Bortezomib sensitizes thyroid cancer to BRAF inhibitor in vitro and in vivo

被引:27
作者
Tsumagari, Koji [1 ]
Abd Elmageed, Zakaria Y. [1 ]
Sholl, Andrew B. [2 ]
Green, Erik A. [1 ]
Sobti, Saboori [1 ]
Khan, Abdul Razzaq [1 ]
Kandil, Abdulrahman [1 ]
Murad, Fadi [1 ]
Friedlander, Paul [3 ]
Boulares, A. Hamid [4 ,5 ]
Kandil, Emad [1 ,3 ]
机构
[1] Tulane Univ, Sch Med, Dept Surg, New Orleans, LA 70112 USA
[2] Tulane Univ, Sch Med, Dept Pathol, New Orleans, LA 70112 USA
[3] Tulane Univ, Sch Med, Dept Otolaryngol, 1430 Tulane Ave, New Orleans, LA 70112 USA
[4] Louisiana State Univ, Hlth Sci Ctr, Stanley Scott Canc Ctr, New Orleans, LA USA
[5] Louisiana State Univ, Hlth Sci Ctr, Dept Pharmacol, New Orleans, LA USA
关键词
BRAFV600E; NF-kappa B; thyroid cancer; Vemurafenib; Bortezomib; INTENSITY FOCUSED ULTRASOUND; RADIOFREQUENCY THERMAL ABLATION; DOUBLE-BLIND; THERAPY; NODULES; CARCINOMA; PAPILLARY; MELANOMA; MANAGEMENT; MECHANISM;
D O I
10.1530/ERC-17-0182
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Although overall survival rate for patients with thyroid cancer (TC) is high, there is an alarming 10-year recurrence rate of up to 30% conferring a similar to 50% survival among these high-risk patients. The BRAFV600E mutation is estimated to be present in over 50% of papillary thyroid cancer (PTC) cases besides being associated with carcinogenesis and poor prognosis. We assessed the status of NF-kappa B, Ki-67, cyclin D1 and BRAFV600E in TC tissues and TC cell lines using immunohistochemistry and Western blot analysis. Concurrently, we evaluated the outcomes of combined targeting of the proteasome pathway in addition to selective BRAF inhibitors in cases of PTC. In this study, BRAFV600E-bearing TC cells were treated with BRAFV600E inhibitor, Vemurafenib alone or in combination with the proteasome inhibitor, Bortezomib. The combination of both drugs showed synergistic effects as evidenced by cell growth inhibition (P < 0.05), increased G2-phase cell cycle arrest and induced apoptosis (P < 0.05). In our TC xenograft model, the combination of Vemurafenib and Bortezomib significantly reduced tumor size (P < 0.05) and expression of the markers of cell growth and proliferation, Ki-67 and cyclin D1 (P < 0.001), when compared to monotherapy. Further analysis demonstrated that treatment with Bortezomib sensitized TC cells to Vemurafenib via mitochondrial dysregulation and apoptosis of TC cells, as evidenced by the increase in the expression of p53, Noxa protein, the loss of mitochondrial membrane potential, cytochrome c release and Poly (ADP-ribose) polymerase cleavage. Our results demonstrate a strong clinical potential for the combination of the Bortezomib and the BRAF inhibitor Vemurafenib as an efficient therapeutic approach for the treatment of TC.
引用
收藏
页码:99 / 109
页数:11
相关论文
共 49 条
[1]   Immunohistochemistry as an accurate tool for evaluating BRAF-V600E mutation in 130 samples of papillary thyroid cancer [J].
Abd Elmageed, Zakaria Y. ;
Sholl, Andrew B. ;
Tsumagari, Koji ;
Al-Qurayshi, Zaid ;
Basolo, Fulvio ;
Moroz, Krzysztof ;
Boulares, A. Hamid ;
Friedlander, Paul ;
Miccoli, Paulo ;
Kandil, Emad .
SURGERY, 2017, 161 (04) :1122-1128
[2]   Use of overpressure to assess the role of bubbles in focused ultrasound lesion shape in vitro [J].
Bailey, MR ;
Couret, LN ;
Sapozhnikov, OA ;
Khokhlova, VA ;
Ter Haar, G ;
Vaezy, S ;
Shi, XG ;
Martin, R ;
Crum, LA .
ULTRASOUND IN MEDICINE AND BIOLOGY, 2001, 27 (05) :695-708
[3]   High-Intensity Focussed Ultrasound in Low-Risk Prostate Cancer - Oncological Outcome and Postinterventional Quality of Life of an Inexperienced Therapy Centre in Comparison with an Experienced Therapy Centre [J].
Baumunk, D. ;
Andersen, C. ;
Heile, U. ;
Ebbing, J. ;
Cash, H. ;
Porsch, M. ;
Liehr, U. -B. ;
Janitzky, A. ;
Wendler, J. J. ;
Schindele, D. ;
Blaschke, S. ;
Miller, K. ;
Schostak, M. .
AKTUELLE UROLOGIE, 2013, 44 (04) :285-292
[4]   Percutaneous ethanol injection therapy in benign solitary solid cold thyroid nodules:: A randomized trial comparing one injection with three injections [J].
Bennedbæk, FN ;
Hegedüs, L .
THYROID, 1999, 9 (03) :225-233
[5]   Treatment of recurrent thyroid cysts with ethanol:: A randomized double-blind controlled trial [J].
Bennedbæk, FN ;
Hegedüs, L .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2003, 88 (12) :5773-5777
[6]   Vemurafenib: the first drug approved for BRAF-mutant cancer [J].
Bollag, Gideon ;
Tsai, James ;
Zhang, Jiazhong ;
Zhang, Chao ;
Ibrahim, Prabha ;
Nolop, Keith ;
Hirth, Peter .
NATURE REVIEWS DRUG DISCOVERY, 2012, 11 (11) :873-886
[7]   Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial [J].
Brose, Marcia S. ;
Nutting, Christopher M. ;
Jarzab, Barbara ;
Elisei, Rossella ;
Siena, Salvatore ;
Bastholt, Lars ;
de la Fouchardiere, Christelle ;
Pacini, Furio ;
Paschke, Ralf ;
Shong, Young Kee ;
Sherman, Steven I. ;
Smit, Johannes W. A. ;
Chung, John ;
Kappeler, Christian ;
Pena, Carol ;
Molnar, Istvan ;
Schlumberger, Martin J. .
LANCET, 2014, 384 (9940) :319-328
[8]   Activating BRAF and PIK3CA Mutations Cooperate to Promote Anaplastic Thyroid Carcinogenesis [J].
Charles, Roch-Philippe ;
Silva, Jillian ;
Iezza, Gioia ;
Phillips, Wayne A. ;
McMahon, Martin .
MOLECULAR CANCER RESEARCH, 2014, 12 (07) :979-986
[9]   BRAF-Mutated Colorectal Cancer: What Is the Optimal Strategy for Treatment? [J].
Cohen, Romain ;
Cervera, Pascale ;
Svrcek, Magali ;
Pellat, Anna ;
Dreyer, Chantal ;
de Gramont, Aimery ;
Andre, Thierry .
CURRENT TREATMENT OPTIONS IN ONCOLOGY, 2017, 18 (02)
[10]   Efficacy and Tolerability of Vemurafenib in Patients with BRAFV600E -Positive Papillary Thyroid Cancer: MD Anderson Cancer Center Off Label Experience [J].
Dadu, Ramona ;
Shah, Komal ;
Busaidy, Naifa L. ;
Waguespack, Steven G. ;
Habra, Mouhammad A. ;
Ying, Anita K. ;
Hu, Mimi I. ;
Bassett, Roland ;
Jimenez, Camilo ;
Sherman, Steven I. ;
Cabanillas, Maria E. .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2015, 100 (01) :E77-E81