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; IC50 at 24 microM), MCF-7 (breast; IC50 at 22 microM), and CX-1 (colon; IC50 at 23 microM), 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 microM AZT. Combination treatment employing a constant concentration (1.25 microM) of the DLC dequalinium chloride (DECA) plus varying concentrations of AZT (0-50 microM) enhanced the AZT-induced cytotoxicity of carcinoma cells at least fourfold for MCF-7 and CX-1 cells (IC50 at 5 microM AZT), and twofold for DU-145 cells (IC50 at 11 microM AZT). Similar results were obtained in DU-145 cells using a constant concentration of the DLC MKT-077 (1.0 microM) and varying concentrations of AZT (IC50 at 12.5 microM). 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.
Modica-Napolitano
Josephine S
JS
Department of Biology, Merrimack College, 315 Turnpike Street, North Andover, MA 01845, USA. josephine.modicanapolitano@merrimack.edu
Nalbandian
Raffi
R
Kidd
Marianne E
ME
Nalbandian
Angele
A
Nguyen
Chilinh C
CC
D000255:Adenosine Triphosphate / Q000032:analysis; D002277:Carcinoma / Q000188:drug therapy*; D002412:Cations / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D006801:Humans; D008297:Male; D011725:Pyridines / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000008:administration & dosage / Q000494:pharmacology*
D002412:Cations; D011725:Pyridines; D013844:Thiazoles; D015215:Zidovudine; D000255:Adenosine Triphosphate; C097880:MKT 077; D013936:Thymidine