The selective BCL‐2 inhibitor ABT‐199 induces cell death via the intrinsic apoptotic pathway in canine B‐cell and T‐cell lymphoma cell lines

Abstract

The B cell lymphoma 2 (BCL‐2) family of proteins are critical regulators of apoptosis, acting as either activators or inhibitors of the intrinsic apoptotic pathway. Evasion of apoptosis by shifting the balance toward anti‐apoptotic proteins including BCL‐2 is an established mechanism of cancer cells. Lymphoma is a leading cause of cancer‐related deaths in dogs and there is evidence that BCL2 is overexpressed and can contribute to a therapy‐resistant phenotype. A selective BCL2 inhibitor, ABT‐199, shows clinical activity in human lymphoid malignancies but the effect in canine lymphoma is unknown. This study evaluated the effects of ABT‐199 on cell growth and different stages of apoptosis in two canine B‐cell lymphoma (CLBL‐1, 17–71) and three canine T‐cell lymphoma (OSW, Ema, Nody) cell lines. Cells were cultured for 72h in the presence of ABT‐199 at increasing concentrations to establish half maximal inhibitory concentrations (IC50). Nody (IC50: 0.49 μM), CLBL‐1 (2.72 μM), Ema (3.53 μM), and OSW (3.6 μM) were more sensitive to anti‐proliferative effects of ABT‐199 than 17–71 (12.93 μM). ABT‐199 rapidly induced key features of apoptosis including loss of mitochondrial membrane potential, increased caspase−3/−7 activity, and externalization of phosphatidylser‐ine. This effect was abrogated in cells co‐cultured with the pan‐caspase inhibitor Z‐VAD(OMe)‐FMK. The responses to ABT‐199 treatment are currently correlated with expression levels of BCL‐2 family members. These findings support that ABT‐199 induces cytotoxicity via induction of the intrinsic apoptotic pathway in canine lymphoma cell lines and that ABT‐199 shows promise to overcome drug resistance and to improve outcome in dogs with lymphoma.Support or Funding InformationThis study was supported by the University of Georgia VMES Research Grant 2926GR207002.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.