The selective in vitro cytotoxicity of carcinoma cells by AZT is enhanced by concurrent treatment with delocalized lipophilic cations

This study assessed the selective growth inhibitory effect on cultured carcinoma cells by 3′-azido-3′-deoxythymidine (AZT), as a single agent, and in combination with delocalized lipophilic cations (DLCs) that are known to inhibit mitochondrial function. In cytotoxicity assays, treatment of cells with varying concentrations of AZT induced a dose-dependent inhibition of cell growth of the human carcinoma lines DU-145 (prostate; IC 50 at 24 μM), MCF-7 (breast; IC 50 at 22 μM), and CX-1 (colon; IC 50 at 23 μM), yet caused no significant effect on the growth of the control epithelial cell line CV-1 (monkey kidney) at a concentration as high as 50 μM AZT. Combination treatment employing a constant concentration (1.25 μM) of the DLC dequalinium chloride (DECA) plus varying concentrations of AZT (0–50 μM) enhanced the AZT-induced cytotoxicity of carcinoma cells at least fourfold for MCF-7 and CX-1 cells (IC 50 at 5 μM AZT), and twofold for DU-145 cells (IC 50 at 11 μM AZT). Similar results were obtained in DU-145 cells using a constant concentration of the DLC MKT-077 (1.0 μM) and varying concentrations of AZT (IC 50 at 12.5 μM). As expected, the drug combination of constant DLC and varying AZT had no significant effect on the growth of CV-1 cells. Clonogenic assays demonstrated up to 20-fold enhancement of selective carcinoma cell killing by combination vs. single agent treatment, depending on the specific drug combination and concentrations used. It is hypothesized that the efficacy of the AZT/DLC drug combination in carcinoma cell killing may be based on a dual selectivity involving inhibition of mitochondrial energy metabolism and inhibition of DNA synthesis due to limited deoxythymidine monophosphate availability.