Alterations in the apoptotic machinery and their potential role in anticancer drug resistance.
Anticancer drugs can potentially kill cells in two fundamentally different ways, by interfering with cellular processes that are essential for maintenance of viability or by triggering an endogenous physiological cell death mechanism. Apoptosis is a form of physiological cell death mediated by caspases, a unique family of intracellular cysteine proteases. Zymogen forms of these proteases are found in virtually all somatic cells, but remain latent until their activation is induced by ligation of specific cell surface receptors (the so-called "death receptors"), by mitochondrial alterations that allow release of cytochrome c and other intermembrane components, or possibly by other mechanisms. Most anticancer drugs activate the mitochondrial pathway. This apoptotic pathway is regulated by pro- and antiapoptotic members of the Bcl-2 family of proteins. Once activated, certain caspases might also be controlled by the inhibitor of apoptosis (IAP) proteins. Alterations in apoptotic pathway components or their regulators have been detected in a variety of cancers, suggesting that loss of the ability of cells to undergo apoptosis might contribute to carcinogenesis. Because cancer therapies such as radiation, glucocorticoids, and chemotherapeutic drugs exert their beneficial effects, at least in part, by inducing apoptosis of cancer cells, the same alterations in apoptotic pathways would be predicted to contribute to resistance. A key issue is whether the direct toxic activity of these treatments is of benefit when neoplastic cells contain changes that diminish their ability to undergo apoptosis.
Kaufmann
Scott H
SH
Division of Oncology Research, Guggenheim 1342C, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Kaufmann.Scott@Mayo.edu
Vaux
David L
DL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*
D000970:Antineoplastic Agents