Biochem Pharmacol 2025 Dec 07;244:117613. doi: 10.1016/j.bcp.2025.117613.

Semisynthetic indole alkaloids restrain the invasiveness of glioblastoma cell lines and inhibit human Aquaporin-1 water channels.

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The clinical challenge for treating glioblastoma (GBM) brain cancers is that even with best therapy, median survival time is still only ∼15 months after diagnosis. The unmet need is how to control lethal spreading of these highly invasive cells. We tackled this challenge by running blinded high-throughput screens of the rigorously curated Davis Open Access Compound Library. Positive hits captured a structurally-related array of five novel indole alkaloid compounds (RAD116, RAD117, RAD118, RAD119, RAD120) derived from a natural indole alkaloid scaffold (RAD114). The agents at 1 µM reduced invasiveness of pediatric and adult GBM lines U87-MG, U251-MG, KNS-42, and DBTRG-05 in transwell assays. RAD116 and RAD117 were most effective, reducing invasiveness in all lines up to 76 %. In adult lines, RAD118 and RAD119 reduced invasiveness by 27-47 %, and RAD120 blocked invasion by 14-32 %. RAD114 was least effective, causing 12-30 % reduction in two lines. The candidate mechanism of action involves block of Aquaporin-1 (AQP1) water channels, which are located in leading edges of GBM cells and linked to high cell motility. RAD117 blocked human AQP1 water flux in Xenopus laevis assays at sub-micromolar doses, making it the most potent inhibitor of AQP1 water channels identified to date. High potency and low toxicity of the novel indole alkaloids introduced here support feasibility for further preclinical testing, and may hold promise for future clinical translation as an adjunct therapy to hold GBM cells in place while other first line treatments are in progress.

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