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

Fortunati, Nicoletta; Catalano, Maria Graziella; Marano, Francesca; Mugoni, Vera; Pugliese, Mariateresa; Bosco, Ornella; Mainini, F; Boccuzzi, Giuseppe

doi:10.1007/s10549-010-0789-z

Cited by 23 publications

(21 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The present report follows our previous observation in breast cancer cells where we observed a potent cytotoxic activity of LBH589 in both estrogen-sensitive and -insensitive cells (16). Our present data demonstrate that LBH589 induces E-cadherin gene expression in aggressive TNBC cells.…”

Section: Discussionsupporting

confidence: 92%

“…The appearance of E-cadherin in MDA-MB-231 cells treated with LBH589 could be due to the reactivation of ERα pathway in TNBC cells since other DCI were reported to act similarly in several studies. For example, DCI in association with demethylating agents like 5-aza-2'-deoxycytidine were shown to reactivate ERα expression in ER-negative breast cancer cells (22,39,40); the DCI valproic acid was demonstrated to enhance the efficacy of the anti-estrogen tamoxifen through increasing ER-mediated transcription (16) and also to induce ERα, PR, pS2 and FoxA1, giving to MDA-MB-231 cells an estrogen-sensitive 'phenotype' and restoring their sensitivity to anti-estrogen therapy (18).…”

Section: Discussionmentioning

confidence: 99%

“…DCI vorinostat (13), for example, in association with paclitaxel and bevacizumab induced a partial or complete response in >50% of patients with metastatic breast cancer. The antiproliferative and re-differentiating effect of several DCI was reported in vitro by a number of laboratories (14)(15)(16)(17). In recent years, the pan-deacetylase inhibitor panobinostat (LBH589) has been taken into consideration.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The pan-histone deacetylase inhibitor LBH589 (panobinostat) alters the invasive breast cancer cell phenotype

Fortunati

Marano

Bandino

et al. 2013

International Journal of Oncology

View full text Add to dashboard Cite

Abstract. Triple-negative breast cancer (TNBC) is a very aggressive type of tumour and its aggressiveness is linked to E-cadherin downregulation. In estrogen-sensitive breast cancer, high levels of E-cadherin fit with high levels of ERα and MTA3 (a component of the transcription Mi-2/NuRD complex with intrinsic DAC activity). In TNBC the E-cadherin downregulation could be due to epigenetic silencing of the CDH1 gene as well as to the lack of a fully functioning ERα-activated pathway. We report that the pan-histone deacetylase inhibitor LBH589, a potent anti-proliferative agent, induced E-cadherin expression on cell membranes of MDA-MB-231 cells (TNBC), determining a reduction of cell invasion and migration. Even though E-cadherin expression in breast cancer is also regulated by estradiol and the ERα/MTA3/Snail/Slug pathway, LBH589 is able to increase E-cadherin without affecting the estrogen pathway. In fact, no expression of ERα, PR and FoxA1 was observed in MDA-MB-231 cells before and after LBH589 treatment; furthermore, the drug caused an increase in Snail and Slug expression with a concomitant reduction of MTA3 levels. Taking into consideration its anti-proliferative and anti-invasive properties, we suggest the use of LBH589 in aggressive breast cancer refractory to hormonal therapy. IntroductionBreast cancer, the most common cancer in women all over the world (1), is generally managed with success thank to available treatments (2). Regrettably, resistance to conventional therapy and increasing in metastatic and aggressive disease are emerging problems (3,4). A particular aggressive subtype of breast cancer is the triple-negative breast cancer (TNBC) that is defined by the absence of ER, PR and Her2/neu (5,6). TNBC generally occurs more frequently in younger women, frequently presents early metastatic spread and has poor overall prognosis (7,8).In breast cancer, as well as in other tumour types, epigenetic modifications are considered a crucial mechanism involved in cancer growth, dedifferentiation and aggressiveness; indeed, epigenetic deregulation can alter a number of molecular pathways involved in the control of cell function. Epigenetic drugs, able to restore normal epigenome in cancer cells, are under extensive pharmacological research (9). In breast cancer, histone acetylation state is considered of great importance. Histone acetylation and deacetylation, controlled by the enzymes histone acetyltransferases (HATs) and histone deacetylases (HDACs), affect chromatin conformation and, therefore, gene transcription, DNA repair and replication, and cell cycle checkpoints (10). Altered expression of HDACs has been reported in breast cancer by several authors (11,12). Therefore, HDAC inhibitors (DCI) are considered valuable therapeutic tools and have been under extensive evaluation. DCI vorinostat (13), for example, in association with paclitaxel and bevacizumab induced a partial or complete response in >50% of patients with metastatic breast cancer. The antiproliferative and re-differentiating effect of sev...

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The pan-histone deacetylase inhibitor LBH589 (panobinostat) alters the invasive breast cancer cell phenotype

Fortunati

Marano

Bandino

et al. 2013

International Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…This finding is in contrast to the study by Gupta et al 11 in diffuse and large B-cell lymphoma in which panobinostat effectively inhibited mTORC1 and underlines the divergences that can occur between different cell lines. As previously reported in other cancer types, 22,23 panobinostat induced a cell-cycle arrest in G 2 /M in HL cell lines. Moreover, the combination of panobinostat with everolimus was also more effective to induce this cell-cycle arrest in G 2 /M than the use of panobinostat alone.…”

Section: Discussionsupporting

confidence: 86%

The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines

Lemoine

Derenzini

Buglio

et al. 2012

Blood

View full text Add to dashboard Cite

AbstractThe pan-deacetylase inhibitor panobinostat (LBH589) recently has been shown to have significant clinical activity in patients with relapsed Hodgkin lymphoma, but its mechanism of action in Hodgkin lymphoma remains unknown. In this study, we demonstrate that panobinostat has potent antiproliferative activity against Hodgkin lymphoma–derived cell lines. At the molecular level, panobinostat activated the caspase pathway, inhibited STAT5 and STAT6 phosphorylation, and down-regulated hypoxia-inducible factor 1 α and its downstream targets, glucose transporter 1 (GLUT1) and vascular endothelial growth factor. Paradoxically, panobinostat inhibited LKB1 and AMP-activated protein kinase, leading to activation of mammalian target of rapamycin (mTOR) that promotes survival. Combining panobinostat with the mTOR inhibitor everolimus (RAD001) inhibited panobinostat-induced mTOR activation and enhanced panobinostat antiproliferative effects. Collectively, our data demonstrate that panobinostat is a potent deacetylase inhibitor against Hodgkin lymphoma–derived cell lines, and provide a mechanistic rationale for combining panobinostat with mTOR inhibitors for treating Hodgkin lymphoma patients. Furthermore, the effect of panobinostat on GLUT1 expression suggests that panobinostat may modulate the results of clinical diagnostic imaging tests that depend of functional GLUT1, such as fluorodeoxyglucose positron emission tomography.

show abstract

“…Other stimulators, such as prolactin, insulin, and insulin growth factor (IGF)-I and II, are able to increase NIS mRNA levels in MCF7 cells also in the absence of RA [66]. Fortunati and coworkers reported that the HDAC inhibitor LBH589 significantly induced NIS mRNA and protein levels as well as iodine uptake in several BC cell lines [67]. Table 3 summarizes the data regarding the stimulation of iodide uptake in breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Sodium iodide symporter (NIS) in extrathyroidal malignancies: focus on breast and urological cancer

et al. 2014

View full text Add to dashboard Cite

BackgroundExpression and function of sodium iodide symporter (NIS) is requisite for efficient iodide transport in thyrocytes, and its presence in cancer cells allows the use of radioiodine as a diagnostic and therapeutic tool in thyroid neoplasia. Discovery of NIS expression in extrathyroidal tissues, including transformed cells, has opened a novel field of research regarding NIS-expressing extrathyroidal neoplasia. Indeed, expression of NIS may be used as a biomarker for diagnostic, prognostic, and therapeutic purposes. Moreover, stimulation of endogenous NIS expression may permit the radioiodine treatment of extrathyroidal lesions by concentrating this radioisotope.ResultsThis review describes recent findings in NIS research in extrathyroidal malignancies, focusing on breast and urological cancer, emphasizing the most relevant developments that may have clinical impact.ConclusionsGiven the recent progress in the study of NIS regulation as molecular basis for new therapeutic approaches in extrathyroidal cancers, particular attention is given to studies regarding the relationship between NIS and clinical-pathological aspects of the tumors and the regulation of NIS expression in the experimental models.

show abstract

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

Cited by 23 publications

References 38 publications

The pan-histone deacetylase inhibitor LBH589 (panobinostat) alters the invasive breast cancer cell phenotype

The pan-histone deacetylase inhibitor LBH589 (panobinostat) alters the invasive breast cancer cell phenotype

The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines

Sodium iodide symporter (NIS) in extrathyroidal malignancies: focus on breast and urological cancer

Contact Info

Product

Resources

About