Various modes of cell death induced by DNA damage

Surova, Olga; Zhivotovsky, Boris

doi:10.1038/onc.2012.556

Cited by 286 publications

(226 citation statements)

References 71 publications

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“…In addition, many recent studies show that cellular senescence is one of the outcomes of the cell fate decision process, where a cell halts the cell cycle if the accumulated genomic errors cannot be repaired, and it would be detrimental if such errors were left unrepaired. In a normal cell, the accumulation of DNA damage can also trigger activation of oncogenes or deactivation of tumor suppressor genes, which can initiate carcinogenesis or cell death response might be initiated, though only the latter can be true for cancer cells (Surova and Zhivotovsky, 2013). Given that both outcomes, death and carcinogenesis, are harmful, to maintain cellular viability the senescence growth arrest program can also be initiated through a cell fate decision process that is not very well characterized.…”

Section: Introductionmentioning

confidence: 99%

Temporally distinct roles of ATM and ROS in genotoxic-stress-dependent induction and maintenance of cellular senescence

Nair

Bagheri

Saini

2015

Journal of Cell Science

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Cells exposed to genotoxic stress induce cellular senescence through a DNA damage response (DDR) pathway regulated by ATM kinase and reactive oxygen species (ROS). Here, we show that the regulatory roles for ATM kinase and ROS differ during induction and maintenance of cellular senescence. Cells treated with different genotoxic agents were analyzed using specific pathway markers and inhibitors to determine that ATM kinase activation is directly proportional to the dose of the genotoxic stress and that senescence initiation is not dependent on ROS or the p53 status of cells. Cells in which ROS was quenched still activated ATM and initiated the DDR when insulted, and progressed normally to senescence. By contrast, maintenance of a viable senescent state required the presence of ROS as well as activated ATM. Inhibition or removal of either of the components caused cell death in senescent cells, through a deregulated ATM-ROS axis. Overall, our work demonstrates existence of an intricate temporal hierarchy between genotoxic stress, DDR and ROS in cellular senescence. Our model reports the existence of different stages of cellular senescence with distinct regulatory networks.

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Section: Introductionmentioning

confidence: 99%

Temporally distinct roles of ATM and ROS in genotoxic-stress-dependent induction and maintenance of cellular senescence

Nair

Bagheri

Saini

2015

Journal of Cell Science

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“…Whilst extrinsic apoptosis is mediated by death receptors and characterized by caspase 8 activation (22), intrinsic apoptosis is mitochondria mediated and usually triggered by intracellular signals including hypoxia and DNA damage (23). During intrinsic apoptosis, the overexpression of pro-apoptotic Bcl-2 proteins disrupts the mitochondrial membrane and eventually leads to the release of cytochrome c (24).…”

Section: Combined Pitavastatin and Dtic Treatment Induces G1 Cell Cycmentioning

confidence: 99%

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Al-Qatati

Aliwaini

2017

Oncol Lett

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Abstract. Melanoma is an aggressive skin cancer and its incidence is increasing faster than any other type of cancer. Whilst dacarbazine (DTIC) is the standard chemotherapy for metastatic melanoma, it has limited success. Statins, including pitavastatin, have been demonstrated to have a range of anticancer effects in a number of human cancer cell lines. The present study therefore explored the anti-cancer activity of combined DTIC and pitavastatin in A375 and WM115 human melanoma cells. Cell survival assays demonstrated that combined DTIC and pitavastatin treatment resulted in synergistic cell death. Cell cycle analyses further revealed that this combined treatment resulted in a G1 cell cycle arrest, as well as a sub-G1 population, indicative of apoptosis. Activation of apoptosis was confirmed by Annexin V-fluorescein isothiocyanate/propidium iodide double-staining and an increase in the levels of active caspase 3 and cleaved poly (ADP-ribose) polymerase. Furthermore, it was demonstrated that apoptosis occurs through the intrinsic pathway, evident from the release of cytochrome c. Finally, combined DTIC and pitavastatin treatment was demonstrated to also activate autophagy as part of a cell death mechanism. The present study provides novel evidence to suggest that the combined treatment of DTIC and pitavastatin may be effective in the treatment of melanoma. IntroductionMelanoma is a particularly aggressive skin cancer and its incidence is increasing faster than any other cancer worldwide (1). At present, the 10-year survival rate of patients diagnosed with advanced (stage IV) metastatic melanoma is <10% (2), which highlights the importance of early detection and treatment. The Food and Drug Administration approved the chemotherapeutic agent dacarbazine (DTIC) for the treatment of metastatic melanoma in 1975, and it remains the only licensed chemotherapeutic agent in use today (1). DTIC is a methylating agent which causes DNA damage, cell cycle arrest and apoptosis. Despite this, only 2% of all patients with metastatic melanoma receiving this treatment demonstrate a significant response and only 11.2% demonstrate a partial response (3). Resistance to DTIC has been associated with the upregulation of pro-survival signals and anti-apoptotic molecules in cancer cells. Despite its moderate effects, DTIC continues to be the standard treatment for metastatic melanoma as no other chemotherapeutic treatment has been demonstrated to have a significantly increased chance of survival when compared with DTIC (4,5). Provided the limited efficacy of the current metastatic melanoma chemotherapies in addition to the increasing incidence of melanoma cases, there appears to be a need for the development of more effective treatment strategies.Statins are a group of drugs commonly used for the reduction of cholesterol levels (6). They work by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a critical enzyme in the mevalonate pathway, which is responsible for cholesterol synthesis (6,7). In addition, statins have been de...

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“…[1][2][3] In response to the attack of cellular DNA by endogenous metabolites and exogenous causes, all organisms have evolved delicate DNA repairing mechanisms that are able to detect DNA damages, to activate the productions of correlated proteins, and to further repair their damaged DNA. [4][5][6] Besides these well-recognized chemical damages to DNA, physical alterations of canonical B-form of DNA (e.g., formations of G-quadruplex and cruciform) occur prevalently in organisms that serve as signals for specified cellular events.…”

Section: Introductionmentioning

confidence: 99%

Disintegration of cruciform and G-quadruplex structures during the course of helicase-dependent amplification (HDA)

Zhang

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Various modes of cell death induced by DNA damage

Cited by 286 publications

References 71 publications

Temporally distinct roles of ATM and ROS in genotoxic-stress-dependent induction and maintenance of cellular senescence

Temporally distinct roles of ATM and ROS in genotoxic-stress-dependent induction and maintenance of cellular senescence

Combined pitavastatin and dacarbazine treatment activates apoptosis and autophagy resulting in synergistic cytotoxicity in melanoma cells

Disintegration of cruciform and G-quadruplex structures during the course of helicase-dependent amplification (HDA)

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