ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo

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Molecular Cancer Therapeutics 7, 3265-3274, October 1, 2008. doi:

10.1158/1535-7163.MCT-08-0268

ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in

vivo

Ackler, Yu Xiao, J. Mitten, , Anatol Oleksijew, n

Refici, Sally Schlessinger, Baole Wang, Sanjay R. Chemburkar, Joy Bauch,

Christin Tse, J. Frost, W. Fesik, Saul H. Rosenberg, W.

Elmore and R. Shoemaker

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott

Park, Illinois

Requests for reprints: Ackler, Global Pharmaceutical Research and

Development, Abbott Laboratories, Building AP3/105, 100 Abbott Park Road, Abbott

Park, IL 60064-6074. Phone: 847-935-1792; Fax: 847-938-4777. E-mail:

scott.ackler@...

Abstract

ABT-263 is a potent, orally bioavailable inhibitor of the antiapoptotic Bcl-2

family members Bcl-2, Bcl-xL, and Bcl-w, which is currently in phase I clinical

trials. Previous work has shown that this compound has low nanomolar

cell-killing activity in a variety of lymphoma and leukemia cell lines, many of

which overexpress Bcl-2 through a variety of mechanisms. Rapamycin is a

macrolide antibiotic that inhibits the mammalian target of rapamycin complex,

leading to cell cycle arrest and inhibition of protein translation. Rapamycin

(and its analogues) has shown activity in a variety of tumor cell lines

primarily through induction of cell cycle arrest. Activity has also been shown

clinically in mantle cell lymphoma and advanced renal cell carcinoma. Here, we

show that treatment of the follicular lymphoma lines DoHH-2 and SuDHL-4 with 100

nmol/L rapamycin induces substantial G0-G1 arrest. Addition of as little as 39

nmol/L ABT-263 to the rapamycin regimen induced a 3-fold increase in sub-G0

cells. Combination of these agents also led to a significant increase in Annexin

V staining over ABT-263 alone. In xenograft models of these tumors, rapamycin

induced a largely cytostatic response in the DoHH-2 and SuDHL-4 models.

Coadministration with ABT-263 induced significant tumor regression, with DoHH-2

and SuDHL-4 tumors showing 100% overall response rates. Apoptosis in these

tumors was significantly enhanced by combination therapy as measured by staining

with an antibody specific for cleaved caspase-3. These data suggest that

combination of ABT-263 and rapamycin or its analogues represents a promising

therapeutic strategy for the treatment of lymphoma. [Mol Cancer Ther

2008;7(10):3265-74]

Footnotes

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1 Supplementary material for this article is available at Molecular Cancer

Therapeutics Online (http://mct.aacrjournals.org/).