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VOL. 72 (1), 27-36, 2006 ANTIAPOPTOTIC PROTEINS BCL2 AND BCLX...

These results confirm that Bcl2 and BclX conferred complete
resistance to imatinib-mediated apoptosis. Although it has been
proposed that apoptosis induction is a major mechanism for the
cytotoxic effect of imatinib in vitro (5, 6) our results underscores the
importance of apoptosis-independent mechanisms for imatinib
antiproliferative activity. It is conceivably that non-apoptotic
mechanisms are responsible for the cytostatic effect of imatinib, and
allows the restoration of cell growth when the drug is removed. In
consistency with this result, it has been reported that imatinib
selectively suppresses CML primitive progenitors by reversing
abnormally increased proliferation but does not significantly increase
apoptosis (10).

Thus, our results suggest that the growth inhibitory effect of
imatinib is mediated two concomitant mechanisms: one cytotoxic
mechanism that triggers an apoptotic program and another cytostatic
mechanism unrelated to apoptosis. This second mechanism would
be the responsible for the growth retardation induced in cells
expressing Bcl2 and BclX. Also, the results suggest that this cytostatic
mechanism could be important for the imatinib activity in vivo.

ACKNOWLEDGEMENTS

We thank Pilar Frade, María Aramburu and Guillermo Santana
for technical assistance, Novartis for imatinib, Roche España for
interferon a and Jose Luis Fernández-Luna for KbclX cell line. The
work was supported by grant PM98-0109 and SAF2002-04193 from
Spanish Ministry of Science and Technology to J.L.

REFERENCES

(1) KIRKIN, V.; JOOS, S. and ZORNIG, M. (2004): The role of Bcl-2 family members
in tumorigenesis. Biochim. Biophys. Acta 1644: 229-49.

(2) RAVANDI, F.; KANTARJIAN, H. M.; TALPAZ, M.; O’BRIEN, S.; FADERL, S.; GILES, F.J.;
THOMAS, D.; CORTES, J.; ANDREEFF, M.; ESTROV, Z.; RIOS, M. B. and ALBITAR, M.
(2001) Expression of apoptosis proteins in chronic myelogenous leukemia:
associations and significance. Cancer 91: 1964-72.

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