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Blood, 1 January 2009, Vol. 113, No. 1, pp. 149-153.
Prepublished online as a Blood First Edition Paper on October 3, 2008; DOI 10.1182/blood-2008-02-138560.
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Submitted February 11, 2008
Accepted August 16, 2008
AT-101 induces apoptosis in CLL B-cells and overcomes stromal cell-mediated Mcl-1 induction and drug resistance
Kumudha Balakrishnan, Jan A Burger, William G. Wierda, and Varsha Gandhi*
Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: vgandhi{at}mdanderson.org.
Resistance to apoptosis in CLL B-cells is associated with overexpression of Bcl-2-family-anti-apoptotic proteins. Their expression is endogenous, but is also induced by signals from the microenvironment resulting in intrinsic and extrinsic drug resistance. Because AT-101 binds to the BH3 motif of all Bcl-2-family-anti-apoptotic proteins, we hypothesized that this molecule could overcome resistance. AT-101 treatment (20 µM for 24hr) resulted in a median 72% apoptosis in CLL cells (patients; n=32, p=0.0001). Stromal cells protected CLL B-cells from spontaneous and fludarabine-induced apoptosis (p=0.003) by increasing the Mcl-1 protein levels. However, AT-101 induced similar extent of down-regulation of Mcl-1 and apoptosis in CLL lymphocytes cultured in suspension or on stroma (p=1.00). Stromal cells expressed undetectable levels of anti-apoptotic but high levels of activated ERK and AKT proteins and had low or no apoptosis with AT-101. Collectively, these data demonstrate that AT-101 induces apoptosis in CLL B-cells and overcomes microenvironment-mediated resistance while sparing normal stromal cells.
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