ArticleNaunyn-Schmiedeberg's archives of pharmacology2026
Simvastatin enhances the antitumor activity of temsirolimus through AMPK-associated metabolic modulation in clear-cell renal cell carcinoma.
Article in Naunyn-Schmiedeberg's archives of pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Clear-cell renal cell carcinoma (ccRCC) is characterized by VHL-associated metabolic reprogramming, including enhanced glycolysis and lipid biosynthesis, which may create therapeutic vulnerabilities. However, mTOR inhibitors such as temsirolimus often show limited efficacy due to adaptive metabolic compensation. We investigated whether simvastatin-induced metabolic stress enhances sensitivity to mTOR inhibition in a context-dependent manner in ccRCC. VHL-mutant (A498) and VHL-wild-type (Caki1) ccRCC cells were treated with simvastatin and temsirolimus, alone or in combination. Cell viability, colony formation, migration, Seahorse metabolic flux analysis, and Western blotting were performed. Mechanistic studies included shRNA-mediated knockdown of LKB1/AMPKα1/α2 and pharmacological modulation using Compound C and AICAR. Antitumor efficacy was evaluated in a Caki1 subcutaneous xenograft model in nude mice. Temsirolimus induced modest growth inhibition, whereas simvastatin produced stronger dose- and time-dependent effects. Combination treatment (simvastatin 2.5 µM + temsirolimus 100 nM) further reduced cell viability. Interaction analysis revealed a cell-dependent response, with synergism in A498 cells (combination index (CI), 0.31-0.77) and antagonistic-to-additive effects in Caki1 cells (CI, 1.6-2.7). Mechanistically, simvastatin activated LKB1-AMPK signaling, suppressed AKT/mTOR activity, reduced glycolysis (↓pPFKFB2), increased FBP1 expression, and downregulated lipid biosynthesis enzymes (FASN, SCD), thereby promoting ER stress and apoptosis. In vivo, combination therapy significantly suppressed tumor growth compared with monotherapy and alleviated temsirolimus-induced hypercholesterolemia without apparent toxicity. Simvastatin-induced metabolic perturbation enhances mTOR inhibition in a cell-dependent manner, supporting dual metabolic targeting as a potential therapeutic strategy in ccRCC.
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