| ABT-737 is a small molecule that occupies the pro-apoptotic Bcl-2 homology domain (BH3) binding groove of anti-apoptotic Bcl-2 family members, and, thereby, strongly and selectively inhibits Bcl-2, Bcl-XL, and Bcl-w with high affinity (Ki< 1 nM) but binds weakly (Ki>460 nM) to other antiapoptotic BCL-2 family members, including MCL-1 and BFL-1. The IC50 values of ABT-737 are 2.4, 0.23, 0.008, 0.23, and 6.79 μM in adult T-cell leukemia/lymphoma (ATLL) cell lines MT-1, MT-2, HUT 102, Jurkat, and Ramos cells, respectively.[1] ABT-737 treatment of multiple myeloma (MM) cell lines (MM.1S, OPM1, KMS-12PE, INA-6, KMS-12BM, MC/CAR) induces a dose-dependent significant decrease in viability in all cell lines (IC50 range 2-12 μM). MM.1S cells treated with ABT-737 (2 μM) show a marked increase in nuclear condensation, whereas, untreated control cells exhibit homogeneous and intact nuclei. However, ABT-737 (0-8 μM) does not significantly decrease the viability of normal peripheral blood mononuclear cells and MM bone marrow stromal cells. ABT-737 (2 μM) abrogates MM cell growth triggered by interleukin-6 or insulin-like growth factor-1. Besides, ABT-737-induced apoptosis is associated with activation of caspase-8, caspase-9 and caspase-3 in MM.1S cells, followed by poly(ADP-ribose) polymerase cleavage. ABT-737 (1 μM) triggers minimal decrease in viability in MM.1S cells, whereas ABT-737??G132 induces significant decrease in viability cells.[2] In 11 SCLC cell lines (NCI-H889, NCI-H1963, NCI-H1417, NCI-H146, NCI-187, DMS79, NCI-1048, NCI-H82, NCI-H196, H69AR, and DMS114), the cellular responses based on the cell proliferation EC50 values of ABT-737 range from 20 nM for NCI-H889 cells to >100 μM for DMS114 cells. Chronic ABT-737 exposure decreases Bcl-2 and Noxa levels and increases Mcl-1 levels in H146 cells. The apparent EC50 of ABT-737 in H196 cells following Mcl-1 siRNA transfection is 0.14 μM, which represents approximately a 400-fold increase in the sensitivity of H196 cells to ABT-737 treatment.[3] In the ATLL cell line HUT 102 xenograft model, ABT-737 (100 mg/kg/day) significantly decreases the mean tumor volume, weight, and serum level of soluble IL-2 receptor α (sIL-2Rα) in C.B-17/Icr-SCID mice. ABT-737 also induces massive apoptosis in the tumors of mice .[1] In the ovarian cancer cell line IGROV-1 xenograft model, either carboplatin (30 mg/kg, i.p., once weekly), ABT-737 (100 mg/kg, i.p. daily), or both carboplatin and ABT-737 seem to be well tolerated with <5% decrease in mean body weights over the duration of the experiment. When used as single agents, both ABT-737 and carboplatin have a modest effect. However, the tumor volume and tumor mass following treatment with both ABT-737 and carboplatin is substantially reduced.[4] |
