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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3492.
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IMMUNOBIOLOGY
Comment on Janssen et al, page 3662
Taxol therapy revisited
Shida Yousefi, and
Hans-Uwe Simon
UNIVERSITY OF BERN DEPARTMENT OF PHARMACOLOGY
In this issue of Blood, Janssen and colleagues report the essential role of apoptosome formation for taxol-induced apoptosis and suggest a role for Apaf-1 and caspase-9 in tumor development.
There have been contrasting reports regarding the role of caspase-9 and Apaf-1 for tumor development and anticancer drug resistance. Although these 2 key players of the mitochondrial death pathway were initially considered as tumor suppressors,1 recent reports suggest that etoposide and doxorubicin do not require the cytochrome c/Apaf-1/caspase-9 apoptosome.2 Janssen and colleagues have used a genetic approach to investigate key players in taxol-induced cell death. In contrast to a previous report, which used a pharmacological approach,3 there was no evidence that taxol would require caspase-10 to mediate cytotoxicity. Instead, caspase-9 and Apaf-1 were shown to be indispensable for caspase activation and apoptosis. Moreover, mitochondrial activation appeared to occur via a pathway involving Bim and Bax, but not Bid and Bak.
Cell recovery from cytotoxic insults has important implications for anticancer drug therapy. Therefore, the clonogenic assays performed by Janssen and colleagues are of great interest, since they imply a potential role for Apaf-1 and caspase-9 in tumor development. Such an assumption is supported by long-term observations in mice, in which the mitochondrial death pathway was somehow altered. For instance, mice deficient in Bim or Bax/Bak develop splenomegaly and lymphadenopathy after 3 to 4 months. A similar phenotype was observed in mice expressing a mutated form of cytochrome c that is unable to activate the apoptosome after 12 months.4
Several questions remain. Why is clonogenic survival during taxol treatment as a consequence of apoptosome deficiency cell-type dependent? Why do etoposide and doxorubicin, which block, like taxol, the cell cycle in the G2/M phase, kill cells independent of the apoptosome? It appears that these drugs influence other cell functions that are related to cell death and proliferation, such as autophagy, and this again might differ between different cells.5
Footnotes
Conflict-of-interest disclosure: The authors declare no competing financial interests. 
REFERENCES
- Soengas MS, Alarcon RM, Yoshida H, et al. Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science 1999; 284:156–159.[Abstract/Free Full Text]
- Ekert PG, Read SH, Silke J, et al. Apaf-1 and caspase-9 accelerate apoptosis, but do not determine whether factor-deprived or drug-treated cells die. J Cell Biol 2004; 165:835–842.[Abstract/Free Full Text]
- Park SJ, Wu CH, Gordon JD, Zhong X, Emami A, Safa AR. Taxol induces caspase-10-dependent apoptosis. J Biol Chem 2004; 279:51057–51067.[Abstract/Free Full Text]
- Hao Z, Duncan GS, Chang CC, et al. Specific ablation of the apoptotic functions of cytochrome c reveals a differential requirement for cytochrome c and apaf-1 in apoptosis. Cell 2007; 121:579–591.[CrossRef]
- Yousefi S and Simon HU. Apoptosis regulation by autophagy gene 5. Crit Rev Oncol Hematol 2007; 63:241–244.[CrossRef][Medline]
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Apaf-1 and caspase-9 deficiency prevents apoptosis in a Bax-controlled pathway and promotes clonogenic survival during paclitaxel treatment
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