Abstract A93: Targeting the increased invasive capability of non-small cell lung cancer platinum-resistant cells by histone deacetylase inhibitors.
Authors: Zuco Valentina , Cassinelli Giuliana , Cossa Giacomo , Gatti Laura , Favini Enrica , Zunino Franco , Zaffaroni Nadia , Lanzi Cinzia , Perego Paola 
Published: August 2014

Abstract
Cellular resistance to antitumor drugs involves multiple changes including modulation of pro-angiogenic and invasive properties. Since epigenetic alterations have been implicated in the aggressive behavior of lung cancer, a disease for which platinum-based therapy is available, we examined the capability of SAHA [a pan-histone deacetylase (HDAC) inhibitor) and ST3595 (a hydroxamate-based HDAC inhibitor) to interfere with proliferative as well as invasive potential of non-small cell lung cancer (NSCLC) cell systems. Cellular, biochemical and molecular approaches were employed including growth inhibition and invasion assays, western blot analyses and proteome profilers, quantitative RT-PCR including TaqMan arrays, and gain of function assays by cDNA transfection. We used two experimental systems of NSCLC, H460, and A549 cell lines, and generated the cisplatin-resistant variants (H460/Pt, A549/Pt), which were found to exhibit increased invasive abilities as compared to parental cells. These features were associated with a wide modulation of the levels of angiogenesis- and invasion-related factors in the cell conditioned media. In the H460/Pt model, several bioactive molecules (e.g., angiogenin, endothelin-1, ADAMTS1) were upregulated compared to the parental counterpart. The levels of uPA, IL8, and MIF were found to be increased in the conditioned media from both H460/Pt and A549/Pt cells. SAHA and ST3595 produced a marked antiproliferative effect in both platinum-sensitive and -resistant cell lines and induced a strong inhibition of cell invasive properties, that was more marked after ST3595 exposure. The analysis of the modulation of the mRNAs of genes involved in the metastatic process indicated that both SAHA and ST3595 up-regulated the metastasis suppressor KiSS1. Quantitative RT-PCR analysis of TXNIP, which has been reported to be an up-stream regulator of KiSS1 suggested that TXNIP might be involved in KiSS1 induction. Up-modulation of this metastasis suppressor by cell exposure to HDAC inhibitors was evident also at the protein level. Forced expression of KiSS1 resulted in significant decrease of invasive capability, whereas no change in cisplatin sensitivity was found. Such findings indicate that HDAC inhibitors overcome platinum resistance in NSCLC cell systems and counteract the invasive potential of resistant cells through mechanisms involving KiSS1.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A93.
Citation Format: Valentina Zuco, Giuliana Cassinelli, Giacomo Cossa, Laura Gatti, Enrica Favini, Franco Zunino, Nadia Zaffaroni, Cinzia Lanzi, Paola Perego. Targeting the increased invasive capability of non-small cell lung cancer platinum-resistant cells by histone deacetylase inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A93.