Interestingly, in several drug-resistant cancer cells, a strong induction of caveolin-1 expression has been reported, suggesting a role for caveolin-1 in the acquisition and/or the maintenance of the multidrug resistance phenotype. In order to better understand the observation in human lung tumors, we treated drug-sensitive lung cancer cells (ie, A549, Calu-6, or NCI-H69 cells) with various cytotoxic drugs (ie, taxol, doxorubicin, or etoposide). Exposure to chemotherapeutic agents was sufficient to strongly up-regulate both caveolin-1 and caveolin-2 messenger RNA and protein levels. This up-regulation was sustained even a week after drug removal. The up-regulation of caveolin expression was dose-dependent. Our results suggest that caveolin-1 has tumor suppressor activity and is down-regulated during the development of lung cancer. Caveolin up-regulation is an early cellular response to a cytotoxic stress taking place well before drug resistance is manifested.