TY - JOUR
T1 - AT-101 induces apoptosis in CLL B cells and overcomes stromal cell-mediated Mcl-1 induction and drug resistance
AU - Balakrishnan, Kumudha
AU - Burger, Jan A.
AU - Wierda, William G.
AU - Gandhi, Varsha
PY - 2009/1/1
Y1 - 2009/1/1
N2 - Resistance to apoptosis in CLL B cells is associated with overexpression of Bcl-2 family antiapoptotic 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 antiapoptotic proteins, we hypothesized that this molecule could overcome resistance. AT- 101 treatment (20 μM for 24 hours) resulted in a median 72% apoptosis in CLL cells (patients; n = 32, P < .001). Stromal cells protected CLL B cells from spontaneous and fludarabine-induced apoptosis (P = .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 = .999). Stromal cells expressed undetectable levels of antiapoptotic 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.
AB - Resistance to apoptosis in CLL B cells is associated with overexpression of Bcl-2 family antiapoptotic 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 antiapoptotic proteins, we hypothesized that this molecule could overcome resistance. AT- 101 treatment (20 μM for 24 hours) resulted in a median 72% apoptosis in CLL cells (patients; n = 32, P < .001). Stromal cells protected CLL B cells from spontaneous and fludarabine-induced apoptosis (P = .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 = .999). Stromal cells expressed undetectable levels of antiapoptotic 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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U2 - 10.1182/blood-2008-02-138560
DO - 10.1182/blood-2008-02-138560
M3 - Article
C2 - 18836097
AN - SCOPUS:59449095496
SN - 0006-4971
VL - 113
SP - 149
EP - 153
JO - Blood
JF - Blood
IS - 1
ER -