In vitro studies on subtypes and regulation of active cell death

Active cell death (ACD) comprises several subtypes as indicated by morphology at light- and electron-microscopical level: for example type I ACD or apoptosis, with nuclear condensation, fragmentation, cytoplasmic condensation; type II ACD, nuclear pyknosis, cytoplasmic autophagy. Morphologically different types of cell death are considered to reflect differences in the underlying biochemical and molecular events eventually leading to cell collapse. However, currently no simple biochemical or molecular marker for detection of ACD subtypes is available and, therefore, morphological methods are still required to classify ACD. Sometimes, distinction of ACD from necrosis may be equivocal. Type I ACD occurs in primary hepatocyte cultures treated with TGF-beta1 and in colonie adenoma cell cultures treated with the proteinkinase C inhibitor H7 (1[5-iso-quinolylsulfonyl]-2-methylpiperazine). The anti-survival activity of TGF-beta1 was confirmed in vivo as TGF-beta1 strongly induced apoptosis in normal tissue and in preneoplastic lesions of rat liver. Type II ACD was observed in human mammary carcinoma cells (MCF-7) after treatment with tamoxifen. The anti-survival activity of H7 and of the anti-oestrogens tamoxifen, 4-hydroxy-tamoxifen, ICI 164384 could be dissociated from their anti-proliferative action. In conclusion, cell culture studies provide a means to select compounds with high anti-survival activity for further exploration in preclinical and clinical testing.