The Autophagic Response to Radiation: Relevance for Radiation Sensitization in Cancer Therapy

Gewirtz, David A.

doi:10.1667/rr13774.1

Cited by 36 publications

(29 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is extensive evidence that radiation can promote autophagy [10]. Autophagy can function as a pro-survival mechanism or as pro-death mechanism, depending on the agents used and the experimental systems.…”

Section: Introductionmentioning

confidence: 99%

Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

Alotaibi¹,

Sharma²,

Saleh³

et al. 2016

Radiation Research

Self Cite

View full text Add to dashboard Cite

Radiotherapy continues to be a primary modality in the treatment of cancer. DNA damage induced by radiation can promote apoptosis as well as both autophagy and senescence, where autophagy and senescence can theoretically function to prolong tumor survival. A primary aim of this work was to investigate the hypothesis that autophagy and/or senescence could be permissive for DNA repair, thereby facilitating tumor cell recovery from radiation-induced growth arrest and/or cell death. In addition, studies were designed to elucidate the involvement of autophagy and senescence in radiation sensitization by PARP inhibitors and the re-emergence of a proliferating tumor cell population. In the context of this work, the relationship between radiation-induced autophagy and senescence was also determined. Studies were performed using DNA repair proficient HCT116 colon carcinoma cells and a repair deficient Ligase IV (−/−) isogenic cell line. Irradiation promoted a parallel induction of autophagy and senescence that was strongly correlated with the extent of persistent H2AX phosphorylation in both cell lines; however inhibition of autophagy failed to suppress senescence, indicating that the two responses were dissociable. Irradiation resulted in a transient arrest in the HCT116 cells while arrest was prolonged in the Ligase IV (−/−) cells; however, both cell lines ultimately recovered proliferative function, which may reflect maintenance of DNA repair capacity. The PARP inhibitors (Olaparib) and (Niraparib) increased the extent of persistent DNA damage induced by radiation as well as the extent of both autophagy and senescence; neither cell line underwent significant apoptosis by radiation alone or in the presence of the PARP inhibitors. Inhibition of autophagy failed to attenuate radiation sensitization, indicating that autophagy was not involved in the action of the PARP inhibitors. As with radiation alone, despite sensitization by PARP inhibition, proliferative recovery was evident within a period of 10–20 days. While inhibition of DNA repair via PARP inhibition may initially sensitize tumor cells to radiation via the promotion of senescence, this strategy does not appear to interfere with proliferative recovery, which could ultimately contribute to disease recurrence.

show abstract

Section: Introductionmentioning

confidence: 99%

Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

Alotaibi¹,

Sharma²,

Saleh³

et al. 2016

Radiation Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition, ionizing irradiation such as X-rays can "trigger" genetic and DNA dysfunction leading to cell death. 1,2,25 The data and results of this research has identified specific drugs that can be used to counter-act the dysfunctional mechanisms thus lending credence to the treatment concept of the "magic bullet " that can disarm the effects of the offending "trigger".…”

Section: Discussionmentioning

confidence: 79%

Coupling of physical characteristics of non-ionizing irradiation to specific mechanisms of cell death: are we there yet?

Thomsen¹

2015

Energy-Based Treatment of Tissue and Assessment VIII

View full text Add to dashboard Cite

The recent discovery of the various specific" triggers" and mechanisms of cell life and death responses suggests that certain non-ionizing irradiation spectra and other physical signals could be coupled with specific cellular "triggers" to improve diagnostic or treatment effects. Genetic, chemical and/or physical modifications of specific extrinsic cellular "triggers" have centered on chemical binding of specific molecules to specific receptors, i.e. chemical " triggers" thus allowing development of specific drugs to counteract the initiating function of the "triggers" in single cells. Investigations of non-ionizing irradiation effects on cells and tissues indicate that their "triggers" involve intimate interactions of linked components of the extracellular matrix and the cytoskeleton in tissues. Therefore, the search for single "triggers" that may work well for chemical "triggers" in single cells in culture may not be effective for discovery of the mechanisms that initiate sensing of the stimulations of non-ionizing irradiation and mechanical force.In cell biology, the mechanisms of life and death usually involve a series of complex, chemical, mechanical and/or electrical events that are highly interactive with many other physiological and pathological mechanisms within and outside the cell. To distinguish one event from any of the others the following things have to be established:1. Precise description of the ultimate cellular response to be studied i.e. cell death, cell movement, energy production, protein synthesis, cell division, etc. The definitions of these responses could and should be refined as an investigator finds out more information about the events in his studies. For example, cell death could be due to apoptosis (identified by production of apoptotic bodies) therefore future studies could be focused on finding markers of the extrinsic or intrinsic apoptotic pathways.2. Identification of a specific act or " triggered" reaction that initiates a series of events which produces the cellular response to be studied. For example, apoptosis can be "triggered" by ligand binding of tumor necrosis factor (TNF) to the "death receptor" found on the surfaces of certain cells.3. "Markers" are the key substance(s) or reaction(s) that distinguish a specific series of events. The series can produce several markers along the way. For instance, a key marker of apoptosis is the production of caspase 8.4. Identification of "end points", the results or cellular responses of the series of events or a subset of events. These are frequently are measureable thus useful for mathematical modeling. Ultimate cell responses such as cell death are "endpoints" but other well-defined products or reactions found within the series of events, such as caspase 8 production which occurs early in apoptosis also can be designated as desired endpoints of study. Keynote Paper Energy-based Treatment of Tissue and Assessment VIII, edited by Thomas P. Ryan Proc. of SPIE Vol. 9326, 932603 · © 2015 SPIE · CCC code: 1605-7422/15/$18

show abstract

“…Autophagy plays a very important role in cell physiology, either as a form of cell death or as a protective mechanism against apoptosis [39, 40]. Therefore, there is a growing interest on the pharmacological approaches aimed to regulate autophagy, which represent a new area for the development of therapeutics protocols.…”

Section: Resultsmentioning

confidence: 99%

Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia

et al. 2016

View full text Add to dashboard Cite

An attractive molecular target for novel anti-cancer therapies is the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway which is commonly deregulated in many types of cancer. Nevertheless, the effects of PI3K/Akt/mTOR inhibitors on T lymphocytes, a key component of immune responses, have been seldom explored. In this study we investigated the effects on human CD4+ T-cells of a panel of PI3K/Akt/mTOR inhibitors: BGT226, Torin-2, MK-2206, and ZSTK474. We also assessed their efficacy against two acute leukemia T cell lines. T lymphocytes were stimulated with phytohemagglutinin. Inhibitor effects on cell cycle and apoptosis were analyzed by flow cytometry, while cytotoxicity was assessed by MTT assays. In addition, the activation status of the pathway as well as induction of autophagy were analyzed by Western blotting.Quiescent healthy T lymphocytes were unaffected by the drugs whereas mitogen-stimulated lymphocytes as well as leukemic cell lines displayed a cell cycle block, caspase-dependent apoptosis, and dephosphorylation of key components of the signaling pathway. Autophagy was also induced in proliferating lymphocytes and in JURKAT and MOLT-4 cell lines. When autophagy was inhibited by 3-methyladenine or Bafilomycin A1, drug cytotoxicity was increased, indicating that autophagy is a protective mechanism.Therefore, our findings suggest that PI3K/Akt/mTOR inhibitors preserve lymphocyte viability. This is a valuable result to be taken into account when selecting drugs for targeted cancer therapy in order to minimize detrimental effects on immune function.

show abstract

The Autophagic Response to Radiation: Relevance for Radiation Sensitization in Cancer Therapy

Cited by 36 publications

References 66 publications

Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

Coupling of physical characteristics of non-ionizing irradiation to specific mechanisms of cell death: are we there yet?

Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia

Contact Info

Product

Resources

About