Abstract 3491: Development of a new approach to kill non-small cell lung cancer cells with resistance to standard chemotherapy using parthenolide analogues

Abstract

Abstract Lung cancer is the leading cause of cancer death in men and women worldwide. The poor prognosis of advanced non-small cell lung cancer (NSCLC) is due, in part, to emergence of tumor resistance to chemotherapy. Recent data indicate that human tumors including NSCLC contain a small subset of cancer stem/ progenitor cells (CSC) responsible for drug resistance and tumor maintenance. If such minute subsets of CSC drive tumor formation and drug resistance, therapies targeting the bulk tumor mass but not CSC will fail. We now confirm identification of subpopulations of chemotherapy-resistant human NSCLC cells with enrichment for CSC biomarkers and exhibiting significant CSC activity. We identified CD133+/ALDH+ tumor stem/progenitor cells from human lung cancer cells in vitro using established Aldefluor assays in combination with labeled anti-CD133 antibodies. Estrogen, a known risk factor for lung cancer progression, stimulated a modest increase in the numbers of CSC. In contrast to control CD133-/ALDH- tumor cell subsets, CSC subpopulations grew as tumor spheres and maintained self-renewal capacity in vitro and exhibited a greater tumorigenic capability than non-CSC subsets in vivo, properties indicative of CSC. Furthermore, resistance of CSC-like cells to cisplatin (a standard chemotherapy for NSCLC treatment) was fully reversed by treatment with parthenolide (PTL), a naturally-occurring sesquiterpene lactone compound with strong antitumor activity in leukemia and prostate cancer while sparing normal cells. The antitumor effect of PTL appears due to its action as a potent inhibitor of nuclear factor-βB (NF-κB) which is markedly activated by chemotherapy. To target CSC and suppress tumor progression, we synthesized and tested novel analogs of PTL with improved antitumor properties and aqueous solubility. PTL analogs inhibit proliferation of H157 NSCLC cells using both bulk cell preparations and CSC-subpopulations, with effects significantly different from control at P<0.05. Dose-dependent increments of PTL analogs increase apoptosis of CSC when compared with bulk cells. Moreover, PTL analogs inhibit cell proliferation of H23, A549 and H1975 NSCLC cells with known resistance to cisplatin (P<0.01). These compounds were able to sensitize cells to cisplatin-induced cytotoxicity (P<0.01) when cells were exposed to sub-optimal concentrations of cisplatin. Using Western blots, we find that PTL congeners inhibit phosphorylation of the p65 subunit of phospho-NF-κB and activation of IKKα/β. Thus, targeted inhibition of NF-κB may reverse tumor drug resistance by interfering with known NF-κB actions to regulate genes involved in proliferation, DNA damage response, antiapoptosis and angiogenesis. Further development of PTL analogs as therapeutics may lead to new strategies to treat NSCLC in the clinic. [Funded by CDMRP Lung Cancer Research Program LC 090297]. 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 3491. doi:1538-7445.AM2012-3491