Receptor independent apoptosis

Cephalostatin 1 (repeatedly the most active in the series) has recently been shown to induce a novel pathway of receptor-independent apoptosis of leukaemia cells at nanomolar concentrations [26]. Given the unique profile of activity of 1 in the NCI 60 cell line screen, this compound was identified in 2000 as a Rapid Access to Intervention Development (RAID) project by the NCI [27], Unfortunately, preclinical development... 

Dirsch VM, Stuppner H, VoUmar AM (2001) Helenalin Triggers a CD95 Death receptor independent apoptosis that is not affected by overexpression of Bcl-xL or Bcl-21. Cancer Res 6 5817... 

Gill C, Walsh SE, Morrissey C, Fitzpatrick JM, Watson RW. 2007. Resveratrol sensitizes androgen independent prostate cancer cells to death-receptor mediated apoptosis through multiple mechanisms. Prostate 67 1641-1653. 

Miura, S., and Karnik, S. S. 2000. Ligand-independent signals from angiotensin II type 2 receptor induce apoptosis. EMBO J 19 4026-4035. 

The doses of retinol that are protective in animals are in the toxic range (Section 2.5.1) and are unlikely to be useful in cancer therapy or prevention. A number of synthetic retinoids have been developed, in a search for compounds that show anticancer activity, but are metabolized, stored, and transported differently, or bind to different subtypes of retinoid receptor and are less toxic. RXR-selective ligands are less toxic and more active in animal cancer models than RAR ligands (Lippman and Lotan, 2000). Fenretinamide, and possibly other retinoids that have antitumor activity, exerts at least part of its action by induction of apoptosis by a receptor-independent mechanism (Wu et al., 2001). 

The essential role of cytochrome c release from injured mitochondria in the activation of caspase 9 has been alluded to above. This pathway is especially important in proapoptotic stimuli that are not initiated by surface receptors for apoptosis, such as UV irradiation, and may involve mitochondrial dependent pathways [83]. Continued respiration in the presence of an open mitochondrial pore may result in the generation of reactive oxygen species. Release of cytochrome c may be mediated by the opening of the mitochondrial FT pore, a non-selective channel whose composition is only partially defined [84]. Inhibitors of FT pore opening, such as cyclosporine, which binds to the adenine nucleotide translocator (ANT), a component of the FT pore, and bongkrekic acid, as well as Bcl-2, prevent cytochrome c release and inhibit apoptosis [85] whereas activators of the FT pore, such as atractyloside and Bax induce it [86]. Oxidants can rupture the outer membrane of mitochondria and release caspase-activating proteins [87]. Some studies have shown cytochrome c release before collapse of the mitochondrial membrane potential [83] suggesting alternate control of the FT pore. Many, but not all, of the members of the Bd-2 family of proteins reside in the inner mitochondrial membrane, form ionic channels in hpid membranes and increase rates of proton extrusion in mitochondria [88] and thus may control the FT pore. The antiapoptotic and mitochondrial affects of Bd-2 are independent of caspase activity as they occur in the presence of caspase inhibitors and also in yeast that lack caspases [86]. 

In addition to its importance for inflammatory responses, NF-kB also plays a role in the regulation of cell homeostasis and apoptosis [62-64] and it was thus straightforward to assume a link between the known cytotoxic activity of STLs and their NF-kB inhibitory activity [3], It was demonstrated that helenalin indeed induces apoptosis and that it does so via a CD95 death receptor independent pathway and requires the activation of caspases [43], Further STLs for which quite detailed studies on pro-apoptotic activity and mechanism exist are the germacronolides parthenolide and costunolide (structures 32 and 52 in Fig. (9)) [44, 45]. 

Ruiz, L., Miguel, A., and Diaz-Laviada, I. (1999) Delta9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism, FEBS Letters 458 400 04. 

Totzke G, Schultze-Osthoff K, Janicke RU. Cyclooxygenase-2 (cox-2) inhibitors sensitize tumor cells specifically to death receptor-induced apoptosis independently of COX-2 inhibition. Oncogene 2003 22 8021-8030. 

Teijeiro R, Bios R, Costoya JA et al (2002) Activation of human somatostatin receptor 2 promotes apoptosis through a mechanism that is independent from induction of p53. Cell Physiol Biochem 12 31-38... 

Transactivation of proapoptotic genes is not the only way that p53 protein can activate the apoptotic program. There is evidence that variants of p53, which are independent of Bax protein and do not operate at the transcription level, can also result in apoptosis (see Haffner and Oren, 1995 Ko and Prives, 1996). Thus, a p53-regulated redistribution of the Fas death receptor from the cytosol to the cell membrane has been demonstrated (Beimet et al., 1998). Overall, these mechanisms are poorly understood. 

Other Mechanisms Resveratrol activated caspase-2 and -8, resulting in the activation of downstream caspases, and induced cell death in a death receptor-or mitochondria-independent manner [Mohan et al., 2006]. The induction of apoptosis in HCT-116 (Bax+ / ) cells by resveratrol was mediated via activation of caspase 6 and subsequent degradation of nuclear coat protein lamin A [Lee et al., 2006]. Resveratrol induced a senescence-like growth arrest in HCT-116 cells via ROS-dependent activation of p38 MAP kinase and ATM kinase, and subsequent phosphorylation of p53 and induction of p21WAF1 CIP1 [Heiss et al., 2007]. In contrast, a p53-independent mechanism for resveratrol-induced apoptosis of HCT-116 cells was reported [Mahyar-Roemer et al., 2001, 2002]. 

---