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Quinoxaline 1,4‐dioxides: Hypoxia‐selective therapeutic agents
Author(s) -
DiabAssef Mona,
Haddadin Makhluf J.,
Yared Pierre,
Assaad Chafika,
GaliMuhtasib Hala U.
Publication year - 2002
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.10036
Subject(s) - hypoxia (environmental) , cytotoxicity , biology , cytotoxic t cell , quinoxaline , tumor hypoxia , tirapazamine , pharmacology , cell culture , in vitro , cancer research , biochemistry , radiation therapy , chemistry , medicine , oxygen , genetics , organic chemistry
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) 1α 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 μM with an HCR of 100 and significantly reduced the levels of HIF‐1α transcript and protein. The 2‐benzoyl‐3‐phenyl derivative (BPQ) had a hypoxia potency of 20 μM 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‐1α 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. © 2002 Wiley‐Liss, Inc.