Poster Presentation Advances in Neuroblastoma Research Congress 2016

Combination of HDAC and mitochondrial-targeted metabolism inhibitors exhibits strong therapeutic synergy in vitro and in vivo against neuroblastoma (#361)

Patrick Kim 1 , Aldwin Suryo Rahmanto 1 , Owen Tan 1 , Selina Sutton 1 , Pierre J. Dilda 2 , Sylvia Chung 3 , Murray Norris 1 , Michelle Haber 1 , Philip Hogg 4 , Belamy Cheung 1 , Glenn Marshall 5
  1. Children's Cancer Institute, Randwick, NSW, Australia
  2. Cancer Drug Development Group, Adult Cancer Program, Prince of Wales Clinical School, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Sydney, Australia
  3. Cure for Life Neuro-Oncology Group, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, Sydney, Australia
  4. ACRF-Centenary Cancer Research Centre, The Charles Perkins Centre, The University of Sydney , NSW 2006, Australia
  5. Kids Cancer Centre, Sydney Children’s Hospital , Randwick 2031, Sydney, Australia.

Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor that targets class I and class II HDACs, and has broad cytopathic effects on cancer cells. PENAO (4-(N-(S-penicillaminylacetyl) amino) phenylarsonous acid) is a tumour metabolism inhibitor that targets adenine nucleotide translocase of the inner-mitochondrial membrane. We have now shown that in vitro treatment of neuroblastoma cells with the combination of SAHA (1 µM) + PENAO (1.5 µM) synergistically decreased cell viability by up to 90% and induced intrinsic apoptosis by up 50-70%, with little effect on normal fibroblasts. Intrinsic apoptosis was confirmed by the induction of mitochondrial depolarisation. The combination of 20 mg/kg of PENAO and 17.5 mg/kg of SAHA was used to treat two different neuroblastoma tumour cell lines, as BALB/c nude mouse xenograft models. The combination prolonged survival from 9 to 19 days. Expression array analysis of neuroblastoma cells treated with SAHA + PENAO showed significant down-regulation of genes involved in cancer metabolism, oncogene transcription, cancer cell growth, and drug resistance. We confirmed that combination treatment of neuroblastoma cells repressed transcription and translation of the two down-regulated gene candidates, early growth response protein 1 (EGR1) and heme oxygenase 1 (HMOX1), by 5.4 and 4.5 fold, respectively. Further research is necessary to confirm the exact role of these candidate genes in the cytotoxic action of SAHA + PENAO. Since both SAHA and PENAO are currently in human cancer trials, our promising in vitro and in vivo data on the combination of SAHA + PENAO in neuroblastoma warrant further investigation of the combination for early phase trials in children with relapsed neuroblastoma.