Abstract 2741: Synergistic inhibition of tumor growth and overcoming chemo-resistance by simultaneously targeting key components in DNA damage/repair, epigenetic, and putative cancer stem cell signaling pathways using novel dual-functional DNA-alkylating/HDAC inhibitor and tumor suppressor gene nanoparticles in lung cancer

Abstract

Abstract In this study we explored a novel therapeutic strategy aimed to simultaneously target multiple key components in DNA damage/repair, epigenetic, and putative cancer stem cell (CSC) signaling pathways using a novel dual-target DNA-alkylating nitrogen mustard/HDAC inhibitor (DANM/HDACi) and tumor suppressor gene (TSG) nanoparticles to promote antitumor synergy and overcome drug resistance in lung cancer. We evaluated therapeutic effects of a new class DNAM/HDACi, NL10, as a single agent or in combination with novel TSGs NPRL2, a regulator of the DNA damage checkpoint pathway, and p53, a regulator of apoptosis and drug resistance in the DNA damage/repair pathway in more than 50 human NSCLC and SCLC cell lines. We detected a high anti-tumor potency by NL101 treatment across lung cancer cell lines, with IC50 doses ranging from nanomolar to lower micromolar levels. A 20 to 100-fold higher level of cytotoxicity was observed across these cell lines, particularly in SCLC cell lines, treated by NL101 than in those treated by bendamustine, a nitrogen mustard that is currently in Phase II/III clinical trials in SCLC patients. We analyzed the NL101-induced DNA damage in NSCLC H1299 cells and found that NL101 induced a significantly higher degree of DNA damage than that induced by either bendamustine or cisplatin at the same IC20 dose level for each agent. We analyzed the DNA-damage-induced apoptosis in NSCLC cells treated by NL101 alone or in combination with DOTAP:Cholesterol (DC)-complexed NPRL2- or p53-expressing plasmid DNA nanoparticles. We detected a significantly enhanced apoptosis in both combination treatments with NL101+DC-NPRL2 and NL101+DC-p53. We also found that combination treatment with NL101 and DC-NPRL2 nanoparticles promoted a synergistic inhibitory effect on tumor cell-induced clonogenecity in H1299 cells and on tumor cell growth in SCLC H69 and GLC16 cells at effective dose levels of NL101 from IC10 to IC75. Furthermore, we found that the sensitivity of lung cancer cells to NL101 treatment showed a significantly negative correlation with expression levels of the HDAC family proteins HDAC1, HDAC2, HDAC3, and HDAC5 and the putative lung cancer stem cell (CSC) marker ALDH1 protein. We found a dose-dependent inhibition of multiple HDACs and CSC markers in both NSCLC and SCLC cells. Our results suggest that a combination treatment using a novel DANM/HDACi with pro-apoptotic TSGs targeting the DNA damage/repair, epigenetic, and CSC signaling pathways will enhance chemotherapeutic sensitivity, promote anti-cancer synergism, overcome drug resistance, and block tumor progression and relapse by targeting putative CSCs. (Supported by grants P50CA70907, RO1 CA-116322, and W81XWH0920139) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2741. doi:1538-7445.AM2012-2741