The Combination of RAF265, SB590885, ZSTK474 on Thyroid Cancer Cell Lines Deeply Impact on Proliferation and MAPK and PI3K/Akt Signaling Pathways

Overview

Journal Invest New Drugs

Publisher Springer

Specialty Oncology

Date 2014 May 14

PMID 24821574

Citations 17

Authors

Susi Barollo

Loris Bertazza

Enke Baldini

Salvatore Ulisse

Elisabetta Cavedon

Marco Boscaro

Raffaele Pezzani

Caterina Mian

Affiliations

Soon will be listed here.

Abstract

Papillary thyroid cancer (PTC) is the most frequent thyroid cancer entity, accounting for 88 % of cases. It may metastasize and loose iodine uptake capability, preventing any radioiodine or surgical treatment. The main gene altered in PTC is BRAF, which is found altered in over 50 % of cases. Moreover MAPK and PI3K/Akt pathways are greatly implicated in PTC development. Many target therapies for PTC are currently under investigation, unfortunately without the expected results. Aim of this study was to characterized the preclinical effectiveness of novel promising drugs, RAF265, SB590885 and ZSTK474 in 3 thyroid cancer cell lines (BCPAP, K1, 8505C). RAF265 and SB590885 target differentially BRAF, while ZSTK474 acts on PI3K. IC50 demonstrated high drug activities ranging from 0.1 to 6.2 μM, depending on drugs and cell type, while combination index revealed an interesting synergistic effect of combination regimen (RAF265 + ZSTK474 and SB590885 + ZSTK474) in almost all cell lines. Moreover this synergistic effect was particularly evident by Western blot, whereas dual MAPK and PI3K/Akt inhibition was detected. In addition, treating cells with SB590885 induced marked morphological changes, leading to massive vacuolization. This suggests an activation of apoptotic process, as underlined by Annexin V flow cytometry analysis. Also cell cycle was altered in treated cells, without evidence of a common pattern, but rather with a more specific effect relying on single drug or combination regimen used. Since beneficial effects of in vitro combination regimen (RAF265 + ZSTK474 and SB590885 + ZSTK474), it is recommended additional investigation. These data suggest the potential use of combination regimen in in vivo experiment or afterwards in human PTC.

Citing Articles

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References

Tuttle R, Lukes Y, Onstad L, Lushnikov E, Abrosimov A, Troshin V . ret/PTC activation is not associated with individual radiation dose estimates in a pilot study of neoplastic thyroid nodules arising in Russian children and adults exposed to Chernobyl fallout. Thyroid. 2008; 18(8):839-46. PMC: 2857448. DOI: 10.1089/thy.2008.0072. View

Pilli T, Prasad K, Jayarama S, Pacini F, Prabhakar B . Potential utility and limitations of thyroid cancer cell lines as models for studying thyroid cancer. Thyroid. 2009; 19(12):1333-42. PMC: 2833173. DOI: 10.1089/thy.2009.0195. View

Davies L, Welch H . Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006; 295(18):2164-7. DOI: 10.1001/jama.295.18.2164. View

Kondo T, Ezzat S, Asa S . Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006; 6(4):292-306. DOI: 10.1038/nrc1836. View

Su Y, Vilgelm A, Kelley M, Hawkins O, Liu Y, Boyd K . RAF265 inhibits the growth of advanced human melanoma tumors. Clin Cancer Res. 2012; 18(8):2184-98. PMC: 3724517. DOI: 10.1158/1078-0432.CCR-11-1122. View

King A, Patrick D, Batorsky R, Ho M, Do H, Zhang S . Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res. 2006; 66(23):11100-5. DOI: 10.1158/0008-5472.CAN-06-2554. View

Saiselet M, Floor S, Tarabichi M, Dom G, Hebrant A, van Staveren W . Thyroid cancer cell lines: an overview. Front Endocrinol (Lausanne). 2012; 3:133. PMC: 3499787. DOI: 10.3389/fendo.2012.00133. View

Hundahl S, FLEMING I, Fremgen A, Menck H . A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see commetns]. Cancer. 1999; 83(12):2638-48. DOI: 10.1002/(sici)1097-0142(19981215)83:12<2638::aid-cncr31>3.0.co;2-1. View

Pezzani R, Rubin B, Redaelli M, Radu C, Barollo S, Cicala M . The antiproliferative effects of ouabain and everolimus on adrenocortical tumor cells. Endocr J. 2013; 61(1):41-53. DOI: 10.1507/endocrj.ej13-0225. View

10.

Dan S, Okamura M, Mukai Y, Yoshimi H, Inoue Y, Hanyu A . ZSTK474, a specific phosphatidylinositol 3-kinase inhibitor, induces G1 arrest of the cell cycle in vivo. Eur J Cancer. 2011; 48(6):936-43. DOI: 10.1016/j.ejca.2011.10.006. View

11.

Mariniello B, Rosato A, Zuccolotto G, Rubin B, Cicala M, Finco I . Combination of sorafenib and everolimus impacts therapeutically on adrenocortical tumor models. Endocr Relat Cancer. 2012; 19(4):527-39. DOI: 10.1530/ERC-11-0337. View

12.

Poulikakos P, Solit D . Resistance to MEK inhibitors: should we co-target upstream?. Sci Signal. 2011; 4(166):pe16. DOI: 10.1126/scisignal.2001948. View

13.

Satyamoorthy K, Li G, Gerrero M, Brose M, Volpe P, Weber B . Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res. 2003; 63(4):756-9. View

14.

Vianello F, Mazzarotto R, Mian C, Lora O, Saladini G, Servodio O . Clinical outcome of low-risk differentiated thyroid cancer patients after radioiodine remnant ablation and recombinant human thyroid-stimulating hormone preparation. Clin Oncol (R Coll Radiol). 2011; 24(3):162-8. DOI: 10.1016/j.clon.2011.02.011. View

15.

Barollo S, Pezzani R, Cristiani A, Redaelli M, Zambonin L, Rubin B . Prevalence, tumorigenic role, and biochemical implications of rare BRAF alterations. Thyroid. 2013; 24(5):809-19. DOI: 10.1089/thy.2013.0403. View

16.

Aksamitiene E, Kiyatkin A, Kholodenko B . Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. Biochem Soc Trans. 2012; 40(1):139-46. DOI: 10.1042/BST20110609. View

17.

Yaguchi S, Fukui Y, Koshimizu I, Yoshimi H, Matsuno T, Gouda H . Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst. 2006; 98(8):545-56. DOI: 10.1093/jnci/djj133. View

18.

Ciampi R, Nikiforov Y . Alterations of the BRAF gene in thyroid tumors. Endocr Pathol. 2005; 16(3):163-72. DOI: 10.1385/ep:16:3:163. View

19.

Wan P, Garnett M, Roe S, Lee S, Niculescu-Duvaz D, Good V . Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004; 116(6):855-67. DOI: 10.1016/s0092-8674(04)00215-6. View

20.

Gonzalez-Polo R, Boya P, Pauleau A, Jalil A, Larochette N, Souquere S . The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death. J Cell Sci. 2005; 118(Pt 14):3091-102. DOI: 10.1242/jcs.02447. View