A problem that confronts clinicians in the treatment of
cancer is the resistance of hypoxic
tumors to
chemotherapy and
radiation therapy. Thus, the development of new drugs that are toxic to hypoxic cells found in solid
tumors is an important objective for effective anticancer
chemotherapy. We recently showed that the heterocyclic aromatic N-
oxides,
quinoxaline 1,4-dioxides (QdNOs), are cytotoxic to tumor cells cultured under
hypoxia. In this study, we evaluated the
hypoxia-selective toxicity of four diversely substituted QdNOs and determined their effect on the expression of
hypoxia inducible factor (HIF) 1alpha in the human
colon cancer cell line T-84. The various QdNOs were found to possess a 50- to 100-fold greater cytotoxicity to T-84 cells cultured under
hypoxia compared with oxia. Interestingly, the
hypoxia cytotoxicity ratio (HCR), the ratio of equitoxic concentrations of the drug under aerobic/anoxic conditions, was highly structure related and depended on the nature of the substituents on the QdNO heterocycle. The most cytotoxic 2-benzoyl-3-phenyl-6,7-dichloro derivative of QdNO (DCQ) was potent at a dose of 1 microM with an HCR of 100 and significantly reduced the levels of HIF-1alpha transcript and
protein. The 2-benzoyl-3-phenyl derivative (BPQ) had a
hypoxia potency of 20 microM and an HCR of 40. By contrast, the 2-aceto-3-methyl and the 2,3-tetramethylene (TMQ) derivatives of QdNO were much less cytotoxic under
hypoxia (HCRs of 8.5 and 6.5, respectively) and reduced the expression of HIF-1alpha
mRNA to a much lesser extent. Because the nonchlorinated analogue BPQ did not demonstrate behavior similar to that of DCQ, we hypothesize that the C-6, C-7-chlorine of DCQ might play a significant role in the selective hypoxic cytotoxicity of the drug.