Deneysel Renal Kanser Modelinde Thymoquinone ve Nivolumab’ın Potansiyel Sinerjistik Etkisi
Year 2026,
Volume: 11 Issue: 1, 92 - 97, 28.01.2026
Ahmet Dirican
,
Özde Elif Gökbayrak
,
Aylin Erol
,
Tekincan Çağrı Aktaş
,
Hatice Efsun Kolatan
,
Efe Özgür Serinan
,
Zekiye Altun
,
Işıl Somalı
,
Osman Yılmaz
,
Safiye Aktaş
Abstract
Amaç: Thymoquinone ve Nivolumab kombinasyonunun deneysel böbrek hücre kanseri modelleri üzerindeki etkilerini araştırdık. Thymoquinone, Nigella sativa tohumlarından çıkarılan biyolojik olarak aktif bir bileşiktir, Thymoquinone 'nun çeşitli kanserlere karşı anti-inflamatuar, antioksidan ve anti-tümör özellikleri vardır.
Gereç ve Yöntem: Thymoquinone ve Nivolumab’ın etkisi, Renca hücre hattı kullanılarak 3-(4,5-dimetiltiyazol-.2-yl)-2,5 difeniltetrazolyum-bromür ve Annexin-V + propidyum iyodür testleri ile analiz edildi. Renca hücreleri 8 haftalık erkek C57BL/6 farelerine subkutan olarak enjekte edildi. Gruplar kontrol, Thymoquinone, Nivolumab, Thymoquinone +Nivolumab olarak tasarlandı. Tümör dokuları, p<0,05 anlamlılık düzeyinde apoptoz/nekroz oranları, immünmarkerlerin ekspresyonu ve ribonükleik asit ekspresyonu açısından analiz edildi.
Bulgular: Bulgularımız, Thymoquinone 'nun hem in vitro hem de in vivo olarak anti-tümör etkileri olduğunu gösterdi. Nivolumab ile kombinasyon tedavisi, immün aracılı tümör hücre ölümü artışına yol açarak tümör dokusunda önemli nekroz veya tedaviye tam yanıt ile sonuçlandı.
Sonuç: Thymoquinone'un böbrek hücreli karsinom üzerinde anti-tümör etkisi olduğu ve Nivolumab'ın bağışıklık hücresi apoptozunu artırdığı sonucuna varılmıştır. Ayrıca, tek başına veya kombinasyon halinde kullanıldığında diğer organlarda yan etkisi yoktur.
Anahtar Kelimeler: Bağışıklık kontrol noktası inhibitörleri, böbrek hücreli kanseri, thymoquinone.
Project Number
2020.KB.SAG.047.
References
-
Lalani A-KA, Heng DYC, Basappa NS, Wood L, Iqbal N, McLeod D, et al. Evolving landscape of first-line combination therapy in advanced renal cancer: a systematic review. Nat Cancer. 2022;14:17588359221108684.
-
Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, et al. Cancer statistics for the year 2020: An overview. Int J Cancer. 2021;149(4):778–89.
-
Kane CJ, Mallin K, Ritchey J, Cooperberg MR, Carroll PR. Renal cell cancer stage migration: analysis of the National Cancer Data Base. Cancer. 2008;113(1):78–83.
-
Cumberbatch MG, Rota M, Catto JWF, La Vecchia C. The Role of Tobacco Smoke in Bladder and Kidney Carcinogenesis: A Comparison of Exposures and Meta-analysis of Incidence and Mortality Risks. Eur Urol. 2016;70(3):458–66.
-
Tsivian M, Moreira DM, Caso JR, Mouraviev V, Polascik TJ. Cigarette smoking is associated with advanced renal cell carcinoma. J Clin Oncol. 2011;29(15):2027–31.
-
Brennan JF, Stilmant MM, Babayan RK, Siroky MB. Acquired renal cystic disease: implications for the urologist. BJU Int. 1991;67(4):342–8.
-
Truong LD, Krishnan B, Cao JT, Barrios R, Suki WN. Renal neoplasm in acquired cystic kidney disease. Am J Kidney Dis. 1995;26(1):1–12.
-
Zisman A, Chao DH, Pantuck AJ, Kim HJ, Wieder JA, Figlin RA, et al. Unclassified renal cell carcinoma: clinical features and prognostic impact of a new histological subtype. J Urol. 2002;168(3):950–5.
-
Effenberger-Neidnicht K, Schobert R. Combinatorial effects of thymoquinone on the anti-cancer activity of doxorubicin. Cancer Chemother Pharmacol. 2011;67(4):867–74.
-
Jafri SH, Glass J, Shi R, Zhang S, Prince M, Kleiner-Hancock H. Thymoquinone and cisplatin as a therapeutic combination in lung cancer: In vitro and in vivo. J Exp Clin Cancer Res. 2010;29(1):87.
-
Li Q-X, Yu DH, Liu G, Ke N, McKelvy J, Wong-Staal F. Selective anticancer strategies via intervention of the death pathways relevant to cell transformation. Cell Death Differ. 2008;15(8):1197–210.
-
Torres MP, Ponnusamy MP, Chakraborty S, Smith LM, Das S, Arafat HA, et al. Effects of thymoquinone in the expression of mucin 4 in pancreatic cancer cells: implications for the development of novel cancer therapies. Mol Cancer Ther. 2010;9(5):1419–31.
-
Yi T, Cho S-G, Yi Z, Pang X, Rodriguez M, Wang Y, et al. Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol Cancer Ther. 2008;7(7):1789–96.
-
Pal SK, Ghate SR, Li N, Swallow E, Peeples M, Zichlin ML, et al. Real-World Survival Outcomes and Prognostic Factors Among Patients Receiving First Targeted Therapy for Advanced Renal Cell Carcinoma: A SEER-Medicare Database Analysis. Clin Genitourin Cancer. 2017;15(4):e573–82.
-
Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277–90.
-
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803–13.
-
Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019;393(10189):2404–15.
-
Gurung RL, Lim SN, Khaw AK, Soon JFF, Shenoy K, Mohamed Ali S, et al. Thymoquinone induces telomere shortening, DNA damage and apoptosis in human glioblastoma cells. PloS one. 2010;5(8):e12124.
-
Sadun RE, Sachsman SM, Chen X, Christenson KW, Morris WZ, Hu P, et al. Immune signatures of murine and human cancers reveal unique mechanisms of tumor escape and new targets for cancer immunotherapy. Clin Cancer Res. 2007;13(13):4016–25.
-
Adinew GM, Messeha SS, Taka E, Badisa RB, Antonie LM, Soliman KFA. Thymoquinone Alterations of the Apoptotic Gene Expressions and Cell Cycle Arrest in Genetically Distinct Triple-Negative Breast Cancer Cells. Nutrients. 2022;14(10):2120.
-
Hashemzaei M, Delarami Far A, Yari A, Heravi RE, Tabrizian K, Taghdisi SM, et al. Anticancer and apoptosis inducing effects of quercetin in vitro and in vivo. Oncol Rep. 2017;38(2):819–28.
-
Gomathinayagam R, Ha JH, Jayaraman M, Song YS, Isidoro C, Dhanasekaran DN. Chemopreventive and Anticancer Effects of Thymoquinone: Cellular and Molecular Targets. J Cancer Prev. 2020;25(3):136–51.
-
Fatfat Z, Fatfat M, Gali-Muhtasib H. Therapeutic potential of thymoquinone in combination therapy against cancer and cancer stem cells. World J Clin Oncol. 2021;12(7):522–43.
-
Almajali B, Al-Jamal HAN, Taib WRW, Ismail I, Johan MF, Doolaanea AA, et al. Thymoquinone, as a Novel Therapeutic Candidate of Cancers. Pharmaceuticals. 2021;14(4).
-
Yıldırım İH, Azzawri AA, Duran T. Thymoquinone induces apoptosis via targeting the Bax/BAD and Bcl-2 pathway in breast cancer cells. Dicle Med J. 2019;46:411–7.
-
Chae IG, Song N-Y, Kim D-H, Lee M-Y, Park J-M, Chun K-S. Thymoquinone induces apoptosis of human renal carcinoma Caki-1 cells by inhibiting JAK2/STAT3 through pro-oxidant effect. Food Chem Toxicol. 2020;139:111253.
-
Zhang M, Du H, Wang L, Yue Y, Zhang P, Huang Z, et al. Thymoquinone suppresses invasion and metastasis in bladder cancer cells by reversing EMT through the Wnt/β-catenin signaling pathway. Chem Biol Interact. 2020;320:109022.
-
Chehl N, Chipitsyna G, Gong Q, Yeo CJ, Arafat HA. Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. HPB (Oxford). 2009;11(5):373–81.
-
Banerjee S, Kaseb AO, Wang Z, Kong D, Mohammad M, Padhye S, et al. Antitumor activity of gemcitabine and oxaliplatin is augmented by thymoquinone in pancreatic cancer. Cancer Res. 2009;69(13):5575–83.
-
Khan MA, Tania M, Fu J. Epigenetic role of thymoquinone: impact on cellular mechanism and cancer therapeutics. Drug Discov Today. 2019;24(12):2315–22.
-
Banerjee S, Padhye S, Azmi A, Wang Z, Philip PA, Kucuk O, et al. Review on Molecular and Therapeutic Potential of Thymoquinone in Cancer. Nutr Cancer. 2010;62(7):938–46.
Potential Therapeutic Synergy of Thymoquinone and Nivolumab in Experimental Models of Renal Cancer
Year 2026,
Volume: 11 Issue: 1, 92 - 97, 28.01.2026
Ahmet Dirican
,
Özde Elif Gökbayrak
,
Aylin Erol
,
Tekincan Çağrı Aktaş
,
Hatice Efsun Kolatan
,
Efe Özgür Serinan
,
Zekiye Altun
,
Işıl Somalı
,
Osman Yılmaz
,
Safiye Aktaş
Abstract
Objective: We investigated the effects of Thymoquinone in combination with Nivolumab on experimental renal cell cancer models. Thymoquinone, a bioactive component extracted from Nigella sativa seeds, exhibits anti inflammatory, antioxidant, and anti-tumor properties against various cancers.
Material and Methods: The effects of Thymoquinone and Nivolumab were analyzed using the Renca cell line with 3 (4,5-dimetiltiyazol-. 2-yl)-2.5- difeniltetrazolium-bromure and Annexin V + propidium iodure assays. Renca cells were subcutaneously injected into 8-week-old male C57BL/6 mice. Groups were designed as control, Thymoquinone, Nivolumab, Thymoquinone+Nivolumab. Tumor tissues were analyzed for apoptosis/necrosis rates, expression of immunomarkers, and ribonucleic acid expression at a significance level of p<0.05.
Results: The results showed that Thymoquinone had anti tumor effects both in vitro and in vivo. The combination treatment with Nivolumab led to an increase in immune-mediated tumor cell death, resulting in significant necrosis or complete response to therapy in the tumor tissue.
Conclusion: Thymoquinone has been found to have an anti tumor effect on renal cell carcinoma, and Nivolumab has been shown to enhance the impact of immune cell apoptosis. Additionally, there are no side effects on other organs when used alone or in combination.
Keywords: Immune checkpoint inhibitors, renal cell cancer, thymoquinone.
Ethical Statement
The study was conducted in accordance with the ethical principles of the 1964 Helsinki Declaration and complied with these standards. All of the experimental procedures involving animals were conducted in accordance with the Experimental Animal Care Regulations of Dokuz Eylul University, Turkey and approved by the Ethics Committee of the Dokuz Eylul University, Turkey with an approved number 22/2017.
Supporting Institution
This study was supported by Dokuz Eylul University Scientific Research Council by project number 2020.KB.SAG.047.
Project Number
2020.KB.SAG.047.
References
-
Lalani A-KA, Heng DYC, Basappa NS, Wood L, Iqbal N, McLeod D, et al. Evolving landscape of first-line combination therapy in advanced renal cancer: a systematic review. Nat Cancer. 2022;14:17588359221108684.
-
Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, et al. Cancer statistics for the year 2020: An overview. Int J Cancer. 2021;149(4):778–89.
-
Kane CJ, Mallin K, Ritchey J, Cooperberg MR, Carroll PR. Renal cell cancer stage migration: analysis of the National Cancer Data Base. Cancer. 2008;113(1):78–83.
-
Cumberbatch MG, Rota M, Catto JWF, La Vecchia C. The Role of Tobacco Smoke in Bladder and Kidney Carcinogenesis: A Comparison of Exposures and Meta-analysis of Incidence and Mortality Risks. Eur Urol. 2016;70(3):458–66.
-
Tsivian M, Moreira DM, Caso JR, Mouraviev V, Polascik TJ. Cigarette smoking is associated with advanced renal cell carcinoma. J Clin Oncol. 2011;29(15):2027–31.
-
Brennan JF, Stilmant MM, Babayan RK, Siroky MB. Acquired renal cystic disease: implications for the urologist. BJU Int. 1991;67(4):342–8.
-
Truong LD, Krishnan B, Cao JT, Barrios R, Suki WN. Renal neoplasm in acquired cystic kidney disease. Am J Kidney Dis. 1995;26(1):1–12.
-
Zisman A, Chao DH, Pantuck AJ, Kim HJ, Wieder JA, Figlin RA, et al. Unclassified renal cell carcinoma: clinical features and prognostic impact of a new histological subtype. J Urol. 2002;168(3):950–5.
-
Effenberger-Neidnicht K, Schobert R. Combinatorial effects of thymoquinone on the anti-cancer activity of doxorubicin. Cancer Chemother Pharmacol. 2011;67(4):867–74.
-
Jafri SH, Glass J, Shi R, Zhang S, Prince M, Kleiner-Hancock H. Thymoquinone and cisplatin as a therapeutic combination in lung cancer: In vitro and in vivo. J Exp Clin Cancer Res. 2010;29(1):87.
-
Li Q-X, Yu DH, Liu G, Ke N, McKelvy J, Wong-Staal F. Selective anticancer strategies via intervention of the death pathways relevant to cell transformation. Cell Death Differ. 2008;15(8):1197–210.
-
Torres MP, Ponnusamy MP, Chakraborty S, Smith LM, Das S, Arafat HA, et al. Effects of thymoquinone in the expression of mucin 4 in pancreatic cancer cells: implications for the development of novel cancer therapies. Mol Cancer Ther. 2010;9(5):1419–31.
-
Yi T, Cho S-G, Yi Z, Pang X, Rodriguez M, Wang Y, et al. Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol Cancer Ther. 2008;7(7):1789–96.
-
Pal SK, Ghate SR, Li N, Swallow E, Peeples M, Zichlin ML, et al. Real-World Survival Outcomes and Prognostic Factors Among Patients Receiving First Targeted Therapy for Advanced Renal Cell Carcinoma: A SEER-Medicare Database Analysis. Clin Genitourin Cancer. 2017;15(4):e573–82.
-
Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277–90.
-
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803–13.
-
Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019;393(10189):2404–15.
-
Gurung RL, Lim SN, Khaw AK, Soon JFF, Shenoy K, Mohamed Ali S, et al. Thymoquinone induces telomere shortening, DNA damage and apoptosis in human glioblastoma cells. PloS one. 2010;5(8):e12124.
-
Sadun RE, Sachsman SM, Chen X, Christenson KW, Morris WZ, Hu P, et al. Immune signatures of murine and human cancers reveal unique mechanisms of tumor escape and new targets for cancer immunotherapy. Clin Cancer Res. 2007;13(13):4016–25.
-
Adinew GM, Messeha SS, Taka E, Badisa RB, Antonie LM, Soliman KFA. Thymoquinone Alterations of the Apoptotic Gene Expressions and Cell Cycle Arrest in Genetically Distinct Triple-Negative Breast Cancer Cells. Nutrients. 2022;14(10):2120.
-
Hashemzaei M, Delarami Far A, Yari A, Heravi RE, Tabrizian K, Taghdisi SM, et al. Anticancer and apoptosis inducing effects of quercetin in vitro and in vivo. Oncol Rep. 2017;38(2):819–28.
-
Gomathinayagam R, Ha JH, Jayaraman M, Song YS, Isidoro C, Dhanasekaran DN. Chemopreventive and Anticancer Effects of Thymoquinone: Cellular and Molecular Targets. J Cancer Prev. 2020;25(3):136–51.
-
Fatfat Z, Fatfat M, Gali-Muhtasib H. Therapeutic potential of thymoquinone in combination therapy against cancer and cancer stem cells. World J Clin Oncol. 2021;12(7):522–43.
-
Almajali B, Al-Jamal HAN, Taib WRW, Ismail I, Johan MF, Doolaanea AA, et al. Thymoquinone, as a Novel Therapeutic Candidate of Cancers. Pharmaceuticals. 2021;14(4).
-
Yıldırım İH, Azzawri AA, Duran T. Thymoquinone induces apoptosis via targeting the Bax/BAD and Bcl-2 pathway in breast cancer cells. Dicle Med J. 2019;46:411–7.
-
Chae IG, Song N-Y, Kim D-H, Lee M-Y, Park J-M, Chun K-S. Thymoquinone induces apoptosis of human renal carcinoma Caki-1 cells by inhibiting JAK2/STAT3 through pro-oxidant effect. Food Chem Toxicol. 2020;139:111253.
-
Zhang M, Du H, Wang L, Yue Y, Zhang P, Huang Z, et al. Thymoquinone suppresses invasion and metastasis in bladder cancer cells by reversing EMT through the Wnt/β-catenin signaling pathway. Chem Biol Interact. 2020;320:109022.
-
Chehl N, Chipitsyna G, Gong Q, Yeo CJ, Arafat HA. Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. HPB (Oxford). 2009;11(5):373–81.
-
Banerjee S, Kaseb AO, Wang Z, Kong D, Mohammad M, Padhye S, et al. Antitumor activity of gemcitabine and oxaliplatin is augmented by thymoquinone in pancreatic cancer. Cancer Res. 2009;69(13):5575–83.
-
Khan MA, Tania M, Fu J. Epigenetic role of thymoquinone: impact on cellular mechanism and cancer therapeutics. Drug Discov Today. 2019;24(12):2315–22.
-
Banerjee S, Padhye S, Azmi A, Wang Z, Philip PA, Kucuk O, et al. Review on Molecular and Therapeutic Potential of Thymoquinone in Cancer. Nutr Cancer. 2010;62(7):938–46.