Involvement of p53 in gemcitabine mediated cytotoxicity and radiosensitivity in breast cancer cell lines

Salem, S.; Abou-Tarboush, Faisal M.; Saeed, Nadeem M.; Al-Qadasi, Waheeb D.; Farah, Mohammad Abul; Al-Buhairi, Muneera; Al-Harbi, Najla; Alhazza, Ibrahim M.

doi:10.1016/j.gene.2012.01.099

Cited by 14 publications

(13 citation statements)

References 36 publications

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“…S1). This phenomenon was also reported in other cancers, such as breast cancer [40] and melanoma [41], which are consistent with our findings. Yet, more experiments are still needed to investigate its mechanism.…”

Section: Discussionsupporting

confidence: 93%

MicroRNA-449a Enhances Radiosensitivity in CL1-0 Lung Adenocarcinoma Cells

et al. 2013

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Lung cancer is the leading cause of cancer-related mortality worldwide. Radiotherapy is often applied for treating lung cancer, but it often fails because of the relative non-susceptibility of lung cancer cells to radiation. MicroRNAs (miRNAs) have been reported to modulate the radiosensitivity of lung cancer cells and have the potential to improve the efficacy of radiotherapy. The purpose of this study was to identify a miRNA that can adjust radiosensitivity in lung adenocarcinoma cells. Two lung adenocarcinoma cell lines (CL1-0 and CL1-5) with different metastatic ability and radiosensitivity were used. In order to understand the regulatory mechanisms of differential radiosensitivity in these isogenic tumor cells, both CL1-0 and CL1-5 were treated with 10 Gy radiation, and were harvested respectively at 0, 1, 4, and 24 h after radiation exposure. The changes in expression of miRNA upon irradiation were examined using Illumina Human microRNA BeadChips. Twenty-six miRNAs were identified as having differential expression post-irradiation in CL1-0 or CL1-5 cells. Among these miRNAs, miR-449a, which was down-regulated in CL1-0 cells at 24 h after irradiation, was chosen for further investigation. Overexpression of miR-449a in CL1-0 cells effectively increased irradiation-induced DNA damage and apoptosis, altered the cell cycle distribution and eventually led to sensitization of CL1-0 to irradiation.

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Section: Discussionsupporting

confidence: 93%

MicroRNA-449a Enhances Radiosensitivity in CL1-0 Lung Adenocarcinoma Cells

et al. 2013

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“…Earlier studies have shown that the antiproliferative effects of amiloride in several cancer cell types may result from apoptosis (Park et al, 2009;Chang et al, 2011aChang et al, , 2011b. In contrast, other agents, for example, lactate and gemcitabine, are reported to, respectively, increase radioresistance (Hirschhaeuser et al, 2011) and decrease radiosensitivity (Salem et al, 2012). The current study of GBM8401 glioblastoma cells showed a larger antiproliferative effect in amiloride-treated cells with IR post-treatment compared to amiloride-treated cells with IR pretreatment.…”

Section: Discussionmentioning

confidence: 42%

“…I rradiation causes DNA damage and induces cell death via apoptosis, mitotic catastrophe, autophage, or senescence (Dunne et al, 2003;Ishikawa et al, 2006;Chen et al, 2012;Salem et al, 2012). However, since cells may survive DNA damage by activating survival signal pathways (Cataldi et al, 2009), cellular radiosensitivity, an important factor in the tumor response to radiotherapy, may be affected by the balance between cell death and survival.…”

Section: Introductionmentioning

confidence: 99%

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Modulating Roles of Amiloride in Irradiation-Induced Antiproliferative Effects in Glioblastoma Multiforme Cells Involving Akt Phosphorylation and the Alternative Splicing of Apoptotic Genes

Tang

Chang

2013

DNA and Cell Biology

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Apoptosis is a key mechanism for enhanced cellular radiosensitivity in radiation therapy. Studies suggest that Akt signaling may play a role in apoptosis and radioresistance. This study evaluates the possible modulating role of amiloride, an antihypertensive agent with a modulating effect to alternative splicing for regulating apoptosis, in the antiproliferative effects induced by ionizing radiation (IR) in glioblastoma multiforme (GBM) 8401 cells. Analysis of cell viability showed that amiloride treatment significantly inhibited cell proliferation in irradiated GBM8401 cells ( p < 0.05) in a time-dependent manner, especially in cells treated with amiloride with IR posttreatment. In comparison with GBM8401 cells treated with amiloride alone, with GBM8401 cells treated with IR alone, and with human embryonic lung fibroblast control cells (HEL 299), GBM8401 cells treated with IR combined with amiloride showed increased overexpression of phosphorylated Akt, regardless of whether IR treatment was performed before or after amiloride administration. The alternative splicing pattern of apoptotic proteaseactivating factor-1 (APAF1) in cells treated with amiloride alone, IR alone, and combined amiloride-IR treatments showed more consistent cell proliferation compared to that in other apoptosis-related genes such as baculoviral IAP repeat containing 5 (BIRC5), Bcl-X, and homeodomain interacting protein kinase-3 (HIPK3). In GBM8401 cells treated with amiloride with IR post-treatment, the ratio of prosurvival (-XL,-LC) to proapoptotic (-LN,-S) splice variants of APAF1 was lower than that seen in cells treated with amiloride with IR pretreatment, suggesting that proapoptotic splice variants of APAF1 (APAF1-LN,-S) were higher in the glioblastoma cells treated with amiloride with IR post-treatment, as compared to glioblastoma cells and fibroblast control cells that had received other treatments. Together, these results suggest that amiloride modulates cell radiosensitivity involving the Akt phosphorylation and the alternative splicing of APAF1, especially for the cells treated with amiloride with IR posttreatment. Therefore, amiloride may improve the effectiveness of radiation therapy for GBMs.

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“…

RE false(t; T_{i} = 0, T_{d} \neq 0 false) = 1 + \frac{2 r_{0} λ_{d}}{false(normalμ - λ_{d} false) false(\frac{α}{β} false)} \frac{normalA - normalB}{C}

normalA = \frac{1 - e^{- 2 λ_{d} t}}{2 λ_{d}}, normalB = \frac{1 - e^{- false(normalμ + λ_{d} false) t}}{normalμ + λ_{d}}, normalC = 1 - e^{- λ_{d} t}

where r 0 is the initial dose rate, μ is the rate constant for exponential sublethal DNA damage repair with first order kinetics (0.46 h −1 for V-79 cells and 0.23 h −1 for MDA-MB-231 cells) (15, 31, 32), and λ d (T d = ln(2)/λ d ) is the rate constant for an exponentially decreasing dose rate, and t is the time over which irradiation takes place. Using Eq.…”

Section: Methodsmentioning

confidence: 99%

Cellular Response to Exponentially Increasing and Decreasing Dose Rates: Implications for Treatment Planning in Targeted Radionuclide Therapy

et al. 2017

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The treatment of cancer using targeted radionuclide therapy is of interest to nuclear medicine and radiation oncology because of its potential for killing tumor cells while minimizing dose-limiting toxicities to normal tissue. The ionizing radiations emitted by radiopharmaceuticals deliver radiation absorbed doses over protracted periods of time with continuously varying dose rates. As targeted radionuclide therapy becomes a more prominent part of cancer therapy, accurate models for estimating the biologically effective dose (BED) or equieffective dose (EQD2α/β) will become essential for treatment planning. This study examines the radiobiological impact of the dose rate increase half-time during the uptake phase of the radiopharmaceutical. MDA-MB-231 human breast cancer cells and V79 Chinese hamster lung fibroblasts were irradiated chronically with 662 keV γ rays delivered with time-varying dose rates that are clinically relevant. The temporal dose-rate patterns were: 1. acute, 2. exponential decrease with a half-time of 64 h (Td = 64 h), 3. initial exponential increase to a maximum (half time Ti = 2, 8 or 24 h) followed by exponential decrease (Td = 64 h). Cell survival assays were conducted and surviving fractions were determined. There was a marked reduction in biological effect when Ti was increased. Cell survival data were tested against existing dose-response models to assess their capacity to predict response. Currently accepted models that are used in radiation oncology overestimated BED and EQD2α/β at low-dose rates and underestimated them at high-dose rates. This appears to be caused by an adaptive response arising as a consequence of the initial low-dose-rate phase of exposure. An adaptive response function was derived that yields more accurate BED and EQD2α/β values over the spectrum of dose rates and absorbed doses delivered. Our experimental data demonstrate a marked increase in cell survival when the dose-rate-increase half-time is increased, thereby suggesting an adaptive response arising as a consequence of this phase of exposure. We have modified conventional radiobiological models used in the clinic for brachytherapy and external beams of radiation to account for this phenomenon and facilitate their use for treatment planning in targeted radionuclide therapy.

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Involvement of p53 in gemcitabine mediated cytotoxicity and radiosensitivity in breast cancer cell lines

Cited by 14 publications

References 36 publications

MicroRNA-449a Enhances Radiosensitivity in CL1-0 Lung Adenocarcinoma Cells

MicroRNA-449a Enhances Radiosensitivity in CL1-0 Lung Adenocarcinoma Cells

Modulating Roles of Amiloride in Irradiation-Induced Antiproliferative Effects in Glioblastoma Multiforme Cells Involving Akt Phosphorylation and the Alternative Splicing of Apoptotic Genes

Cellular Response to Exponentially Increasing and Decreasing Dose Rates: Implications for Treatment Planning in Targeted Radionuclide Therapy

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