ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo.
ABT-263 is a potent, orally bioavailable inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-x(L), 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 G(0)-G(1) arrest. Addition of as little as 39 nmol/L ABT-263 to the rapamycin regimen induced a 3-fold increase in sub-G(0) 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.
Ackler
Scott
S
Global Pharmaceutical Research and Development, Abbott Laboratories, Building AP3/105, 100 Abbott Park Road, Abbott Park, IL 60064-6074, USA. scott.ackler@abbott.com
Xiao
Yu
Y
Mitten
Michael J
MJ
Foster
Kelly
K
Oleksijew
Anatol
A
Refici
Marion
M
Schlessinger
Sally
S
Wang
Baole
B
Chemburkar
Sanjay R
SR
Bauch
Joy
J
Tse
Christin
C
Frost
David J
DJ
Fesik
Stephen W
SW
Rosenberg
Saul H
SH
Elmore
Steven W
SW
Shoemaker
Alex R
AR
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology* / Q000628:therapy; D051379:Mice; D016513:Mice, SCID; D012074:Remission Induction; D020123:Sirolimus / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D013449:Sulfonamides; D020123:Sirolimus; C528561:navitoclax