Abstract 1774: Dihydroartemisinin (DHA): A potent enhancer of PARP inhibitors and DNA-damaging agents activity in human tumor models

Abstract

Abstract Synthetic lethality (SL) is a cellular condition in which two or more non-allelic and non-essential mutations, which are not lethal on their own, become deadly when present within the same cell. PARP inhibitors (PARPi) represent a paradigmatic example of therapeutic application of the SL approaches. In cancer cells with BRCA1 or BRCA2 loss of function, inhibition of PARP1 activity leads to an accumulation of single strand breaks converted to double strand breaks but cannot be repaired by homologous recombination. However, preclinical and preliminary clinical evidences suggest a potentially broader scope for PARPi. Currently, several PARPi are under different phases of clinical investigation as monotherapy or in combination with DNA damaging agents. Although PARPi in monotherapy are quite safe, their combination with cytotoxic agents leads to exacerbation of the typical cytotoxic-related side effects, thus reducing the potentiality to improve the therapeutic index (T.I.) of these combinations. The study aim was to assess if the combination of PARPi and DNA-damaging agents with the widely used antimalarial agent DHA could improve both their antitumor activity and T.I. We have preliminary observed, in different cancer cells, that DHA was an inducer of endoplasmic reticulum (ER) stress (increased expression of typical ER stress-related genes), activation of checkpoint kinases and transcriptional up-regulation of different p53-target genes and of mitochondrial membrane depolarization. A consequence is PARP activation that, in absence of other factors, leads the cells to recover from damage and to their rescue. On the contrary, we observed that the simultaneous use of DHA with a PARPi or cytotoxic agents causes a massive cell death. More specifically a strong synergism was observed on tumor cells, when DHA was combined with different drugs: doxorubicin and platinum compounds on NCI-H460, temozolomide (TMZ) on MDA-MB436 and CAPAN-1. In addition, a synergistic interaction was identified between DHA and the PARPi (ABT-888 or AZD-2281) on various tumor cells (e.g., A431, HCT116, SW620, MDA-MB436, NCI-H460, A2780/DDP, CAPAN-1). In vivo, the combination of DHA (delivered at 200 mg/kg p.o. according to the schedule qdx5/w) with ABT-888 or AZD-2281, resulted in a significantly higher tumor growth inhibition than with monotherapy in NCI-H460 NSCLC, HCT116 colon ca. and MDA-MB436 triple-negative breast cancer BRCA1 negative xenografted in nude mice. DHA was also able to synergize in vivo with the alkylating agent TMZ against MDA-MB436 tumor model. No toxic effects of administrations of DHA in combination with chemotherapeutics in terms of body weight recordings were found throughout the experiments.Taken together, these results clearly pinpoint the clinical potential offered by DHA in the SL approaches in developing less toxic and more efficacious therapies to treat cancer patients. 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 1774. doi:1538-7445.AM2012-1774