Carcinogenesis, cancer therapy and chemoprevention

Blagosklonny, Mikhail V.

doi:10.1038/sj.cdd.4401610

Cited by 90 publications

(69 citation statements)

References 144 publications

(155 reference statements)

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“…Consequently, survival under unfavourable growth conditions may be the outcome of several interactive mechanisms, many of which underlie resistance to chemotherapy when they are mutated in transformed cells and thus multi-targeting therapy has been suggested to abrogate cell survival and to effectively manage resistance (Nicholson et al 2004, Blagosklonny 2005). …”

Section: Crosstalk Between Chemotherapy and The Stress Responsementioning

confidence: 99%

Chemotherapy: induction of stress responses

Tiligada

2006

Endocr Relat Cancer

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Eukaryotic cells, from yeast to mammals, respond and adapt to environmental and microenvironmental stressors by evolutionary conserved multicomponent endogenous systems that utilise a network of signal transduction pathways to regulate the adaptive and protective phenotype. The balance between cell survival and cell death is decisive for sensitivity or resistance to DNA-damaging chemotherapeutic agents. Anticancer drugs may themselves act as stressors to induce adaptive signals that could limit their clinical value. Related research has been focused on the modulation of the expression and function of the heat shock proteins, the unfolded protein response, the mechanisms of subcellular translocation of signalling components, the genomic and non-genomic actions of drugs and endogenous functional components like hormonal pathways, the input of inflammation and alterations in the microenvironmental milieu and on the control of the cell cycle and proliferation. The outcome seems to be driven by the first-line responses that support cellular integrity and by specific mechanisms that depend on the type of cell and the nature, and duration and severity of the noxious stimulus. Data obtained from experimental organisms like the yeast have added valuable information on the basic conservation in cellular stress-related processes in eukaryotes and on the consequences that may accompany the adaptive and protective phenotype during the stress response to anticancer agents. Understanding the complex molecular pathways mediating these processes has started to contribute to the reevaluation of the current therapeutic regiments and to revolutionise the approaches for improved anticancer therapy.

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Section: Crosstalk Between Chemotherapy and The Stress Responsementioning

confidence: 99%

Chemotherapy: induction of stress responses

Tiligada

2006

Endocr Relat Cancer

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“…Utilisation of 'proteotoxic stress overload' as an inducer of cancer cell death is the rationale for the use of proteasome inhibitors such as Velcade®, in the treatment of a variety of cancer types (Neznanov et al 2011;Workman and Davies 2011;Dou and Li 1999). However, while tumour cells show increased sensitivity to enhanced proteotoxic stresses, undergoing cell death more readily than non-transformed cells, tumour cells that persist following these treatments have been shown to characteristically exhibit a more advanced malignant phenotype and may prove problematic in the event of tumour relapse (Blagosklonny 2005a).…”

Section: Introductionmentioning

confidence: 99%

Heat stress induces epithelial plasticity and cell migration independent of heat shock factor 1

Lang

Nguyen

et al. 2012

Cell Stress and Chaperones

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Current cancer therapies including cytotoxic chemotherapy, radiation and hyperthermic therapy induce acute proteotoxic stress in tumour cells. A major challenge to cancer therapeutic efficacy is the recurrence of therapyresistant tumours and how to overcome their emergence. The current study examines the concept that tumour cell exposure to acute proteotoxic stress results in the acquisition of a more advanced and aggressive cancer cell phenotype. Specifically, we determined whether heat stress resulted in an epithelial-to-mesenchymal transition (EMT) and/or the enhancement of cell migration, components of an advanced and therapeutically resistant cancer phenotype. We identified that heat stress enhanced cell migration in both the lung A549, and breast MDA-MB-468 human adenocarcinoma cell lines, with A549 cells also undergoing a partial EMT. Moreover, in an in vivo model of thermally ablated liver metastases of the mouse colorectal MoCR cell line, immunohistological analysis of classical EMT markers demonstrated a shift to a more mesenchymal phenotype in the surviving tumour fraction, further demonstrating that thermal stress can induce epithelial plasticity. To identify a mechanism by which thermal stress modulates epithelial plasticity, we examined whether the major transcriptional regulator of the heat shock response, heat shock factor 1 (HSF1), was a required component. Knockdown of HSF1 in the A549 model did not prevent the associated morphological changes or enhanced migratory profile of heat stressed cells. Therefore, this study provides evidence that heat stress significantly impacts upon cancer cell epithelial plasticity and the migratory phenotype independent of HSF1. These findings further our understanding of novel biological downstream effects of heat stress and their potential independence from the classical heat shock pathway.

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“…For example, similar to BPDE (present study), a garlic-derived cancer chemopreventive agent (diallyl trisulfide) inhibits growth of H460 cells in association with cell cycle arrest and apoptosis induction (Singh, unpublished observations). As postulated by Blagosklonny, 44 the cell cycle arrest and apoptosis induction following exposure of already transformed cells to carcinogens like BPDE may be a natural defense mechanism against cancer progression.…”

Section: Bpde Treatment Caused Apoptotic Cell Death In H460 Cellsmentioning

confidence: 93%

Benzo[a]pyrene-7,8-diol-9,10-epoxide causes caspase-mediated apoptosis in H460 human lung cancer cell line

Xiao

Rawal²,

Hahm³

et al. 2007

Cell Cycle

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KEy woRdS Benzo[a]pyrene, BPDE, apoptosis, lung cancer AcKnowlEdgEMEntSThe authors thank the late Dr. Stanley J. Korsmeyer for the generous gift of the SV40 immortalized MEFs derived from wildtype, Bid knockout and Bak and Bax double knockout mice, and pSFFV-Bcl-2 and pSFFVneo plasmids. This investigation was supported in part by USPHS grants ES09140, awarded by the National Institute of Environmental Health Sciences, and CA076348, awarded by the National Cancer Institute. AbStRActWe have shown previously that wild-type p53 renders H460 human lung cancer cells more sensitive to apoptosis induction by environmental carcinogen benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), but the mechanism of cell death is not fully understood. The present study provides insights into the mechanism by which BPDE causes apoptosis in H460 cells. Exposure of H460 cells to BPDE resulted in a concentration-dependent apoptotic cell death characterized by cleavage of poly(ADP-ribose)polymerase, DNA condensation, and apoptotic histone-associated DNA fragments released into the cytosol. The BPDE-mediated release of apoptotic histone-associated DNA fragments into the cytosol was also observed in a normal bronchial epithelial cell line BEAS-2B. The BPDE-induced apoptosis in H460 cells correlated with up-regulation of pro-apoptotic protein Bak, downregulation of anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-xL, release of cytochrome c from mitochondria to the cytosol without a change in mitochondrial membrane potential or mitochondrial morphology (electron microscopy), and cleavage of caspase-8, -9, and -3. Ectopic expression of Bcl-2 failed to confer significant protection against BPDE-induced apoptosis in H460 cells. The SV40 immortalized mouse embryonic fibroblasts (MEFs) derived from Bak and Bax double knockout mice, but not Bid knockout mice, were significantly more resistant to BPDE-induced apoptosis compared with the MEFs derived from wild-type mice. The BPDE-induced apoptosis was partially but statistically significantly attenuated in the presence of specific inhibitors of caspase-9 (z-LEHDfmk) and caspase-8 (z-IETDfmk). In conclusion, the present study reveals that BPDE-induced apoptosis in H460 cells is associated with Bak induction and caspase activation but independent of Bcl-2.

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Carcinogenesis, cancer therapy and chemoprevention

Cited by 90 publications

References 144 publications

Chemotherapy: induction of stress responses

Chemotherapy: induction of stress responses

Heat stress induces epithelial plasticity and cell migration independent of heat shock factor 1

Benzo[a]pyrene-7,8-diol-9,10-epoxide causes caspase-mediated apoptosis in H460 human lung cancer cell line

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