Because apoptosis can be detected in circulating leukemia cells after institution of antileukemic therapy (6-10) and in murine solid tumors after effective antineoplastic treatment in vivo (2,11,12), there has been considerable interest in identifying the apoptotic pathway(s) activated by various antineoplastic agents. Many agents, including doxorubicin, etoposide and teniposide, methotrexate, cisplatin, and bleomycin, induce the synthesis of FasL (200,201) by activating the transcription factors NF-kB and AP-1 (202,203). In addition, Fas receptor expression is upregulated in a p53-dependent fashion by DNA-damaging agents (204). Although these observations have been used to implicate the death receptor pathway (Chap. 2) in drug-induced killing, several observations suggest that Fas/FasL interactions might not be required for killing by most agents. First, cells with defects in Fas expression or Fas-mediated signaling remain susceptible to a variety of drugs (205-210). Second, blocking anti-Fas antibodies inhibit the cytotoxic effects of agonistic anti-Fas antibodies or upregulated Fas but not the previously mentioned anticancer drugs (205-207,211). Third, inhibition of the death receptor pathway by crmA, an inhibitor of caspases 8 and 10 (212), fails to inhibit the induction of apoptosis by these drugs (205,209).
Although these observations suggest that signaling through the Fas/FasL pathway is not absolutely required for anticancer drug-induced apoptosis, the possibility that induction of Fas and FasL contributes to apoptosis, particularly after prolonged exposure to low doses of DNA-damaging agents (135,213), has not been ruled out. This possibility is discussed in greater detail in Chap. 2. In addition, whereas most drug-induced apoptosis occurs independent of Fas/FasL signaling, a small group of drugs do in fact appear to trigger apoptosis by activating death receptor pathways. These include 5-fluorouracil (214), 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (215), proteasome inhibitors (216), trans-retinoic acid (217), CI-1040 (135), and fenretinide (218) as well as depsipeptide (219) and other histone deacetylase inhibitors (220). Interestingly, in instances where it has been critically examined, this reliance on the death receptor pathway appears to vary from one cell line to another (135,218,221). In the case of colon cancer cells treated with fluoropyrimidines, the presence of wild-type p53 reportedly determines whether drug-induced apoptosis proceeds through the Fas pathway (222). The critical determinant for other drugs is currently unknown but is almost certainly not p53.
For the majority of anticancer drugs, previous studies not only ruled out an essential role for the Fas/FasL pathway in drug-induced apoptosis (see first paragraph of this Section) but also directly implicated the mitochondrial pathway in this process. Observations that are important in this regard include the demonstration that cytochrome c release accompanies induction of apoptosis by a variety of agents (113,120,223,224), the determination that Bax translocates to mitochondria in response to various drugs independent of (i.e., upstream of) caspase activity (83,225), and the demonstration that combined deletion of BAX and BAK inhibits drug-induced apoptosis (87,226). As might be expected, if the mitochondrial pathway plays a predominant role, dominant-negative caspase-9 constructs (227,228) and antiapoptotic Bcl-2 family members (210,229) inhibit drug-induced apoptosis. The demonstration that Caspase9 or Apaf-1 gene deletion delays the induction of apoptosis by staurosporine, dexamethasone, etoposide, and ionizing radiation in mouse fibroblasts or thymocytes, whereas Caspase8 deletion does not, provides additional support for the view that most agents activate the mitochondrial pathway (1). For some drugs in some cell types, the signaling immediately upstream of Bax and/or Bak activation appears to involve changes in expression or localization of BH3-only family members (see Section 6), but in other cells and for other drugs, the changes that lead to Bax and/or Bak activation still require clarification.
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