Apoptosis of tumor cells

Anthracyclins. Figure 2 Mechanisms of anthracycline-induced apoptosis of tumor cells. ROS, reactive oxygen species topo II, topoisomerase II cyt c, cytochrome c. 

It would be interesting to learn whether 4,5-dihydro-5 a-hydroxy-4 a-methoxy-6a,12a-dehydro-a-toxicarol interferes with the enzymatic activity of topoisomerase. Note that taxol, a successful chemotherapeutic agent that hampers the normal microtubule machinery, has been suggested to involve additional cytotoxic pathways including p53-independent apoptosis of tumor cells and inhibition of topoisomerase II (42). 

Three lipids A have been more intensively studied in animal models, all of them having indirect effects, mediated in vivo by the immune system. For two of them, DT-5461 and ONO-4007, TNF-a is an important mediator acting at the vascular level that provokes tumor necrosis. For the third one, OM-174, the treatment induces the accumulation of IFN-y and EL-1 P in tumors, which activate NOS II transcription in tumor cells that produce autotoxic NO, which then provokes the apoptosis of tumor cells. At the same time this treatment inhibits the production of TGF-pi by tumor cells which reduces the TGF-pi induced immunosuppression and enhances NO production. Acquired immune response, probably completes the tumor regression started by the apoptosis process and, most probably induces specific memory. 

Many clinically relevant NSAIDs exert off-target effects unrelated to their ability to inhibit COX enzymes. For example, INDO and SS induce apoptosis of tumor cells and modulate y-secretase activity (15, 16). INDO also activates the nuclear transcription factor PPARy (17). The complexity of in vivo pharmacologic effects makes it a challenge to separate the contribution of COX inhibition from other effects in a given pharmacologic response. Thus, the removal of COX inhibitory activity by a minor modification, such as the removal of a methyl group, provides an opportunity to dissect COX-dependent and COX-independent effects of certain NSAIDs. In fact, DM-INDO and DM-SS activate PPARy in HCA-7 cells with dose responses similar to those of the parent drugs (14). Likewise, the rfei -methyl compounds exhibit potency similar to the parent compounds in their ability to induce apoptosis in RKO cells, a human colon cancer cell line, and to activate PPARy in cellular reporter assays. 

In the case of antitumor peptides, it is clear that the numerous binding and internalization experiments associated with cytotoxicity of several tumor cell lines must be followed by in vivo experiments to select those peptides that are relevant in oncotherapy. With the advanced knowledge on the mechanisms of apoptosis of tumor cells, there is a perspective that the mechanisms of action of several... 

Molecular imaging has also been used to measure general processes such as angiogenesis, inflammation, hypoxia, or arteriosclerosis. As many diseases result in abnormalities of these processes (also named common denominators ), drug-based therapies aim at their modification. In other cases - such as the apoptosis of tumor cells - a change in this process is a desired therapeutic effect. For these reasons, quantitative measurement of the status of these processes may represent potential biomarkers of drug efficacy. 

A new glycosylated component is related to apoptosis of tumor cells, which is found in E. fetida by Xie et al. [81] recently, and is highly homologous to EFEs and some serine proteases, such as F-I-l, -1-2, -II,... 

Wang JL, Liu D, Zhang ZJ, Shan S, Han X, Srinivasula SM, Croce CM, Ahiemri ES, Huang Z. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci USA 2000a 97 7124-7129. 

Second, oleanolic acid (43) could induce their early phosphorylation of two such as p38 mitogen-activated protein kinase (p38 MAPK) of) a class of mitogen-activated protein kinases that are responsive to the stress stimuli such as cytokines, ultraviolet irradiation, heat shock, osmotic shock, cell differentiation, apoptosis and autophagy and p42/44 mitogen-activated protein kinase (p42/44 MAPK) [31] that regulated by p53 mitogen-activated protein kinase and nitric oxide in human pulmonary arterial smooth muscle cells. However, oleanolic acid (43) could not induce the early phosphorylation of c-Jun N-terminal kinase-1 (JNK-1) [32] that mediate both survival and apoptosis of tumor cells [33]. 

Kim M, Rao MV, Tweardy DJ, Prakash M, Galili U, Gorelik E (1993) Lectin induced apoptosis of tumor cells. Glycobiology 3 447-453. 

One of the mechanisms that cause cytotoxicity (apoptosis) of tumor cells by nitric oxide is the nitrosative stress which occurs via S-nitrosylation by the interaction of NO with the biological thiols of proteins. Nitrosative stress can promote apoptosis because of the activation of mitochondrial apoptotic pathways, such as the release of cytochrome c, an apoptosis-inducing factor, and endonuclease G from mitochondria. Another mechanism of NO-induced apoptosis is the nitrosylation of NF-kB which causes the downstream inhibition of several anti-apoptotic proteins. These NO functions facilitate the activation of apoptotic pathways with both chemotherapy and immunotherapy. In this chapter we review the mechanisms whereby S-nitrosylation and nitrosative stress regulate the apoptotie signal cascade. The cytotoxic effects of NO in this section are illustrated in Figs. 6.1 and 6.2. 

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