The Effects of Protein Phosphatase 2A Activation with Novel Tricyclic Sulfonamides on Hepatoblastoma

Background: The tumor suppressor, protein phosphatase 2A (PP2A), is downregulated in hepato-blastoma. We aimed to examine the effects of two novel compounds of the tricyclic sulfonamide class, ATUX-3364 (3364) and ATUX-8385 (8385), designed to activate PP2A without causing immunosup-pression, on human hepatoblastoma.Methods: An established human hepatoblastoma cell line, HuH6, and a human hepatoblastoma patient -derived xenograft, COA67, were treated with increasing doses of 3364 or 8385, and viability, prolifera-tion, cell cycle and motility were investigated. Cancer cell stemness was evaluated by real-time PCR and tumorsphere forming ability. Effects on tumor growth were examined using a murine model.Results: Treatment with 3364 or 8385 significantly decreased viability, proliferation, cell cycle pro-gression and motility in HuH6 and COA67 cells. Both compounds significantly decreased stemness as demonstrated by decreased abundance of OCT4, NANOG, and SOX2 mRNA. The ability of COA67 to form tumorspheres, another sign of cancer cell stemness, was significantly diminished by 3364 and 8385. Treatment with 3364 resulted in decreased tumor growth in vivo.Conclusion: Novel PP2A activators, 3364 and 8385, decreased hepatoblastoma proliferation, viability, and cancer cell stemness in vitro. Animals treated with 3364 had decreased tumor growth. These data provide evidence for further investigation of PP2A activating compounds as hepatoblastoma therapeutics.(c) 2023 Elsevier Inc. All rights reserved.