Inhibition of mitochondrial translocase SLC25A5 and histone deacetylation is an effective combination therapy in neuroblastoma. Issue 7 (17th November 2022)

• Record Type: Journal Article
• Authors: Seneviratne, Janith A.; Carter, Daniel R.; Mittra, Rituparna; Gifford, Andrew; Kim, Patrick Y.; Luo, Jie‐Si; Mayoh, Chelsea; Salib, Alice; Rahmanto, Aldwin S.; Murray, Jayne; Cheng, Ngan C.; Nagy, Zsuzsanna; Wang, Qian; Kleynhans, Ane; Tan, Owen; Sutton, Selina K.; Xue, Chengyuan; Chung, Sylvia A.; Zhang, Yizhuo; Sun, Chengtao; Zhang, Li; Haber, Michelle; Norris, Murray D.; Fletcher, Jamie I.; Liu, Tao; Dilda, Pierre J.; Hogg, Philip J.; Cheung, Belamy B.; Marshall, Glenn M.
• Is Part Of: International journal of cancer. Volume 152:Issue 7(2023)
• Page Start: 1399
• Page End: 1413
• Publication Date: 2022-11-17
• Subjects: neuroblastoma -- PENAO -- SAHA -- SLC25A5; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.34349
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common solid cancer in young children with poor clinical outcomes following conventional chemotherapy. We sought druggable mitochondrial protein targets in neuroblastoma cells. Among mitochondria‐associated gene targets, we found that high expression of the mitochondrial adenine nucleotide translocase 2 ( SLC25A5/ANT2 ), was a strong predictor of poor neuroblastoma patient prognosis and contributed to a more malignant phenotype in pre‐clinical models. Inhibiting this transporter with PENAO reduced cell viability in a panel of neuroblastoma cell lines in a TP53 ‐status‐dependant manner. We identified the histone deacetylase inhibitor, suberanilohydroxamic acid (SAHA), as the most effective drug in clinical use against mutant TP53 neuroblastoma cells. SAHA and PENAO synergistically reduced cell viability, and induced apoptosis, in neuroblastoma cells independent of TP53 ‐status. The SAHA and PENAO drug combination significantly delayed tumour progression in pre‐clinical neuroblastoma mouse models, suggesting that these clinically advanced inhibitors may be effective in treating the disease. Abstract : What's new? Therapies that target the mitochondria can have a strong apoptotic effect and also increase the effectiveness of standard chemotherapy. Here, the authors went looking for druggable mitochondrial protein targets in neuroblastoma cells. They found that high expression of the mitochondrial adenine nucleotide translocase 2 (SLC25A5/ANT2) predicted poor prognosis in NB patients. Inhibiting this mitochondrial protein with phenylarsonous acid (PENAO) in combination with suberanilohydroxamic acid (SAHA) treatment delayed tumour progression of neuroblastoma in mouse models, regardless of TP53 mutation status. The two drugs worked synergistically against drug‐resistant, TP53 ‐mutant NB xenograft tumours.