Konvansiyonel Kemoterapötikler ve Isı Şok Protein 90 İnhibitör Kombinasyonunun Mesane Kanseri Hücreleri Üzerine Apoptotik Etkisi

Yıl 2019, , 230 - 236, 28.06.2019

Nuray Varol

https://doi.org/10.31832/smj.512684

Öz

AMAÇ: Isı şok protein 90
(IŞP90), ATP-bağımlı moleküler şaperonlardır ve hücresel fonksiyonların
gerçekleştirilmesinden sorumlu çok sayıda önemli proteinin konformasyonel
katlanması ve stabilizasyonu için gereklidir. Bu çalışmada amacımız, IŞP90
inhibitörü geldanamisin, kemoterapötik ajanlar gemsitabin ve sisplatinin tek
başlarına ve/veya kombinasyonlarının kullanımının, insan mesane kanser hücre
hattı T24’de apoptotik yolak üzerindeki sinerjik etkilerinin araştırılmasıdır.

GEREÇ VE YÖNTEM:
Gemsitabin (0-500 nM) ve sisplatin (0-10 μM), tek başına ve/veya birlikte T24
hücreleri üzerinde anti-tümör etkileri WST-1 testi ile belirlendi. 1 μM
geldanamisin ile belirtilen ilaçların tek başlarına ve/veya kombine
kullanımının, Bax ve Bcl2 genlerinin protein ekspresyon seviyelerindeki
varyasyonları ise western blot yöntemi ile belirlendi.

BULGULAR: Proapoptotik
gen Bax protein ifadelenmesi, geldanamisin, sisplatin ve gemsitabin tek
başlarına ve/veya kombinasyonları sonrasında translasyonel düzeyde artarken
anti apoptotik gen Bcl2 protein düzeyinde önemli bir değişiklik gözlenmemiştir.
Bununla birlikte, üçlü kombinasyon (geldanamisin, sisplatin ve gemsitabin),
kontrolle karşılaştırıldığında Bax protein düzeylerinde artışla birlikte Bcl2
protein seviyesinde önemli bir azalmaya neden olmuştur. 

SONUÇ: Geldanamisin, gemsitabin ve sisplatin üçlü
kombinasyonunun kullanımı kemoterapötiklerin apoptotik aktivitesinde bir artışa
yol açmıştır. IŞP90 inhibitörlerinin ve
kemoterapötiklerin kombine kullanımı, mesane kanserinin tedavisi için umut
verici bir tedavi seçeneği olabilir.

Anahtar Kelimeler

: IŞP90 inhibitör, Konvansiyonel Kemoterapötikler

Kaynakça

• Chehab M, Caza T, Skotnicki K, Landas S, Bratslavsky G, Mollapour M, et al. Targeting Hsp90 in urothelial carcinoma. Oncotarget 2015;6:8454-73.Wong MCS, Fung FDH, Leung C, Cheung WWL, Goggins WB, Ng CF. The global epidemiology of bladder cancer: a joinpoint regression analysis of its incidence and mortality trends and projection. Sci Rep 2018;8(1):112.Ma L, Sato F, Sato R, Matsubara T, Hirai K, Yamasaki M, et al. Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer. Oncol Rep 2014;31(6):2482-92.Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 2009;15:1126-32. da Silva GN, de Castro Marcondes JP, de Camargo EA, da Silva Passos Júnior GA, Sakamoto-Hojo ET, Salvadori DM. Cell cycle arrest and apoptosis in TP53 subtypes of bladder carcinoma cell lines treated with cisplatin and gemcitabine. Exp Biol Med 2010;5:814-24. Gahr S, Ocker M, Ganslmayer M, Zopf S, Okamoto K, Hartl A, et al. The combination of the histone-deacetylase inhibitor trichostatin A and gemcitabine induces inhibition of proliferation and increased apoptosis in pancreatic carcinoma cells. International Journal Of Oncology 2007;31:567-576.Tharakan ST, Inamoto T, Sung B, Aggarwal BB, Kamat AM. Curcumin potentiates the antitumor effects of gemcitabine in an orthotopic model of human bladder cancer through suppression of proliferative and angiogenic biomarkers. Biochem Pharmacol 2010;79:218-28.Chen MK, Qin ZK, Zhou FJ, Han H, Liu ZW, Li YH, et al. Intra-arterial chemotherapy is reliable in preventing high-risk superficial bladder cancer from recurrence and progression. J Chemother 2009;21:681-6.Vaishampayan U. Systemic therapy of advanced urothelial cancer. Curr Treat Options Oncol 2009;10:256-66. Yafi FA, Kassouf W. Is neoadjuvant chemotherapy with gemcitabine plus cisplatin beneficial in patients with muscle-invasive bladder cancer? Expert Rev Anticancer Ther 2009;9:747-52.Gazzaniga P, Silvestri I, Gradilone A, Scarpa S, Morrone S, Gandini O, et al. Gemcitabine-induced apoptosis in 5637 cell line: an in-vitro model for high-risk superficial bladder cancer. Anticancer Drugs 2007;18:179-85.Breinig M, Caldas-Lopes E, Goeppert B, Malz M, Rieker R, Bergmann F, et al. Targeting heat shock protein 90 with non-quinone inhibitors: a novel chemotherapeutic approach in human hepatocellular carcinoma. Hepatology 2009;50(1):102-12Li J, Soroka J, Buchner J. The Hsp90 chaperone machinery: Conformational Dynamics and regulation by co-chaperones. Biochimica et Biophysica Acta 2012;1823:624-35.Tatokoro M, Koga F, Yoshida S, Kihara K. Heat shock protein 90 targeting therapy: state of the art and future perspective. EXCLI J 2015;14:48-58. Ischia J, So AI. The role of heat shock proteins in bladder cancer. Nature Reviews Urology 2013; 10(7):386-95.Çoban N. Mesane Kanser Hücrelerinde Hsp90 İnhibitörlerinin Histon Metilasyonu Üzerine Etkisi. Yüksek Lisans Tezi. Afyonkarahisar: Afyon Kocatepe Üniversitesi Tıp Fakültesi, Tıbbi Genetik Anabilim Dalı, 2018.Sun CH, Chang YH, Pan CC. Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder. Histopathology. 2011;58(7):1054-63.Safa AR. Resistance to Cell Death and Its Modulation in Cancer Stem Cells. Crit Rev Oncog 2016;21(3-4):203-19.Jeon HG, Yoon CY, Yu JH, Park MJ, Lee JE, Jeong SJ, et al. Induction of Caspase Mediated Apoptosis and Down-Regulation of Nuclear Factor-κB and Akt Signaling are Involved in the Synergistic Antitumor Effect of Gemcitabine and the Histone Deacetylase Inhibitor Trichostatin A in Human Bladder Cancer Cells. J Urol 2011;186: 2084-93.Varol N, Konac E, Onen IH, Gurocak S, Alp E, Yilmaz A, et al. The Epigenetically Regulated Effects of Wnt Antagonists on the Expression of Genes in the Apoptosis Pathway in Human Bladder Cell Line (T24). DNA and Cell Biology 2014;33:408-17.Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999;13:2905-27.Lee SY, Liu S, Mitchell RM, Slagle-Webb B, Hong YS, Sheehan JM, et al. HFE polymorphisms influence the response to chemotherapeutic agents via induction of p16INK4A. Int J Cancer 2011;129(9):2104-14.Mohammadian M, Zeynali S, Azarbaijani AF, Khadem Ansari MH, Kheradmand F. Cytotoxic effects of the newly-developed chemotherapeutic agents 17-AAG in combination with oxaliplatin and capecitabine in colorectal cancer cell lines. Res Pharm Sci 2017;12(6):517-525.
• Wong MCS, Fung FDH, Leung C, Cheung WWL, Goggins WB, Ng CF. The global epidemiology of bladder cancer: a joinpoint regression analysis of its incidence and mortality trends and projection. Sci Rep 2018;8(1):112.
• Ma L, Sato F, Sato R, Matsubara T, Hirai K, Yamasaki M, et al. Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer. Oncol Rep 2014;31(6):2482-92.
• Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 2009;15:1126-32.
• da Silva GN, de Castro Marcondes JP, de Camargo EA, da Silva Passos Júnior GA, Sakamoto-Hojo ET, Salvadori DM. Cell cycle arrest and apoptosis in TP53 subtypes of bladder carcinoma cell lines treated with cisplatin and gemcitabine. Exp Biol Med 2010;5:814-24.
• Gahr S, Ocker M, Ganslmayer M, Zopf S, Okamoto K, Hartl A, et al. The combination of the histone-deacetylase inhibitor trichostatin A and gemcitabine induces inhibition of proliferation and increased apoptosis in pancreatic carcinoma cells. International Journal Of Oncology 2007;31:567-576.
• Tharakan ST, Inamoto T, Sung B, Aggarwal BB, Kamat AM. Curcumin potentiates the antitumor effects of gemcitabine in an orthotopic model of human bladder cancer through suppression of proliferative and angiogenic biomarkers. Biochem Pharmacol 2010;79:218-28.
• Chen MK, Qin ZK, Zhou FJ, Han H, Liu ZW, Li YH, et al. Intra-arterial chemotherapy is reliable in preventing high-risk superficial bladder cancer from recurrence and progression. J Chemother 2009;21:681-6.
• Vaishampayan U. Systemic therapy of advanced urothelial cancer. Curr Treat Options Oncol 2009;10:256-66.
• Yafi FA, Kassouf W. Is neoadjuvant chemotherapy with gemcitabine plus cisplatin beneficial in patients with muscle-invasive bladder cancer? Expert Rev Anticancer Ther 2009;9:747-52.
• Gazzaniga P, Silvestri I, Gradilone A, Scarpa S, Morrone S, Gandini O, et al. Gemcitabine-induced apoptosis in 5637 cell line: an in-vitro model for high-risk superficial bladder cancer. Anticancer Drugs 2007;18:179-85.
• Breinig M, Caldas-Lopes E, Goeppert B, Malz M, Rieker R, Bergmann F, et al. Targeting heat shock protein 90 with non-quinone inhibitors: a novel chemotherapeutic approach in human hepatocellular carcinoma. Hepatology 2009;50(1):102-12.
• Li J, Soroka J, Buchner J. The Hsp90 chaperone machinery: Conformational Dynamics and regulation by co-chaperones. Biochimica et Biophysica Acta 2012;1823:624-35.
• Tatokoro M, Koga F, Yoshida S, Kihara K. Heat shock protein 90 targeting therapy: state of the art and future perspective. EXCLI J 2015;14:48-58.
• Ischia J, So AI. The role of heat shock proteins in bladder cancer. Nature Reviews Urology 2013; 10(7):386-95.
• Çoban N. Mesane Kanser Hücrelerinde Hsp90 İnhibitörlerinin Histon Metilasyonu Üzerine Etkisi. Yüksek Lisans Tezi. Afyonkarahisar: Afyon Kocatepe Üniversitesi Tıp Fakültesi, Tıbbi Genetik Anabilim Dalı, 2018
• Sun CH, Chang YH, Pan CC. Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder.Histopathology. 2011;58(7):1054-63.
• Safa AR. Resistance to Cell Death and Its Modulation in Cancer Stem Cells. Crit Rev Oncog 2016;21(3-4):203-19.
• Jeon HG, Yoon CY, Yu JH, Park MJ, Lee JE, Jeong SJ, et al. Induction of Caspase Mediated Apoptosis and Down-Regulation of Nuclear Factor-κB and Akt Signaling are Involved in the Synergistic Antitumor Effect of Gemcitabine and the Histone Deacetylase Inhibitor Trichostatin A in Human Bladder Cancer Cells. J Urol 2011;186: 2084-93.
• Varol N, Konac E, Onen IH, Gurocak S, Alp E, Yilmaz A, et al. The Epigenetically Regulated Effects of Wnt Antagonists on the Expression of Genes in the Apoptosis Pathway in Human Bladder Cell Line (T24). DNA and Cell Biology 2014;33:408-17.
• Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts, Genes Dev 1999;13:2905-27.
• Lee SY, Liu S, Mitchell RM, Slagle-Webb B, Hong YS, Sheehan JM, et al. HFE polymorphisms influence the response to chemotherapeutic agents via induction of p16INK4A. Int J Cancer 2011;129(9):2104-14.
• Mohammadian M, Zeynali S, Azarbaijani AF, Khadem Ansari MH, Kheradmand F. Cytotoxic effects of the newly-developed chemotherapeutic agents 17-AAG in combination with oxaliplatin and capecitabine in colorectal cancer cell lines. Res Pharm Sci 2017;12(6):517-525.