Article

Apoptotic cell signaling in cancer progression and therapy.

Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, USA.
Integrative Biology (Impact Factor: 4). 02/2011; 3(4):279-96. DOI: 10.1039/c0ib00144a
Source: PubMed

ABSTRACT Apoptosis is a tightly regulated cell suicide program that plays an essential role in the development and maintenance of tissue homeostasis by eliminating unnecessary or harmful cells. Impairment of this native defense mechanism promotes aberrant cellular proliferation and the accumulation of genetic defects, ultimately resulting in tumorigenesis, and frequently confers drug resistance to cancer cells. The regulation of apoptosis at several levels is essential to maintain the delicate balance between cellular survival and death signaling that is required to prevent disease. Complex networks of signaling pathways act to promote or inhibit apoptosis in response to various cues. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Various upstream signaling pathways can modulate apoptosis by converging on, and thereby altering the activity of, common central control points within the apoptotic signaling pathways, which involve the BCL-2 family proteins, inhibitor of apoptosis (IAP) proteins, and FLICE-inhibitory protein (c-FLIP). This review highlights the role of these fundamental regulators of apoptosis in the context of both normal apoptotic signaling mechanisms and dysregulated apoptotic pathways that can render cancer cells resistant to cell death. In addition, therapeutic strategies aimed at modulating the activity of BCL-2 family proteins, IAPs, and c-FLIP for the targeted induction of apoptosis are briefly discussed.

0 Followers
 · 
150 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Spiroquinazolinone compounds have been considered as a new series of potent apoptosis-inducing agents. In this study, anti-proliferative and apoptotic effects of the derivatives from the spiroquinazolinone family were investigated in the human chronic myeloid leukemia K562 cells. The K562 cells were treated with various concentrations of the spiroquinazolinone (10-300 µM) for 3 days and cell viability was determined by MTT growth inhibition assay. 4t-QTC was more active among these compounds with IC50 of 50 ± 3.6 µM and was selected for further studies. Apoptosis, as the mechanism of cell death was investigated morphologically by acridine orange/ethidium bromide (AO/EtBr) double staining, cell surface expression assay of phosphatidyl serine by Annexin V/PI technique, as well as the formation of DNA ladder. The K562 cells underwent apoptosis upon a single dose (at IC50 value) of the 4t-QTC compound, and over-expressed caspase-3 expression by more than 1.7-fold, following a 72 hr treatment. Furthermore, RT-PCR and Western blot analysis revealed that treatment of the K562 cells with 4t-QTC down-regulates and up-regulates the expression of Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic), respectively. Based on the present data, it seems that these compounds from the spiroquinazolinone family are good candidates for further evaluation as an effective chemotherapeutic family acting through induction of apoptosis in chronic myeloid leukemia.
    The Journal of Toxicological Sciences 01/2015; 40(1):115-126. DOI:10.2131/jts.40.115 · 1.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A survivin small interfering RNA sequence specific for a human and mouse homogenous sequence was constructed. Survivin small interfering RNA could significantly inhibit glioma cell proliferation and induce apoptosis when it was transfected into either a human glioma cell line U251 or rat glioma C6 cells in vitro. In addition, treatment of rat orthotopic glioma models with survivin small interfering demonstrated the inhibition of glioma growth in vivo. Our experimental findings suggest that the use of RNA interference techniques to target the survivin sequence may be useful in the treatment of glioma.
    Neural Regeneration Research 04/2012; 7(12):924-31. DOI:10.3969/j.issn.1673-5374.2012.12.008 · 0.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACT — Spiroquinazolinone compounds have been considered as a new series of potent apoptosis-inducing agents. In this study, anti-proliferative and apoptotic effects of the derivatives from the spiroquinazolinone family were investigated in the human chronic myeloid leukemia K562 cells. The K562 cells were treated with various concentrations of the spiroquinazolinone (10-300 μM) for 3 days and cell viability was determined by MTT growth inhibition assay. 4t-QTC was more active among these compounds with IC50 of 50 ± 3.6 μM and was selected for further studies. Apoptosis, as the mechanism of cell death was investigated morphologically by acridine orange/ethidium bromide (AO/EtBr) double staining, cell surface expression assay of phosphatidyl serine by Annexin V/PI technique, as well as the formation of DNA ladder. The K562 cells underwent apoptosis upon a single dose (at IC50 value) of the 4t-QTC compound, and over-expressed caspase-3 expression by more than 1.7-fold, following a 72 hr treatment. Furthermore, RT-PCR and Western blot analysis revealed that treatment of the K562 cells with 4t-QTC down-regulates and up-regulates the expression of Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic), respectively. Based on the present data, it seems that these compounds from the spiroquinazolinone family are good candidates for further evaluation as an effective chemotherapeutic family acting through induction of apoptosis in chronic myeloid leukemia.
    The Journal of Toxicological Sciences 12/2014; 40(1):115-126. · 1.38 Impact Factor

Full-text (2 Sources)

Download
62 Downloads
Available from
May 20, 2014