Src kinase inhibitors induce apoptosis and mediate cell cycle arrest in lymphoma cells.

Src kinases are involved in multiple cellular contexts such as proliferation, adhesion, tumor invasiveness, angiogenesis, cell cycle control and apoptosis. We here demonstrate that three newly developed dual selective Src/Abl kinase inhibitors (SrcK-I) (AZM559756, AZD0530 and AZD0424) are able to induce apoptosis and cell cycle arrest in BCR-ABL, c-KIT and platelet-derived growth factor-negative lymphoma cell lines. Treatment of DOHH-2, WSU-NHL, Raji, Karpas-299, HUT78 and Jurkat cells with SrcK-I revealed that the tested substances were effective on these parameters in the cell lines DOHH-2 and WSU-NHL, whereas the other tested cell lines remained unaffected.

The tyrosine kinase inhibitor AMN107 (Nilotinib) exhibits off-target effects in lymphoblastic cell lines.

The aminopyrimidine inhibitor AMN107 (Nilotinib) was rationally designed to antagonize the aberrant tyrosine kinase activity of Bcr-Abl-positive cells. We here evaluated, whether AMN107 is also able to induce apoptosis in Bcr-Abl-negative cells of lymphatic origin. The B-cell lines DOHH-2 and WSU-NHL and the T-cell lines Jurkat and HUT78 were incubated with increasing amounts of AMN107 corresponding to clinically achievable dosages.

Prostate-apoptosis-response-gene-4 increases sensitivity to TRAIL-induced apoptosis.

The capacity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) to preferentially induce apoptosis in malignant cells while sparing normal tissues renders it an attractive therapeutic agent. Nevertheless, the molecular determinants governing sensitivity towards TRAIL remain to be defined. Acknowledging the previously demonstrated deregulation of prostate-apoptosis-response-gene-4 (par-4) in ex vivo cells of patients suffering from acute and chronic lymphatic leukemia, we here tested the hypothesis that expression of par-4 influences sensitivity to TRAIL.

Daxx overexpression in T-lymphoblastic Jurkat cells enhances caspase-dependent death receptor- and drug-induced apoptosis in distinct ways.

The role of Daxx, in particular, its ability to promote or hinder apoptosis, still remains controversial. In order to elucidate the functional relevance of Daxx in apoptosis signaling of malignant lymphocytes, Jurkat T-cells were stably transfected with a Daxx-expressing vector or with the respective Daxx-negative control vector. We thus demonstrate that ectopic expression of Daxx substantially increases the rate of apoptosis upon incubation with death receptor agonists such as Fas and TRAIL as well as upon incubation with the cytotoxic drug doxorubicin (DOX).

Prostate apoptosis response gene-4 sensitizes neoplastic lymphocytes to CD95-induced apoptosis.

Evaluating the functional consequences of prostate apoptosis response gene-4 (par-4) expression in CD95-induced apoptosis of neoplastic lymphocytes, we demonstrate that par-4 increases apoptosis by upregulating the CD95 receptor on the cell surface and--with a concomitant decrease of the FLICE-like inhibitory protein (FLIP)--by promoting cleavage of the initiator caspases-8 and -10. This results in an enforced activation of the executioner caspases-6, -7, and -3 as well as in an activation of the mitochondrial pathway. Upon inhibition of caspase-8, overexpression of par-4 enables Jurkat cells to maintain a higher sensitivity to CD95-induced apoptosis by downregulating cIAP-2 and XIAP and by enforcing activation of the initiator caspase-10 as well as of the executioner caspases-6, -7, and -3.