Signaling pathways activated by daunorubicin

Abstract

The anthracycline daunorubicin is widely used in the treatment of acute nonlymphocytic leukemia. The drug has, of course, been the object of intense basic research, as well as preclinical and clinical study. As reviewed in this article, evidence stemming from this research clearly demonstrates that cell response to daunorubicin is highly regulated by multiple signaling events, including a sphingomyelinase-initiated sphingomyelin-ceramide pathway, mitogen-activated kinase and stress-activated protein/c-Jun Nterminal kinase activation, transcription factors such as nuclear factor B, as well as the Fas/Fas-ligand system. These pathways are themselves influenced by a number of lipid products (diacylglycerol, sphingosine-1 phosphate, and glucosyl ceramide), reactive oxygen species, oncogenes (such as the tumor suppressor gene p53), protein kinases (protein kinase C and phosphoinositide-3 kinase), and external stimuli (hematopoietic growth factors and the extracellular matrix). In light of the complexity and diversity of these observations, a comprehensive review has been attempted toward the understanding of their individual implication (and regulation) in daunorubicin-induced signaling. IntroductionThe anthracycline daunorubicin (DNR) is one of the major antitumor agents widely used in the treatment of acute myeloid leukemias (AMLs). Cytotoxicity mediated by DNR is generally thought to be the result of drug-induced damage to DNA. This damage is mediated by quinone-generated redox activity, intercalation-induced distortion of the double helix, or stabilization of the cleavable complex formed between DNA and topoisomerase II. 1 However, how and why such events should bring about cell death remains unclear, especially when one considers that DNA interaction may not be a prerequisite for anthracycline cytotoxicity. [2][3][4][5] Hence, the exploration and understanding of the process of apoptosis has forced a reconsideration of the mechanisms whereby myeloid leukemia cells respond to DNR. In this context, we have shown that, within a narrow concentration range (0.2-1 M), DNR can trigger apoptosis in the monocytic U937 or the myelocytic HL-60 AML cells but not in the immature (CD 34 ϩ ) KG1a, KG1, or HEL cells, 6 the latter being more resistant to DNR than the former. 7 These results suggested that DNR triggers apoptotic signals in drug-sensitive AML cells and that inhibition of these signals may contribute to drug resistance and, for example, to the inherent resistance of immature AML cells. For this reason, others and we have investigated the mechanism by which DNR activates apoptosis in DNR-sensitive AML cells. Implication of sphingomyelin metabolism in DNR-induced apoptosis DNR activates the sphingomyelin cycle in sensitive leukemic cellsIn the early 1990s, a number of studies provided growing evidence that sphingomyelin breakdown products (ie, ceramide [CER] and phosphorylcholine) could play an important role in mediating the action of cytokines, including tumor necrosis factor ␣ (TNF␣) and interferon. For example,...

Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation

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Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells

“…The mitochondrial pathway to cell death plays an essential role in apoptosis induced by cytotoxic agents, including the podophyllotoxin derivative etoposide (Schmitt et al, 1999), the anthracyclins such as daunorubicin (Laurent and Jaffrezou, 2001) and the nucleotide analog cytarabin (Hiddemann, 1991), three cytotoxic drugs commonly used for treating AMLs. This pathway leads to cytochrome c-and Apaf-1-mediated activation of caspase-9, a first step in a proteolytic cascade that involves effector caspase-3, -6 and -7 (Dubrez et al, 1996;Slee et al, 1999).…”

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