Top

Published in:

01-12-2010 | Preclinical study

The pan-DAC inhibitor LBH589 is a multi-functional agent in breast cancer cells: cytotoxic drug and inducer of sodium-iodide symporter (NIS)

Authors: N. Fortunati, M. G. Catalano, F. Marano, V. Mugoni, M. Pugliese, O. Bosco, F. Mainini, G. Boccuzzi

Published in: Breast Cancer Research and Treatment | Issue 3/2010

Abstract

New drugs with anti-tumor activity, also able to modify the expression of selected molecules, are under evaluation in breast cancer which is becoming resistant to conventional treatment, or in metastatic disease. The sodium-iodide symporter (NIS), which mediates iodide uptake into thyroid cells, and is the molecular basis of radioiodine imaging and therapy in thyroid cancer, is also expressed in a large portion of breast tumors. Since NIS expression in breast cancer is not sufficient for a significant iodide uptake, drugs able to induce its expression and correct function are under evaluation. In the present study, we report for the first time that the pan-deacetylase (DAC) inhibitor LBH589 (panobinostat) significantly induced NIS, both as mRNA and as protein, through the increase of NIS promoter activity, with the final consequence of obtaining a significant up-take of iodide in MCF7, T47D, and MDA-MB231 breast cancer cells. Moreover, we observed that LBH589 causes a significant reduction in cell viability of estrogen-sensitive and -insensitive breast cancer cells within nanomolar range. The anti-tumor effect of LBH589 is sustained by apoptosis induction and cell cycle arrest in G₂/M. In conclusion, our data suggest that LBH589 might be a powerful tool in the management of breast cancer due to its multiple effects and support a potential application of LBH589 in the diagnosis and treatment of this disease.

Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108CrossRefPubMed

Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, Mandelblatt JS, Yakovlev AY, Habbema JD, Feuer EJ, Cancer Intervention and Surveillance Modeling Network (CISNET) Collaborators (2005) Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353:1784–1792CrossRefPubMed

Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN (2007) Overview of resistance to systemic therapy in patients with breast cancer. Adv Exp Med Biol 608:1–22CrossRefPubMed

Cardoso F, Bedard PL, Winer EP, Pagani O, Senkus-Konefka E, Fallowfield LJ, Kyriakides S, Costa A, Cufer T, Albain KS, ESO-MBC Task Force (2009) International guidelines for management of metastatic breast cancer: combination vs sequential single-agent chemotherapy. J Natl Cancer Inst 101:1174–1181CrossRefPubMed

Dai G, Levy O, Carrasco N (1996) Cloning and characterization of the thyroid iodide transporter. Nature 379:458–460CrossRefPubMed

Reiners C, Dietlein M, Luster M (2008) Radio-iodine therapy in differentiated thyroid cancer: indications and procedures. Best Pract Res Clin Endocrinol Metab 22:989–1007CrossRefPubMed

Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Zhao QH, Deng HF, Amenta PS, Fineberg S, Pestell RC, Carrasco N (2000) The mammary gland iodide transporter is expressed during lactation and in breast cancer. Nat Med 6:871–878CrossRefPubMed

Wapnir IL, van de Rijn M, Nowels K, Amenta PS, Walton K, Montgomery K, Greco RS, Dohán O, Carrasco N (2003) Immunohistochemical profile of the sodium/iodide symporter in thyroid, breast, and other carcinomas using high density tissue microarrays and conventional sections. J Clin Endocrinol Metab 88:1880–1888CrossRefPubMed

Wapnir IL, Goris M, Yudd A, Dohan O, Adelman D, Nowels K, Carrasco N (2004) The Na+/I− symporter mediates iodide uptake in breast cancer metastases and can be selectively down-regulated in the thyroid. Clin Cancer Res 10:4294–4302CrossRefPubMed

10.

Moon DH, Lee SJ, Park KY, Park KK, Ahn SH, Pai MS, Chang H, Lee HK, Ahn IM (2001) Correlation between 99mTc pertechnetate uptakes and expressions of human sodium iodide symporter gene in breast tumor tissues. Nucl Med Biol 28:829–834CrossRefPubMed

11.

Boelaert K, Franklyn JA (2003) Sodium iodide symporter: a novel strategy to target breast, prostate, and other cancers? Lancet 361:796–797CrossRefPubMed

12.

Kogai T, Kanamoto Y, Li AI, Che LH, Ohashi E, Taki K, Chandraratna RA, Saito T, Brent GA (2005) Differential regulation of sodium/iodide symporter gene expression by nuclear receptor ligands in MCF-7 breast cancer cells. Endocrinology 146:3059–3069CrossRefPubMed

13.

Willhauck MJ, Sharif-Samani B, Senekowitsch-Schmidtke R, Wunderlich N, Göke B, Morris JC, Spitzweg C (2008) Functional sodium iodide symporter expression in breast cancer xenografts in vivo after systemic treatment with retinoic acid and dexamethasone. Breast Cancer Res Treat 109:263–272CrossRefPubMed

14.

Ohashi E, Kogai T, Kagechika H, Brent GA (2009) Activation of the PI3 kinase pathway by retinoic acid mediates sodium/iodide symporter induction and iodide transport in MCF-7 breast cancer cells. Cancer Res 69:3443–3450CrossRefPubMed

15.

Unterholzner S, Willhauck MJ, Cengic N, Schütz M, Göke B, Morris JC, Spitzweg C (2006) Dexamethasone stimulation of retinoic acid-induced sodium iodide symporter expression and cytotoxicity of 131-I in breast cancer cells. J Clin Endocrinol Metab 91:69–78CrossRefPubMed

16.

Kitazono M, Robey R, Zhan Z, Sarlis NJ, Skarulis MC, Aikou T, Bates S, Fojo T (2001) Low concentrations of the histone deacetylase inhibitor, depsipeptide (FR901228), increase expression of the Na(+)/I(+) symporter and iodine accumulation in poorly differentiated thyroid carcinoma cells. J Clin Endocrinol Metab 86:3430–3435CrossRefPubMed

17.

Zarnegar R, Brunaud L, Kanauchi H, Wong M, Fung M, Ginzinger D, Duh QY, Clark OH (2002) Increasing the effectiveness of radioactive iodine therapy in the treatment of thyroid cancer using trichostatin A, a histone deacetylase inhibitor. Surgery 132:984–990CrossRefPubMed

18.

Fortunati N, Catalano MG, Arena K, Brignardello E, Piovesan A, Boccuzzi G (2004) Valproic acid induces the expression of the Na+/I+ symporter and iodine uptake in poorly differentiated thyroid cancer cells. J Clin Endocrinol Metab 89:1006–1009CrossRefPubMed

19.

Botrugno OA, Santoro F, Minucci S (2009) Histone deacetylase inhibitors as a new weapon in the arsenal of differentiation therapies of cancer. Cancer Lett 280:134–144CrossRefPubMed

20.

Lee MJ, Kim YS, Kummar S, Giaccone G, Trepel JB (2008) Histone deacetylase inhibitors in cancer therapy. Curr Opin Oncol 20:639–649CrossRefPubMed

21.

Puppin C, D’Aurizio F, D’Elia AV, Cesaratto L, Tell G, Russo D, Filetti S, Ferretti E, Tosi E, Mattei T, Pianta A, Pellizzari L, Damante G (2005) Effects of histone acetylation on sodium iodide symporter promoter and expression of thyroid-specific transcription factors. Endocrinology 146:3967–3974CrossRefPubMed

22.

Atadja P (2009) Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 280:233–241CrossRefPubMed

23.

Behr M, Schmitt TL, Espinoza CR, Loos U (1998) Cloning of a functional promoter of the human sodium/iodide-symporter gene. Biochem J 331:359–363PubMed

24.

Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784CrossRefPubMed

25.

Zhou Q, Atadja P, Davidson NE (2007) Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation. Cancer Biol Ther 6:64–69PubMed

26.

Fiskus W, Ren Y, Mohapatra A, Bali P, Mandawat A, Rao R, Herger B, Yang Y, Atadja P, Wu J, Bhalla K (2007) Hydroxamic acid analogue histone deacetylase inhibitors attenuate estrogen receptor-alpha levels and transcriptional activity: a result of hyperacetylation and inhibition of chaperone function of heat shock protein 90. Clin Cancer Res 13:4882–4890CrossRefPubMed

27.

Kim IA, No M, Lee JM, Shin JH, Oh JS, Choi EJ, Kim IH, Atadja P, Bernhard EJ (2009) Epigenetic modulation of radiation response in human cancer cells with activated EGFR or HER-2 signaling: potential role of histone deacetylase 6. Radiother Oncol 92:125–132CrossRefPubMed

28.

Giles F, Fischer T, Cortes J, Garcia-Manero G, Beck J, Ravandi F, Masson E, Rae P, Laird G, Sharma S, Kantarjian H, Dugan M, Albitar M, Bhalla K (2006) A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 12:4628–4635CrossRefPubMed

29.

Fortunati N, Bertino S, Costantino L, Bosco O, Vercellinatto I, Catalano MG, Boccuzzi G (2008) Valproic acid is a selective antiproliferative agent in estrogen-sensitive breast cancer cells. Cancer Lett 259:156–164CrossRefPubMed

30.

Dohán O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, Ginter CS, Carrasco N (2003) The sodium/iodide symporter (NIS): characterization, regulation, and medical significance. Endocr Rev 24:48–77CrossRefPubMed

31.

Furuya F, Shimura H, Suzuki H, Taki K, Ohta K, Haraguchi K, Onaya T, Endo T, Kobayashi T (2004) Histone deacetylase inhibitors restore radioiodide uptake and retention in poorly differentiated and anaplastic thyroid cancer cells by expression of the sodium/iodide symporter thyroperoxidase and thyroglobulin. Endocrinology 145:2865–2875CrossRefPubMed

32.

Beyer SJ, Jimenez RE, Shapiro CL, Cho JY, Jhiang SM (2009) Do cell surface trafficking impairments account for variable cell surface sodium iodide symporter levels in breast cancer? Breast Cancer Res Treat 115:205–212CrossRefPubMed

33.

Kogai T, Ohashi E, Jacobs MS, Sajid-Crockett S, Fisher ML, Kanamoto Y, Brent GA (2008) Retinoic acid stimulation of the sodium/iodide symporter in MCF-7 breast cancer cells is mediated by the insulin growth factor-I/phosphatidylinositol 3-kinase and p38 mitogen activated protein kinase signaling pathways. J Clin Endocrinol Metab 93:1884–1892CrossRefPubMed

34.

Dohán O, De la Vieja A, Carrasco N (2006) Hydrocortisone and purinergic signaling stimulate sodium/iodide symporter (NIS)-mediated iodide transport in breast cancer cells. Mol Endocrinol 20:1121–1137CrossRefPubMed

35.

Tanosaki S, Ikezoe T, Heaney A, Said JW, Dan K, Akashi M, Koeffler HP (2003) Effect of ligands of nuclear hormone receptors on sodium/iodide symporter expression and activity in breast cancer cells. Breast Cancer Res Treat 79:335–345CrossRefPubMed

36.

Cho JY, Leveille R, Kao R, Rousset B, Parlow AF, Burak WE Jr, Mazzaferri EL, Jhiang SM (2000) Hormonal regulation of radioiodide uptake activity and NaC/IK symporter expression in mammary glands. J Clin Endocrinol Metab 85:2936–2943CrossRefPubMed

37.

Arturi F, Ferretti E, Presta I, Mattei T, Scipioni A, Scarpelli D, Bruno R, Lacroix L, Tosi E, Gulino A, Russo D, Filetti S (2005) Regulation of iodide uptake and sodium/iodide symporter expression in the MCF-7 human breast cancer cell line. J Clin Endocrinol Metab 90:2321–2326CrossRefPubMed

38.

Knostman KA, McCubrey JA, Morrison CD, Zhang Z, Capen CC, Jhiang SM (2007) PI3K activation is associated with intracellular sodium/iodide symporter protein expression in breast cancer. BMC Cancer 7:137CrossRefPubMed

39.

Kogai T, Kanamoto Y, Che LH, Taki K, Moatamed F, Schultz JJ, Brent GA (2004) Systemic retinoic acid treatment induces sodium/iodide symporter expression and radioiodide uptake in mouse breast cancer models. Cancer Res 64:415–422CrossRefPubMed

Title: The pan-DAC inhibitor LBH589 is a multi-functional agent in breast cancer cells: cytotoxic drug and inducer of sodium-iodide symporter (NIS)
Authors: N. Fortunati
M. G. Catalano
F. Marano
V. Mugoni
M. Pugliese
O. Bosco
F. Mainini
G. Boccuzzi
Publication date: 01-12-2010
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2010
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-010-0789-z

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2010

Expression of HAb18G is associated with tumor progression and prognosis of breast carcinoma

More radiotherapy for radiation-induced second malignancies?

Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age

Association between androgen receptor gene CAG repeat polymorphism and breast cancer risk: a meta-analysis

The androgen receptor in breast cancer: learning from the past

RAD51 135G>C polymorphism contributes to breast cancer susceptibility: a meta-analysis involving 26,444 subjects

Keynote webinar | Spotlight on antibody–drug conjugates in cancer