Apoptosis-inducing factor and colon cancer
ABSTRACT Programmed cell death is a fundamental requirement for embryogenesis, organ metamorphosis, and tissue homeostasis. Since the vast majority of cytotoxic modalities exert their anti-tumor effects by induction of apoptosis, programmed cell death has emerged as a potential target for cancer treatment at various stages of tumor progression. Immuno-regulation and chemoradiosensitization are potential pathways where insight in apoptotic mechanisms may lead to improvement of chemoradiotherapeutic modalities. The central mediator of the intrinsic pathway of apoptosis is the mitochondrion, in which changes of the outer membrane's permeability cause an outflow of cytochrome c and more than 40 molecules involved in apoptosis. These include Smac/DIABLO, Omi/HTR A2, endonuclease G, and apoptosis inducing factor (AIF). AIF, a 57 kDa mitochondrial oxidoreductase, is released into the cytoplasm and translocates to the nucleus to induce cell death in response to poly-(ADP-ribose) polymerase-1 activation, resulting is DNA fragmentation independent of caspase activation. As a caspase-independent mechanism of apoptosis, AIF may be a potential target for chemoradiotherapeutic intervention in a number of malignancies. The aim of this review is to provide the available evidence of the role AIF in several malignancies with a particular emphasis in colon carcinogenesis.
- SourceAvailable from: Sugumaran Manickam
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- "Apoptosis, or programmed cell death is a highly regulated process that occurs in almost all living organisms that eliminates unwanted cells. This process occurs in a systematic fashion and is characterized by a sequence of morphological alterations and biochemical changes upon the activation of a series of molecular signaling cascades in cells (Allen et al., 1997; Hu and Kavanagh, 2003; Wang et al., 2005; Millan and Huerta, 2009). Apoptosis is part of a wide array of normal physiological processes and plays an important role in many normal functions of multicellular organisms by allowing the organism to tightly control cell numbers and tissue size in many developmental and physiological settings (Hengartner, 2000; Hu and Kavanagh, 2003). "
ABSTRACT: Species of Phyllanthus have traditionally been used for hundreds of years for treating many ailments including diabetes, anemia, bronchitis and hepatitis. The present study aims to investigate the cytotoxic and apoptotic effects of methanol (PWM), hexane (PWH) and ethyl acetate (PWE) extracts from the leaves of the endemic plant Phyllanthus watsonii Airy Shaw (Phyllanthaceae) on MCF-7 human breast cancer cells. We observed that the PWM, PWH and PWE extracts were cytotoxic and selectively inhibited the growth and proliferation of MCF-7 cells compared to untreated control in a dose dependent manner with an IC(50) of 12.7±4.65, 7.9±0.60 and 7.7±0.29μg/ml, respectively. However, the extracts were not toxic at these concentrations to normal human lung fibroblast MRC-5 cells. Cell death induced by PWM, PWH and PWE extracts were mainly due to apoptosis which was characterized by apoptotic morphological changes and a nuclear DNA fragmentation. Caspase-3 activation following P. watsonii extracts treatment was also evident for apoptotic cell death which was preceded by an S phase cell cycle perturbation. The results suggested that the cytotoxic activity of P. watsonii extracts was related to an early event of cell cycle perturbation and a later event of apoptosis. Hence, P. watsonii displays potential to be further exploited in the discovery and development of new anticancer agents.Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie 01/2012; 65(3). DOI:10.1016/j.etp.2011.11.005 · 2.01 Impact Factor
The Journal of Pharmacy 01/2012; 6(5):3099.
- "Apoptotic stimulus results in the overexpression of AIFM2 in the cytoplasm that translates into the nucleus. The DNA binds to the amino acid residues in the C-terminal domain of AIFM2 facilitating apoptosis (Alejandro, 2009; Marshall, 2005).The structural features of AIFM2 protein is important for understanding of the protein binding to the DNA. "
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- "Pancreatic beta cell apoptosis plays a crucial role in the pathogenesis of Type 1 Diabetes mellitus (T1DM) (Atkinson, 2005; Eizirik and Mandrup-Poulsen, 2001; Kim and Lee, 2009). This process is initiated by two main pathways: the " extrinsic " or death receptor and the " intrinsic " or mitochondrial apoptosis pathway (Huerta et al., 2007; Millan and Huerta, 2009). The intrinsic death pathway involves loss of mitochondrial homeostasis, particularly of the outer mitochondrial membrane integrity, and subsequently the release of mitochondrial pro-apoptotic factors including cytochrome c. "
ABSTRACT: Pro-inflammatory cytokines are key mediators in the selective and progressive destruction of insulin-producing beta cells during type 1 diabetes development. However, the mechanisms of cytokine-induced beta cell apoptosis are not fully understood. This study demonstrates that pro-inflammatory cytokines strongly modified the expression of the anti-apoptotic protein Bcl-2 and the pro-apoptotic BH3-only proteins Bad, Bim, and Bid in primary rat islets and insulin-producing RINm5F cells. Overexpression of mitochondrially located catalase (MitoCatalase) specifically increased basal Bcl-2 and decreased basal Bax expression, suppressed cytokine-mediated reduction of Bcl-2, and thereby prevented the release of cytochrome c, Smac/DIABLO and the activation of caspase-9 and -3. Thus, cytokine-mediated decrease of Bcl-2 expression and the sequentially changed Bax/Bcl-2 ratio are responsible for the release of pro-apoptotic mitochondrial factors, activation of caspase-9, and ultimately caspase-3. These results indicate that activation of the intrinsic/mitochondrial apoptosis pathway is essential for cytokine-induced beta cell death and the mitochondrial generation of reactive oxygen species, in particular mitochondrial hydrogen peroxide, differentially regulates the Bax/Bcl-2 ratio.Molecular and Cellular Endocrinology 10/2010; 332(1-2):88-96. DOI:10.1016/j.mce.2010.09.017 · 4.24 Impact Factor