Article

Targeting anoikis resistance in prostate cancer metastasis

Department of Surgery/Urology, University of Kentucky College of Medicine, Lexington, KY, USA.
Molecular Aspects of Medicine (Impact Factor: 10.24). 02/2010; 31(2):205-14. DOI: 10.1016/j.mam.2010.02.001
Source: PubMed

ABSTRACT

Anoikis is a mode of apoptotic cell death, consequential to insufficient cell-matrix interactions and a critical player in tumor angiogenesis and metastasis. The events involved in tumor cell progression toward metastasis potential are mediated by integrins, which upon engagement with components of the extracellular matrix (ECM), reorganize to form adhesion complexes. Targeting apoptotic players is of immense therapeutic significance since resistance to apoptosis is not only critical in conferring therapeutic failure to standard treatment strategies, but anoikis (apoptosis upon loss of anchorage and detachment from ECM) also plays an important role in angiogenesis and metastasis. The ability to survive in the absence of adhesion to the ECM, enables tumor cells to disseminate from the primary tumor site, invade a distant site and establish a metastatic lesion. Tumor cells can escape from detachment-induced apoptosis by controlling anoikis pathways, including the extrinsic death receptor pathway and the ECM-integrin mediated cell survival pathway. Considering the functional promiscuity of individual signaling effectors, it is critical to dissect the molecular networks mechanistically driving tumor cells to evade anoikis and embark on a metastatic spread. Resistance to die via anoikis dictates tumor cell survival and provides a molecular basis for therapeutic targeting of metastatic prostate cancer. Further dissection of critical anoikis signaling events will enable the therapeutic optimization of anoikis targeting to impair prostate cancer metastasis prior to its initiation. This review will discuss the molecular understanding of anoikis regulation in the tumor microenvironment and the in vivo pharmacological implementation of a novel class of antitumor-drugs to optimize apoptotic-based therapeutic targeting, bypassing anoikis-resistance to impair prostate cancer progression to metastasis. Potential combination strategies targeting tumor vascularity (via anoikis) and impairing tumor initiation (via "classic" apoptosis), provide strong therapeutic promise for metastatic prostate cancer by preventing the onset of metastasis.

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Available from: Shinichi Sakamoto
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    • "The Bcl-2 protein as one of the Bcl-2 family proteins regulates cytochrome c release from the mitochondria and prevents apoptotic cell death (Plati et al., 2011). Down-regulation of Bax and up-regulation of Bcl-2 in many drug-resistant tumor cells has been reported (Sakamoto and Kyprianou, 2010). In Chronic Myeloid Leukemia (CML) cells, overexpression of Bcl-2 protein and association with Bcr/Abl cause accelerated transfer rate of chronic phase to blastic phase (Tzifi et al., 2011) and leads to tumor progression. "
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    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.
    Full-text · Article · Mar 2015 · The Journal of Toxicological Sciences
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    • "The Bcl-2 protein as one of the Bcl-2 family proteins regulates cytochrome c release from the mitochondria and prevents apoptotic cell death (Plati et al., 2011). Down-regulation of Bax and up-regulation of Bcl-2 in many drug-resistant tumor cells has been reported (Sakamoto and Kyprianou, 2010). In Chronic Myeloid Leukemia (CML) cells, overexpression of Bcl-2 protein and association with Bcr/Abl cause accelerated transfer rate of chronic phase to blastic phase (Tzifi et al., 2011) and leads to tumor progression. "
    [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.
    Full-text · Article · Dec 2014 · The Journal of Toxicological Sciences
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    • "Metastasis necessitates disruption of cellular interactions with the tumor microenvironment, increased migratory and invasion capacity and the ability to overcome the pro-apoptotic signals imparted by diminished intercellular and cell-ECM interactions [14]. The ECM comprises a diverse network of cytokines impacting cell growth, motility and angiogenesis which can be made available for cellular use by enzymatic digestion and remodeling [15]. "
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    Full-text · Article · Jan 2014 · PLoS ONE
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