Effects of Low-Dose Atorvastatin on Hypoxic Response in Statin-Sensitive and Statin-Resistant Cancer Cells

Statins were initially developed as lipid-lowering agents to reduce the risk of cardiovascular and cerebrovascular diseases. Recently, their anti-tumor effects have gained attention in the context of drug repositioning. However, most in vitro studies have been conducted under normoxic conditions, and limited research has examined their effects under hypoxia. Since hypoxia plays a crucial role in the tumor microenvironment by promoting cancer cell proliferation, epithelial-mesenchymal transition, invasion, metastasis, and drug resistance, evaluating the anti-tumor effects of statins under hypoxic conditions is essential. Additionally, previous in vitro studies have used statin concentrations substantially higher than those observed in the serum during hyperlipidemia treatment, raising concerns about their clinical applicability as anti-tumor agents. Here, we demonstrate that a clinically relevant concentration of atorvastatin (0.1 μM) inhibits the migration and invasion of the statin-sensitive non-small cell lung cancer (NSCLC) cell line HOP-92 under hypoxic conditions, without inducing drug resistance. Furthermore, atorvastatin (0.1-1 μM) reduced the expression of hypoxia-inducible factor-1α (HIF-1α) in the statin-resistant NSCLC cell line NCI-H322M, even though it did not inhibit cell proliferation. Since cancer cell migration and invasion are key processes in distant metastasis, and HIF-1α is a critical transcription factor that regulates metastasis, these findings suggest that statins could be repurposed as anti-metastatic agents for NSCLC, particularly under hypoxic conditions.