Nadeem MS, Kazmi I. mTOR as a Potential Target for the Treatment of Microbial Infections, Inflammatory Bowel Diseases, and Colorectal Cancer. Int J Mol Sci. 2022 Oct 18;23(20):12470. doi: 10.3390/ijms232012470.
  • 11. Hua H, Kong Q, Zhang H, Wang J, Luo T, Jiang Y. Targeting mTOR for cancer therapy. J Hematol Oncol. 2019 Jul 5;12(1):71. doi: 10.1186/s13045-019-0754-1.
  • 12. Caputo F, Santini C, Bardasi C, Cerma K, Casadei-Gardini A, Spallanzani A, Andrikou K, Cascinu S, Gelsomino F. BRAF-Mutated Colorectal Cancer: Clinical and Molecular Insights. Int J Mol Sci. 2019 Oct 28;20(21):5369. doi: 10.3390/ijms20215369.
  • 13. Hertzman Johansson C, Egyhazi Brage S. BRAF inhibitors in cancer therapy. Pharmacology & Therapeutics, 2014, 142(2):176-82.
  • 14. Roskoski R. Properties of FDA-approved small molecule protein kinase inhibitors. Pharmacological Research, 2019, 144:19-50.
  • 15. Zaman A, Wu W, Bivona TG. Targeting Oncogenic BRAF: Past, Present, and Future, Cancers (Basel), 2019, 11(8):1197.
  • 16. Stefani C, Miricescu D, Stanescu-Spinu II, Nica RI, Greabu M, Totan AR, Jinga M. Growth Factors, PI3K/AKT/mTOR and MAPK Signaling Pathways in Colorectal Cancer Pathogenesis: Where Are We Now? Int J Mol Sci. 2021 Sep 23;22(19):10260. doi: 10.3390/ijms221910260.
  • 17. Kikuchi K, Hoshino D. Sensitization of HT29 colorectal cancer cells to vemurafenib in three-dimensional collagen cultures. Cell Biol Int. 2020 Feb;44(2):621-629. doi: 10.1002/cbin.11262.
  • 18. Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020 Mar 20;5(1):22. doi: 10.1038/s41392-020-0116-z.
  • 19. Tiwari A, Saraf S, Verma A, Panda PK, Jain SK. Novel targeting approaches and signaling pathways of colorectal cancer: An insight. World J Gastroenterol. 2018 Oct 21;24(39):4428-4435. doi: 10.3748/wjg.v24.i39.4428.
  • 20. Li J, Kim SG, Blenis J. Rapamycin: one drug, many effects. Cell Metab. 2014 Mar 4;19(3):373-9. doi: 10.1016/j.cmet.2014.01.001.
  • 21. Alayev A, Berger SM, Kramer MY, Schwartz NS, Holz MK. The combination of rapamycin and resveratrol blocks autophagy and induces apoptosis in breast cancer cells. J Cell Biochem. 2015 Mar;116(3):450-7.
  • 22. Dai ZJ, Gao J, Ma XB, Kang HF, Wang BF, Lu WF, et.al. Antitumor effects of rapamycin in pancreatic cancer cells by inducing apoptosis and autophagy. Int J Mol Sci. 2012 Dec 21;14(1):273-85.
  • 23. Shafer A, Zhou C, Gehrig PA, Boggess JF, Bae-Jump VL. Rapamycin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and induction of apoptosis. Int J Cancer. 2010 Mar 1;126(5):1144-54.
  • 24. Eng CP, Sehgal SN, Vézina C. Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo). 1984 Oct;37(10):1231-7. doi: 10.7164/antibiotics.37.1231.
  • 25. Li S, Yang G, Zhu X, Cheng L, Sun Y, Zhao Z. Combination of rapamycin and garlic-derived S-allylmercaptocysteine induces colon cancer cell apoptosis and suppresses tumor growth in xenograft nude mice through autophagy/p62/Nrf2 pathway. Oncol Rep. 2017 Sep;38(3):1637-1644.
  • 26. Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, Hirth P. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov. 2012 Nov;11(11):873-86. doi: 10.1038/nrd3847.
  • 27. Kopetz S, Desai J, Chan E, Hecht JR, O'Dwyer PJ, Maru D, Morris V, Janku F, Dasari A, Chung W, Issa JP, Gibbs P, James B, Powis G, Nolop KB, Bhattacharya S, Saltz L. Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer. J Clin Oncol. 2015 Dec 1;33(34):4032-8. doi: 10.1200/JCO.2015.63.2497.
  • 28. Hu M, Yu Z, Mei P, Li J, Luo D, Zhang H, Zhou M, Liang F, Chen R. Lycorine Induces autophagy-associated apoptosis by targeting MEK2 and enhances vemurafenib activity in colorectal cancer. Aging (Albany NY). 2020 Jan 3;12(1):138-155. doi: 10.18632/aging.102606.
  • 29. Hong DS, Morris VK, El Osta B, Sorokin AV, Janku F, Fu S, et.al. Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation. Cancer Discov. 2016 Dec;6(12):1352-1365.
  • 30. Zhi J, Li Z, Lv J, Feng B, Yang D, Xue L, et.al. Effects of PHA-665752 and vemurafenib combination treatment on in vitro and murine xenograft growth of human colorectal cancer cells with BRAFV600E mutations. Oncol Lett. 2018 Mar;15(3):3904-3910.
There are 30 citations in total.

Details

Primary Language Turkish
Subjects Biochemistry and Cell Biology (Other)
Journal Section Research Article
Authors

Hilal Nakkaş 0000-0003-0901-8875

Tuba Özdemir Sancı 0000-0002-9468-4719

Beyza Ecem Öz Bedir 0000-0002-0596-834X

Emine Terzi 0000-0001-9106-3848

Publication Date December 31, 2023
Submission Date October 16, 2023
Acceptance Date November 21, 2023
Published in Issue Year 2023 Volume: 49 Issue: 3

Cite

APA Nakkaş, H., Özdemir Sancı, T., Öz Bedir, B. E., Terzi, E. (2023). Kolorektal Kanserde Rapamisin ve Vemurafenib’in Apoptotik Etkilerinin Karşılaştırılması. Uludağ Üniversitesi Tıp Fakültesi Dergisi, 49(3), 331-336. https://doi.org/10.32708/uutfd.1376556
AMA Nakkaş H, Özdemir Sancı T, Öz Bedir BE, Terzi E. Kolorektal Kanserde Rapamisin ve Vemurafenib’in Apoptotik Etkilerinin Karşılaştırılması. Uludağ Tıp Derg. December 2023;49(3):331-336. doi:10.32708/uutfd.1376556
Chicago Nakkaş, Hilal, Tuba Özdemir Sancı, Beyza Ecem Öz Bedir, and Emine Terzi. “Kolorektal Kanserde Rapamisin Ve Vemurafenib’in Apoptotik Etkilerinin Karşılaştırılması”. Uludağ Üniversitesi Tıp Fakültesi Dergisi 49, no. 3 (December 2023): 331-36. https://doi.org/10.32708/uutfd.1376556.
EndNote Nakkaş H, Özdemir Sancı T, Öz Bedir BE, Terzi E (December 1, 2023) Kolorektal Kanserde Rapamisin ve Vemurafenib’in Apoptotik Etkilerinin Karşılaştırılması. Uludağ Üniversitesi Tıp Fakültesi Dergisi 49 3 331–336.
IEEE H. Nakkaş, T. Özdemir Sancı, B. E. Öz Bedir, and E. Terzi, “Kolorektal Kanserde Rapamisin ve Vemurafenib’in Apoptotik Etkilerinin Karşılaştırılması”, Uludağ Tıp Derg, vol. 49, no. 3, pp. 331–336, 2023, doi: 10.32708/uutfd.1376556.
ISNAD Nakkaş, Hilal et al. “Kolorektal Kanserde Rapamisin Ve Vemurafenib’in Apoptotik Etkilerinin Karşılaştırılması”. Uludağ Üniversitesi Tıp Fakültesi Dergisi 49/3 (December 2023), 331-336. https://doi.org/10.32708/uutfd.1376556.
JAMA Nakkaş H, Özdemir Sancı T, Öz Bedir BE, Terzi E. Kolorektal Kanserde Rapamisin ve Vemurafenib’in Apoptotik Etkilerinin Karşılaştırılması. Uludağ Tıp Derg. 2023;49:331–336.
MLA Nakkaş, Hilal et al. “Kolorektal Kanserde Rapamisin Ve Vemurafenib’in Apoptotik Etkilerinin Karşılaştırılması”. Uludağ Üniversitesi Tıp Fakültesi Dergisi, vol. 49, no. 3, 2023, pp. 331-6, doi:10.32708/uutfd.1376556.
Vancouver Nakkaş H, Özdemir Sancı T, Öz Bedir BE, Terzi E. Kolorektal Kanserde Rapamisin ve Vemurafenib’in Apoptotik Etkilerinin Karşılaştırılması. Uludağ Tıp Derg. 2023;49(3):331-6.
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