[New face of antiapoptotic proteins. I. Protein Mcl-1]. / Nowe oblicze bialek antyapoptotycznych. I. Bialko Mcl 1.

Main regulators of apoptosis belong to Bcl-2 protein family and apoptosis inhibitory proteins--IAPs. In this review the apoptosis inhibitor--Mcl-1 protein is profoundly characterized. It is important that this unique short-living protein--the member of Bcl-2 family may also operate as apoptosis promoting agent, which results of alternative splicing of its pre-mRNA, posttranslational modifications or proteolysis. The review presents also other functions of Mcl-1, i.e. involvement in cell cycle regulation, elongation of telomers. Elevated expression of Mcl-1 accompanies the development of various cancers, neurodegenerative disorders and also infectious diseases. The obtained results indicate that expression level of Mcl-1 may be useful in treatment decisions of large number of diseases. Ablating expression of this protein may be an attractive therapeutic strategy in the treatment of various cancers, and the diseases where Mcl-1 may play a key role in apoptosis supression.

[New face of antiapoptotic proteins. II. Survivin]. / Nowe oblicze bialek antyapoptotycznych. II. Surwiwina.

Survivin (mol.wt. 16.5 kDa; pI 5.1) belongs to the IAPs family--inhibitors of apoptosis. The human survivin protein contains an N-terminal BIR domain connected with a C-terminal, alpha-helical domain interacting with microtubules via a linker region. The BIR domain of the protein exhibits anti-apoptotic activity and plays a role in the binding of the chromosomal passenger complex (CPC) to the centromere regions of chromosomes. Alternative splicing of the human survivin gene gives rise to five different mRNA transcripts yielding wild-type survivin (142 aa) and four isoforms of the protein. In this review, the structure, features, and functions of wild-type survivin and its isoforms in the apoptotic process, cell cycle, and carcinogenesis as well as the significance of this protein as potential neoplastic marker are presented. Moreover, insights into the development of new anti-cancer therapeutic strategies targeting survivin are overviewed.

In vitro sensitivity of B-cell chronic lymphocytic leukemia to cladribine and its combinations with mafosfamide and/or mitoxantrone.

We examined in vitro sensitivity of B-CLL cells exposed to cladribine, mafosfamide, mitoxantrone and combinations ofcladribine with mafosfamide and/or mitoxantrone. The results revealed that each applied treatment of leukemic cells, besides having a cytotoxic effect, affected the events associated with apoptosis. All drugs used alone, and cladribine combinations with mafosfamide and/or mitoxantrone induced DNA fragmentation and the changes in expression/proteolysis level of caspase-3, caspase-9 precursors, PARP-1, lamin B, Bax and Bcl-2; however, each to a different degree. The exposure of leukemic cells to both cladribine combinations induced stronger effects. Moreover, the data showed that the expression of regulatory antiapoptotic protein Bcl-2 generally decreased in drug-treated B-CLL cells, whereas proapoptotic polypeptide Bax increased, resulting in enhancement of Bax-Bcl-2 ratios in comparison with untreated cells. Drug-treatment of the studied cells induced the translocation of Bax protein from the cytosol to the cellular pellet, containing mitochondria, where this polypeptide indicated the capacity for oligomerization. These observations suggest that the examined drugs are able to induce apoptosis of B-CLL cells via the mitochondria pathway.

[Mitochondrial intermembrane space proteins in apoptosis process]. / Bialka przestrzeni miedzyblonowej mitochondriów uczestniczace w procesie apoptozy.

Mitochondria, despite their function in cellular energy metabolism, play an important role in the apoptotic signaling pathways. These organelles in response to the death signal undergo changes resulting in the release of proteins which are essential to conduct apoptosis via mitochondrial pathway. This article is focused on the properties and functions of apoptogenic proteins released from the mitochondrial intermembrane space, i.e., caspases, cytochrome c, Smac/DIABLO, serine protease Omi/HtrA2, AIF and endonuclease G.

Calorimetric study as a potential test for choosing treatment of B-cell chronic lymphocytic leukemia.

Differential scanning calorimetry (DSC) and complementary techniques were utilized to evaluate the sensitivity of B-cell chronic lymphocytic leukemia (B-CLL) cell samples in vitro exposed to cladribine or fludarabine in combination with mafosfamide. Mafosfamide, the active in vitro form of cyclophosphamide with both purine analogs produced the cytotoxic effect on mononuclear cell probes, however, to a different degree. Our results indicated that higher sensitivity of examined leukemic cell samples to the used drug combinations was usually accompanied by a marked decrease or even a complete loss of thermal transition at 95+/-3 degrees C in DSC scans of nuclear preparations as well as by more significant reduction of cell viability, higher extent of DNA damage estimated by the comet assay and by dropping/disappearance of anti-apoptotic protein Mcl-1 in comparison with untreated cells. We have also observed that the reduction of transition at 95+/-3 degrees C in thermal scans of nuclear preparations isolated from blood of B-CLL randomized patients who showed response to cladribine or fludarabine combined with cyclophosphamide, i.e., CC and FC, respectively, corresponded with the decrease or disappearance of anti-apoptotic proteins Bcl-2 and/or Mcl 1. In conclusion, these in vitro and in vivo studies revealed that quick DSC technique, usually supplemented by other methods, is a potent tool to distinguish efficacy of B-CLL treatment and could be helpful in choosing the most effective manner of treatment for this type of leukemia.