Preferential targeting of apoptosis in tumor versus normal cells.
Elimination of cancer cells by early apoptosis is preferred over other forms of cell growth inhibition. Apoptosis directly leads to tumor regression and reduces risks of selecting more aggressive and/or drug-resistant phenotypes that are often responsible for tumor regrowth and treatment failure. Although DNA damage by anticancer drugs is commonly recognized as an apoptotic stimulus, there is enormous variability in the magnitude and timing of such effects. Especially potent and rapid apoptosis seems to be a hallmark of various alkylating anticancer drugs that are regarded as DNA-reactive agents but are observed to react mainly with cellular proteins. Our studies with such dual-action drugs (irofulven, oxaliplatin) suggest that not only DNA damage, but also protein damage, contributes to apoptosis induction. DNA damage is well known to initiate death-signaling pathways leading to mitochondrial dysfunction. Protein damage, in turn, can distort cell redox homeostasis, which facilitates apoptosis execution. Such dual effects can be particularly lethal to tumor cells, which tend to function under pro-oxidative conditions. In contrast to tumor cells that are highly susceptible, normal cells show marginal apoptotic responses to the dual action drugs. This protection of normal cells might reflect their greater ability to buffer pro-oxidative changes and quickly restore redox homeostasis, despite substantial drug uptake and macromolecular binding. Importantly, by targeting the death process at multiple points, DNA- and protein-damaging drugs can be less vulnerable to various bypass mechanisms possible with single targets. The reviewed studies provide a proof of concept that differential apoptosis targeting in cancer versus normal cells can be a basis for tumor selectivity of anticancer drugs.
Woynarowska
Barbara A
BA
Department of Radiation Oncology, The University of Texas Health Science Center, 14960 Omicron Drive, San Antonio, TX 78245, USA. bwoynar@saci.org
Woynarowski
Jan M
JM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010084:Oxidation-Reduction; D012717:Sesquiterpenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D012717:Sesquiterpenes; D000077150:Oxaliplatin; C102714:irofulven