Calpain inhibitor II induces caspase-dependent apoptosis in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells as well as some solidtumor cells

Calpain is a calcium-dependent cysteine protease that is implicated in calc ium-dependent cell death, and calpain inhibitors are generally considered a s inhibitors of apoptosis, To the contrary, in the present study, we found that calpain inhibitor II (CPI-2) triggers rapid apoptosis in acute lymphob lastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) cells. All target ce ll lines were killed by CPI-2, including: ALL-I, a multidrug-resistant BCR- ABL fusion transcript-positive t(9;22) pro-B ALL cell line; RS4;11, a highl y radiation-resistant MLL-AF4 fusion transcript-positive t(4;11) pro-B ALL cell line; RAMOS, a highly radiation-resistant and p53-deficient Burkitt's lymphoma cell line; DAUDI, a Burkitt's leukemia/lymphoma cell line; NALM-6, a pre-B ALL cell line; and JURKAT and MOLT-3, two T-lineage ALL/NHL cell l ines. CPI-2-induced apoptosis in LYN-deficient and BTK-deficient subclones of the DT-40 lymphoma B cell line as effectively as it did in wild-type DT- 40 cells. Thus, CPI-2-induced apoptosis is not dependent on the protein tyr osine kinases LYN or BTK, Notably, caspase inhibitor I effectively inhibite d CPI-2-induced apoptosis, suggesting that the inhibition of a CPI-2-suscep tible protease results in caspase activation, leading to apoptosis in ALL/N HL cells. Unlike the high calpain-expressing ALL/NHL cell lines, myeloid le ukemia cell lines HL-60/AML, K562/CML, and U937/AMML, or solid tumor cell l ines BT-20/breast cancer, PC-3/prostate cancer, U373/ glioblastoma, and HeL a/epitheloid canter, were not susceptible to the cytotoxicity of CPI-2, Tak en together, our results identify calpain as a new molecular target for the treatment of ALL and NHL. CPI-2 and its analogues represent a promising ne w class of antileukemia/lymphoma agents that deserves further development.