The inhibitor of apoptosis protein family (IAPs): an emerging therapeutic target in cancer.
ABSTRACT Apoptosis is a crucial biological process that prevents uncontrolled cell proliferation and eliminates harmful cells. Resistance to apoptotic stimuli is a hallmark feature of various cancers. One of the mechanisms through which tumor cells are believed to acquire resistance to apoptosis is by overexpression of inhibitor of apoptosis proteins (IAPs). IAPs are a group of structurally related proteins that were initially identified in baculoviruses. Mammalian IAPs block apoptosis either by binding and inhibiting caspases or through caspase-independent mechanisms. This family of proteins has become increasingly prominent in the field of cancer biology. To date, overexpression of several IAPs has been detected in various cancers. This paper reviews the recent advances in the research of IAPs. The differential expression and the biological significance of each IAP in various cancer types will be discussed. Finally, we review the most recent advances in the research efforts aimed at using IAPs as potential targets for cancer therapy.
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ABSTRACT: We aimed to investigate the cytotoxic effects of nimbolide, a limonoid present in leaves and flowers of the neem tree (Azadirachta indica) on human breast cancer cells. The molecular mechanisms involved in the apoptotic activity exerted by nimbolide were studied on the estrogen dependent (MCF-7) and estrogen independent (MDA-MB-231) human breast cancer cell lines. The growth inhibitory effect of nimbolide was assessed by MTT assay. Apoptosis induction by nimbolide treatment was determined by JC-1 mitochondrial membrane potential staining, cytochrome c release, caspase activation, cleavage of PARP and AO/EtBr dual staining. The modulation of apoptotic proteins (intrinsic pathway: Bax, bad, Bcl-2, Bcl-xL, Mcl-1, XIAP-1 and caspase-3, 9; extrinsic pathway: TRAIL, FasL, FADDR and Caspase-8) were studied by western blot and real time PCR analysis. Treatment with nimbolide resulted in dose and time-dependent inhibition of growth of MCF-7 and MDA-MB-231 cells. The occurrence of apoptosis in these cells was indicated by JC-1 staining, modulation of both intrinsic and extrinsic apoptotic signaling molecules expression and further apoptosis was confirmed by AO/EtBr dual staining. These events were associated with: increased levels of proapoptotic proteins Bax, Bad, Fas-L, TRAIL, FADDR, cytochrome c and reduced levels of the anti-apoptotic proteins Bcl-2, Bcl-xL, Mcl-1 and XIAP-1. Nimbolide induces the cleavage of pro-caspase-8, pro-caspase-3 and PARP. The above data suggest that nimbolide induces apoptosis by both the intrinsic and extrinsic pathways. With evidence of above data it is suggested that nimbolide exhibit anticancer effect through its apoptosis-inducing property. Thus, nimbolide raises new hope for its use in anticancer therapy.Toxicology Letters 11/2012; 215(2):131–142. DOI:10.1016/j.toxlet.2012.10.008 · 3.36 Impact Factor
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ABSTRACT: Angiogenesis is an essential process in cancer growth maintenance, and metastasis. Angiopoietin-2 promotes tumor angiogenesis by priming the vasculature and potentiating the effects of cytokines at the front of active neovascularization. Enhanced expression of angiopoietin-2 has been reported in lung cancer tissue. Survivin is one of the inhibitors of apoptosis protein that has been shown to play a key role in cancer progression, and in tumor angiogenesis. Also plays a key role in tumor cell resistance to anticancer agents and ionizing radiation. To measure the serum levels of angiopoietin-2 and survivin as possible angiogenic factors in lung cancer patients with the assessment of their interrelationships and clinical significance. Patients with lung cancer as NSCLC (n=70) and healthy volunteers (n=10) were enrolled. Serum angiopoietin-2 and survivin concentrations were measured using enzyme-linked immunosorbent assay (ELIZA). Median serum angiopoietin-2 levels with lung cancer (2730pg/mL) ranged from 1171 to 6541pg/mL was higher than the median of the control group (1795pg/mL) ranged from 1076 to 2730/mL, p<0.001. Median serum survivin levels were also higher in patients with lung cancer (53.0pg/mL) ranged from 39.3 to 96.3pg/mL than the median of the control group (48.8pg/mL) ranged from 38.0 to 74.6pg/mL, but did not reach statistical significance p=0.206. In all patients with lung cancer, serum angiopoietin-2 was not significantly correlated with survivin (r=0.073, p=0.657). Neither serum angiopoietin-2 nor survivin showed significant relation with the serum angiopoietin-2 or survivin levels depending on the cell types, stage progression, and metastasis among the patients with NSCLC. Our study suggests that serum angiopoietin-2 is a useful marker for the diagnosis of NSCLC by ELIZA technique.Journal of the Egyptian National Cancer Institute 03/2012; 24(1):41-5. DOI:10.1016/j.jnci.2011.12.006
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ABSTRACT: Actinic keratosis (AK) occurs on sun-exposed skin and may progress to invasive squamous cell carcinoma (SCC). As for its topical treatment, diclofenac/hyaluronic acid (HA) has been recently approved. The NSAID diclofenac is an inhibitor of COX-2; however, its mode of action in cutaneous epithelial cancer cells is largely unknown. Here, the effects of diclofenac/HA were investigated in relation to death ligand-mediated apoptosis (TNF-alpha, TRAIL, and CD95 activation). Whereas diclofenac/HA only moderately induced apoptosis by itself, it resulted in pronounced enhancement of death ligand-mediated apoptosis in sensitive SCC cell lines (3/4). Apoptosis was associated with activation of initiator caspases of the extrinsic pathway (caspase-8/caspase-10). Furthermore, death ligand and diclofenac/HA-mediated apoptosis were blocked by the same caspase inhibitors, indicating related pathways. The proapoptotic effects of diclofenac/HA appeared independent of the p53 pathway. Also, upregulation of death receptors appeared less important; however, strong downregulation of c-FLIP isoforms was seen after diclofenac/HA treatment. The crucial role of c-FLIP was proven through overexpression and knockdown experiments. Thus, induction of apoptosis appears to be highly characteristic of the mode of action of diclofenac/HA, and the therapeutic effect may be related to sensitization of neoplastic keratinocytes for death ligand-induced apoptosis.Journal of Investigative Dermatology 03/2010; 130(8):2098-109. DOI:10.1038/jid.2010.40 · 6.37 Impact Factor