Arsenic trioxide (AT) is a novel human neutrophil pro-apoptotic agent: effects of catalase on AT-induced apoptosis, degradation of cytoskeletal proteins and de novo protein synthesis.

The anti-cancer drug arsenic trioxide (AT) induces apoptosis in a variety of transformed or proliferating cells. However, little is known regarding its ability to induce apoptosis in terminally differentiated cells, such as neutrophils. Because neutropenia has been reported in some cancer patients after AT treatment, we hypothesised that AT could induce neutrophil apoptosis, an issue that has never been investigated. Herein, we found that AT-induced neutrophil apoptosis and gelsolin degradation via caspases. AT did not increase neutrophil superoxide production and did not induce mitochondrial generation of reactive oxygen species. AT-induced apoptosis in PLB-985 and X-linked chronic granulomatous disease (CGD) cells (PLB-985 cells deficient in gp91(phox) mimicking CGD) at the same potency. Addition of catalase, an inhibitor of H2O2, reversed AT-induced apoptosis and degradation of the cytoskeletal proteins gelsolin, alpha-tubulin and lamin B1. Unexpectedly, AT-induced de novo protein synthesis, which was reversed by catalase. Cycloheximide partially reversed AT-induced apoptosis. We conclude that AT induces neutrophil apoptosis by a caspase-dependent mechanism and via de novo protein synthesis. H2O2 is of major importance in AT-induced neutrophil apoptosis but its production does not originate from nicotinamide adenine dinucleotide phosphate dehydrogenase activation and mitochondria. Cytoskeletal structures other than microtubules can now be considered as novel targets of AT.

Viscum album agglutinin-I (VAA-I) induces apoptosis and degradation of cytoskeletal proteins in human leukemia PLB-985 and X-CGD cells via caspases: lamin B1 is a novel target of VAA-I.

Viscum album agglutinin-I (VAA-I) is a potent inducer of cell apoptosis and possesses anti-tumoral activity. Using PLB-985 and chronic granulomatous disease (X-CGD) cells, which lack expression of gp91(phox), VAA-I was found to induce apoptosis in both cell lines as assessed by cytology, DNA laddering and degradation of the cytoskeletal protein gelsolin. Both cell lines expressed caspase-3 and -8 and VAA-I activated these caspases. We demonstrated that lamin B(1) is a novel target to VAA-I and its degradation was reversed by a pan-caspase inhibitor and by a caspase-6, but not a caspase-8, inhibitor.

Viscum album agglutinin-I induces apoptosis and degradation of cytoskeletal proteins via caspases in human leukaemia eosinophil AML14.3D10 cells: differences with purified human eosinophils.

Although there are several agents that induce neutrophil apoptosis, few are known as inducers of eosinophil apoptosis. As eosinophils are potent effector cells contributing to allergic inflammation and asthma, we investigated whether the pro-apoptotic agent Viscum album agglutinin-I (VAA-I) could induce eosinophil apoptosis. VAA-I was found to induce apoptosis in eosinophilic AML14.3D10 (3D10) cells and that these cells expressed caspases-1, -2, -3, -4, -7, -8, -9 and -10. VAA-I-induced gelsolin degradation was reversed by the pan-caspase inhibitor N-benzyloxycarbonyl-V-A-D-O-methylfluoromethyl ketone (z-VAD). Also, paxillin, vimentin and lamin B1 were cleaved by caspases in VAA-I-induced 3D10 cells. VAA-I activated caspase-3 and -8 in 3D10 cells but, unlike z-VAD, treatment with a caspase-8 inhibitor slightly reversed apoptosis. Treatment of purified human eosinophils with VAA-I was found to induce apoptosis, degradation of gelsolin and lamin B1, but unlike 3D10 cells, cleavage of lamin B1 and cell apoptosis was not reversed by z-VAD. We conclude that VAA-I is a potent inducer of eosinophil apoptosis and that proteases other than those inhibited by z-VAD in 3D10 cells are involved in VAA-I-induced peripheral blood eosinophil apoptosis and lamin B1 cleavage. Thus, VAA-I represents a potential candidate for the reduction of the number of eosinophils in diseases where they play important roles.