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GLİOBLASTOMA’da 5-FU ve CELASTROL’ün SİTOTOKSİK ETKİSİ

Yıl 2018, Cilt 11, Sayı 1, 6 - 10, 08.07.2019

Öz

Glioblastoma (GB), en malign ve en agresif beyin tümörüdür. Fenotipik ve genotipik açıdan yüksek heterojeniteye sahip Glioblastomanın kesin bir tedavi şekli bulunmamaktadır. Glioblastomada kemoterapi uygulamaları tedavide önemli bir yer tutmaktadır. Ancak kemoterapötik direnç tedavi başarısını düşürmektedir. Kemoterapötik direnci azaltmak ve etkili bir kemoterapi iç in bitkisel köken li antikanserojenik mo le küller eliştirilmeye çalışılmaktadır. Son yıllarda, önemli bir tedavi yaklaşımı olara k, bu mo lekü llerin tek uygulanmalarının yanında kemoterapötik ajanlarla kombine uygulamaları artmaktadır. Bu çalış mada, kemoterapötik ajan 5-Fluorourac il ile doğal bir bileşik olan Ce lastrol kombinasyonunun Glioblastomadaki sitotoksik etkisinin araştırılması amaç lan mıştır. MTT sitotoksisite testi sonucunda 2 µM Celastrolün, 50 µM 5-Fluorouracilin sitotoksik etkisini % 19 oranında arttırdığı, 0,5 ve 2 µM’lık Celastrolün

100 µM’lık 5-Fluorouracilin sitotoksik etkisini sırasıyla % 25 ve %37 oranında arttırdığı saptanmıştır. Bu çalış ma, tüm kanser tiplerinde 5-Fluorouracilin ile Celastrolün kombine etkisinin gösterildiğ i ilk çalış madır. Celastrolün 5-Fluorouracil ile birlikte kullanımının önemini ilk kez gösteren bu çalışma, yeni bir tedavi protokülünün geliştirilmesi amacıyla daha ileri düzey araştırmalara temel bir dayanak oluşturabilir.

Kaynakça

  • Acra AM, Sakagami H , Mats uta T , Adachi K, Otsuki S, Nak ajima H ve ark. Effect of thr ee fluor ide compounds on the growth of oral normal and tumor cells. In Vivo. 2012; 26(4) :657-64.
  • Blumenthal DT, Sc hulman SF. Survival outco mes in glioblastoma multiforme,including the impact of adj uvant chemot her apy. Expert Rev Neurother . 2005;5(5):683-90.
  • Boridy S, Le PU, Petr ecca K, Maysinger D. Celastrol tar gets proteostasis and acts synergistically with a heat-shock protein 90 inhibitor to kill human glioblastoma cells. Cell Death Dis. 2014; 5:e1216.
  • Chen M, Rose AE, Doudican N, Osman I, Orlow SJ. Cel astrol synergistically enhances temozolomide cytotoxicity in melanoma cells. Mol Cancer Res. 2009;7(12):1946-53.
  • Cloughesy TF, Landolfi J, Hogan DJ, Bloomfield S, Carter B, Chen CC, ve ark. Phase 1 trial of vocimagene amir etrorepv ec and 5- fluorocytosine for r ecurrent high- grade glioma. Sci Transl Med. 2016;8(341):341ra75.
  • Di Cesar e Mannelli L, Piccolo M, Maione F, Ferraro MG, Ir ace C, De Feo V, ve ark. Tanshinones from Salvia miltiorrhiza Bunge revert chemother apy-induc ed neuropathic pain and reduce glioblastoma cells malignancy. Biomed Pharmacother . 2018;105:1042-1049.
  • Haar CP, Hebbar P, Wallace GC 4th, Das A, Vandergrift WA 3rd, Smith JA. ve ark. Drug resistance in glioblastoma: a mini review. Neurochem Res. 2012;37(6):1192-200.
  • Hanif F, Muzaffar K, Perveen K, Malhi SM, Simjee SU. Glioblastoma Multiforme: A Review of its Epidemiology and Pathogenesis through Clinical Presentation and Treatment. Asian Pac J Cancer Prev. 2017;18(1):3–9.
  • Hu Y, Wang S, Wu X, Zhang J, Chen R, Chen M. ve ark. Chinese herbal medicine der ived compounds for cancer therapy: a focus on hepat ocellul ar carcinoma. J Ethnopharmaco l. 2013; 149(3):601-12.
  • Kang CW, Park MS, Kim NH, Lee JH , Oh CW, Kim HR, ve ark. Hexane extract from Sar gassum serrat ifo lium inhibits the cell proliferat ion and metast atic ability of human glioblastoma U87MG cells. Oncol Rep. 2015; 34(5): 2602-8.
  • Kim SH, Kang JG , Kim CS, Ihm SH, Choi MG, Yoo HJ, v e ark. Cytotoxic effect of celastrol alone or in combination with paclitaxel on anapl astic thyroid carcinoma cells. Tumour Biol. 2017; 39(5):1010428317698369.
  • Krex D, Klınk B, Hartmann C, Von Deımlıng A, Pıetsch T, ve ark. Long-term survival with glioblastoma multiforme. Brain: A J Neurol. 2007;130:2596-606.
  • Li N, Xu M, Bao N, Shi W, Li Q, Zhang X. v e ark. Discovery of novel NO-r eleasing celastrol derivatives with Hsp90 inhibitio n and cytotoxic act ivities. Eur J Med Chem. 2018; 160:1-8.
  • Menei P, Jadaud E, Faisant N, Boisdron-Celle M, Michalak S, Fournier D, v e ark. Ster eotaxic implantation of 5- fluorour acil-rel easing micros pher es in mal ignant gl ioma. Cancer. 2004;100(2):405-10.
  • Messaoudi K, Clavreul A, Lagarce F. Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide. Drug Discov Today. 2015;20(7):899-905.
  • Miller CR, Williams CR, Buchsbaum DJ, Gillespie GY. Intratumor al 5- fl uorourac il produc ed by cytosine deaminas e/5-fluorocytosine gene ther apy is effective for experimental human glioblasto mas. Canc er R es. 2002; 62(3):773- 80.
  • Nutthasirikul N, Hahnvajanawong C, Techasen A, Limpaiboon T, Leelayuwat C,Chau-In S. ve ark. Tar geting the ∆133p53 isoform can restor e chemosens itivity in 5-fluorour acil- resistant cholangiocarcinoma cells. Int J Oncol. 2015; 47(6):2153-64.
  • Paolillo M, Boselli C, Schinelli S. Glioblastoma under Siege: An Overview of Curr ent Therapeutic Str ategies . Brain Sci. 2018; 8(1).
  • Sander P, Mostafa H, Soboh A, Schneider JM, Pala A, Baron AK ve ark. Vacquinol-1 inducible cell death in glioblastoma multiforme is counter regulated by TRPM7 activity induced by exogenous ATP. Oncotarget. 2017; (21):35124-35137.
  • Sat hornsumetee S, Rich JN. Designer therapies for glioblastoma multiforme. Ann N Y Acad Sci. 2008; 1142:108-32.
  • Tolba MF, Abdel-Rahman SZ. Pterostilbine, an act ive component of blueberries,sensitizes colon cancer cells to 5-fluorouracil cytotoxicity. Sci Rep. 2015;5: 15239.
  • Touat M, Idbaih A, Sanson M, Ligon KL. Glioblastoma targeted therapy: updated approaches from recent biological insights. Ann Oncol. 2017;28(7):1457-1472.
  • Uchibor i K, Kasamatsu A, Sunaga M, Yokota S, Sakur ada T, Kobayas hi E. ve ark. Est abl ishment and char acter izat ion of two 5-fl uorouracil-r esist ant hepatoc ellular carcinoma cell l ines. Int J Oncol. 2012; 40(4): 1005-10.
  • Wang F, Zheng Z, Guan J, Qi D, Zhou S, Shen X v e ark. Ident ificat ion of a panel of genes as a prognostic biomarker for glioblastoma. EBioMedicine. 2018;37:68- 77.
  • Wang Z, Zhai Z, Du X. Celastrol inhibits migr ation and invas ion through blocking the NF-κB pathway in ovarian cancer cells . Exp Ther Med. 2017;14(1):819-824.
  • Zheng L, Fu Y, Zhuang L, Gai R, Ma J, Lou J. et . al. Simult aneous NF-κB inhibit ion and E-cadherin upregulation mediate mutually synergistic anticancer activity of celastrol and SAHA in vitro and in vivo. Int J Cancer. 2014;135(7):1721- 32.
  • Zhu H, Yang W, He LJ, Ding WJ, Zheng L, Liao SD. et al. Upregulating Noxa by ER stress, celastrol exerts synergistic anti-cancer activity in comb ination wit h ABT- 737 in human hepatocellular carcinoma cells. PLo S One. 2012; 7(12):e52333.

THE CYTOTOXIC EFFECT of 5-FU AND CELASTRO L on GLIOBLASTO MA

Yıl 2018, Cilt 11, Sayı 1, 6 - 10, 08.07.2019

Öz

Glioblastoma is the most malign and agressive brain tumor. Glioblastoma has heterogeneity in terms of genotypically and phenotypically and also    there   is    no    precise     treatment model. Chemotherapy has a big role in the treatment of glioblastoma but chemotherapeutic resistance decrease the effectiveness of treatment. Anticancerogenic molecules which derived from plants are devoloping with the purpose of decreasing chemotheraupatic resistance and effective treatment. In recent years, as an important treatment approach, the combination of these molecules with chemotherapeutic agents as well as single administration increases. In this study, it was aimed to investigate the cytotoxic effect of the combination of chemotherapeutic agent 5- Fluorouracil and a natural compound Celastrol in glioblastoma. As a result of the MTT cytotoxicity test, it was determined that Celastrol (2µM) has increased the cytotoxic effect of 5- Fluorouracil (50 µM) by 19%, the cytotoxic effect of 5-Fluorouracil (100 µM) has increased by celastrol (0.5 and 2 µM) in ratio of 25% and 37% , respectively. This is the first study to show the effects of 5-Fluorouracil and celastrol combination in all types of cancer. This study, which demonstrated the importance of the use of celastrol with 5-Fluorouracil fo r the first time, may provide a basis for further research in order to develop a new treatment protocol

Kaynakça

  • Acra AM, Sakagami H , Mats uta T , Adachi K, Otsuki S, Nak ajima H ve ark. Effect of thr ee fluor ide compounds on the growth of oral normal and tumor cells. In Vivo. 2012; 26(4) :657-64.
  • Blumenthal DT, Sc hulman SF. Survival outco mes in glioblastoma multiforme,including the impact of adj uvant chemot her apy. Expert Rev Neurother . 2005;5(5):683-90.
  • Boridy S, Le PU, Petr ecca K, Maysinger D. Celastrol tar gets proteostasis and acts synergistically with a heat-shock protein 90 inhibitor to kill human glioblastoma cells. Cell Death Dis. 2014; 5:e1216.
  • Chen M, Rose AE, Doudican N, Osman I, Orlow SJ. Cel astrol synergistically enhances temozolomide cytotoxicity in melanoma cells. Mol Cancer Res. 2009;7(12):1946-53.
  • Cloughesy TF, Landolfi J, Hogan DJ, Bloomfield S, Carter B, Chen CC, ve ark. Phase 1 trial of vocimagene amir etrorepv ec and 5- fluorocytosine for r ecurrent high- grade glioma. Sci Transl Med. 2016;8(341):341ra75.
  • Di Cesar e Mannelli L, Piccolo M, Maione F, Ferraro MG, Ir ace C, De Feo V, ve ark. Tanshinones from Salvia miltiorrhiza Bunge revert chemother apy-induc ed neuropathic pain and reduce glioblastoma cells malignancy. Biomed Pharmacother . 2018;105:1042-1049.
  • Haar CP, Hebbar P, Wallace GC 4th, Das A, Vandergrift WA 3rd, Smith JA. ve ark. Drug resistance in glioblastoma: a mini review. Neurochem Res. 2012;37(6):1192-200.
  • Hanif F, Muzaffar K, Perveen K, Malhi SM, Simjee SU. Glioblastoma Multiforme: A Review of its Epidemiology and Pathogenesis through Clinical Presentation and Treatment. Asian Pac J Cancer Prev. 2017;18(1):3–9.
  • Hu Y, Wang S, Wu X, Zhang J, Chen R, Chen M. ve ark. Chinese herbal medicine der ived compounds for cancer therapy: a focus on hepat ocellul ar carcinoma. J Ethnopharmaco l. 2013; 149(3):601-12.
  • Kang CW, Park MS, Kim NH, Lee JH , Oh CW, Kim HR, ve ark. Hexane extract from Sar gassum serrat ifo lium inhibits the cell proliferat ion and metast atic ability of human glioblastoma U87MG cells. Oncol Rep. 2015; 34(5): 2602-8.
  • Kim SH, Kang JG , Kim CS, Ihm SH, Choi MG, Yoo HJ, v e ark. Cytotoxic effect of celastrol alone or in combination with paclitaxel on anapl astic thyroid carcinoma cells. Tumour Biol. 2017; 39(5):1010428317698369.
  • Krex D, Klınk B, Hartmann C, Von Deımlıng A, Pıetsch T, ve ark. Long-term survival with glioblastoma multiforme. Brain: A J Neurol. 2007;130:2596-606.
  • Li N, Xu M, Bao N, Shi W, Li Q, Zhang X. v e ark. Discovery of novel NO-r eleasing celastrol derivatives with Hsp90 inhibitio n and cytotoxic act ivities. Eur J Med Chem. 2018; 160:1-8.
  • Menei P, Jadaud E, Faisant N, Boisdron-Celle M, Michalak S, Fournier D, v e ark. Ster eotaxic implantation of 5- fluorour acil-rel easing micros pher es in mal ignant gl ioma. Cancer. 2004;100(2):405-10.
  • Messaoudi K, Clavreul A, Lagarce F. Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide. Drug Discov Today. 2015;20(7):899-905.
  • Miller CR, Williams CR, Buchsbaum DJ, Gillespie GY. Intratumor al 5- fl uorourac il produc ed by cytosine deaminas e/5-fluorocytosine gene ther apy is effective for experimental human glioblasto mas. Canc er R es. 2002; 62(3):773- 80.
  • Nutthasirikul N, Hahnvajanawong C, Techasen A, Limpaiboon T, Leelayuwat C,Chau-In S. ve ark. Tar geting the ∆133p53 isoform can restor e chemosens itivity in 5-fluorour acil- resistant cholangiocarcinoma cells. Int J Oncol. 2015; 47(6):2153-64.
  • Paolillo M, Boselli C, Schinelli S. Glioblastoma under Siege: An Overview of Curr ent Therapeutic Str ategies . Brain Sci. 2018; 8(1).
  • Sander P, Mostafa H, Soboh A, Schneider JM, Pala A, Baron AK ve ark. Vacquinol-1 inducible cell death in glioblastoma multiforme is counter regulated by TRPM7 activity induced by exogenous ATP. Oncotarget. 2017; (21):35124-35137.
  • Sat hornsumetee S, Rich JN. Designer therapies for glioblastoma multiforme. Ann N Y Acad Sci. 2008; 1142:108-32.
  • Tolba MF, Abdel-Rahman SZ. Pterostilbine, an act ive component of blueberries,sensitizes colon cancer cells to 5-fluorouracil cytotoxicity. Sci Rep. 2015;5: 15239.
  • Touat M, Idbaih A, Sanson M, Ligon KL. Glioblastoma targeted therapy: updated approaches from recent biological insights. Ann Oncol. 2017;28(7):1457-1472.
  • Uchibor i K, Kasamatsu A, Sunaga M, Yokota S, Sakur ada T, Kobayas hi E. ve ark. Est abl ishment and char acter izat ion of two 5-fl uorouracil-r esist ant hepatoc ellular carcinoma cell l ines. Int J Oncol. 2012; 40(4): 1005-10.
  • Wang F, Zheng Z, Guan J, Qi D, Zhou S, Shen X v e ark. Ident ificat ion of a panel of genes as a prognostic biomarker for glioblastoma. EBioMedicine. 2018;37:68- 77.
  • Wang Z, Zhai Z, Du X. Celastrol inhibits migr ation and invas ion through blocking the NF-κB pathway in ovarian cancer cells . Exp Ther Med. 2017;14(1):819-824.
  • Zheng L, Fu Y, Zhuang L, Gai R, Ma J, Lou J. et . al. Simult aneous NF-κB inhibit ion and E-cadherin upregulation mediate mutually synergistic anticancer activity of celastrol and SAHA in vitro and in vivo. Int J Cancer. 2014;135(7):1721- 32.
  • Zhu H, Yang W, He LJ, Ding WJ, Zheng L, Liao SD. et al. Upregulating Noxa by ER stress, celastrol exerts synergistic anti-cancer activity in comb ination wit h ABT- 737 in human hepatocellular carcinoma cells. PLo S One. 2012; 7(12):e52333.

Ayrıntılar

Birincil Dil Türkçe
Konular Tıp
Bölüm Orijinal Araştırma Makaleleri
Yazarlar

Mehmet TAŞPINAR (Sorumlu Yazar)
VAN YÜZÜNCÜ YIL ÜNİVERSİTESİ, TIP FAKÜLTESİ, TEMEL TIP BİLİMLERİ BÖLÜMÜ, TIBBİ BİYOLOJİ ANABİLİM DALI
Türkiye


Farika Nur DENİZLER Bu kişi benim
VAN YÜZÜNCÜ YIL ÜNİVERSİTESİ, TIP FAKÜLTESİ, TEMEL TIP BİLİMLERİ BÖLÜMÜ, TIBBİ BİYOLOJİ ANABİLİM DALI
Türkiye


Mustafa GÜVEN
VAN YÜZÜNCÜ YIL ÜNİVERSİTESİ, TIP FAKÜLTESİ
0000-0002-7330-9231
Türkiye


Veysel YÜKSEK
VAN YÜZÜNCÜ YIL ÜNİVERSİTESİ, ÖZALP MESLEK YÜKSEKOKULU
Türkiye


Sedat ÇETİN Bu kişi benim
VAN YÜZÜNCÜ YIL ÜNİVERSİTESİ, VETERİNER FAKÜLTESİ, TEMEL BİLİMLER BÖLÜMÜ, VETERİNERLİK BİYOKİMYASI ANABİLİM DALI
Türkiye


Semiha DEDE
VAN YÜZÜNCÜ YIL ÜNİVERSİTESİ, VETERİNER FAKÜLTESİ, TEMEL BİLİMLER BÖLÜMÜ, VETERİNERLİK BİYOKİMYASI ANABİLİM DALI
0000-0001-5744-6327
Türkiye

Yayımlanma Tarihi 8 Temmuz 2019
Başvuru Tarihi 10 Kasım 2018
Kabul Tarihi 12 Aralık 2018
Yayınlandığı Sayı Yıl 2018, Cilt 11, Sayı 1

Kaynak Göster

APA Taşpınar, M. , Denizler, F. N. , Güven, M. , Yüksek, V. , Çetin, S. & Dede, S. (2019). GLİOBLASTOMA’da 5-FU ve CELASTROL’ün SİTOTOKSİK ETKİSİ . Van Sağlık Bilimleri Dergisi , 11 (1) , 6-10 . Retrieved from https://dergipark.org.tr/tr/pub/vansaglik/issue/46922/588597

ISSN 

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