Background: The NO-modified form of the HIV inhibitor saquinavir (Saq-NO) inhibited the growth of a variety of can- cer cell lines in vitro and in vivo more potently than the orig- inal compound in a nontoxic fashion. In addition, chemo- and immunosensitizing properties were observed. The aim of the present study was to evaluate its anticancer action against non-small cell lung carcinoma cells in their doxoru- bicin (DOXO) sensitive and resistant phenotype (NCI-H460 and NCI-H460/R).
Methods: The viability of cells was analyzed by MTT and crystal violet assays. DR5 expression was estimated by real time RT-PCR and flow cytometry. Activity of P-glycoprotein (P-gp) pumps was evaluated by the Rho123 accumulation assay.
Results: Saq-NO diminished the viability of lung cancer cells through induction of cell cycle arrest in the Gq/G1 phase in- dependently of the overexpression of the P-gp pumps. In addition, Saq-NO elevated or completely reconstituted the doxorubicin efficacy in NCI-H460 and NCI-H460/R, respec- tively. The chemosensitizing effect in DOXO resistant cells was a consequence of P-gp inhibition which was found to be more potent than that observed with dex-verapamil, a con- ventional inhibitor of P-gp. Sensitization to DOXO upon Saq- NO was accompanied by elevated DR5 expression, but the resistance to TRAIL was not abrogated.
Conclusions: The NO-modified HIV inhibitor saquinavir dis- played equal antiproliferative and chemosensitizing proper- ties in DOXO sensitive and resistant non-small cell lung car- cinoma cells, suggesting the importance of the evaluation of this drug as an antineoplastic agent.