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PURPOSE: Ferroptosis is a new mode of regulated cell death, which is completely distinct from other cell death modes based on morphological, biochemical, and genetic criteria. This study evaluated the therapeutic role of ferroptosis in classic chemotherapy drugs, including the underlying mechanism. MATERIALS AND METHODS: Cell viabilitywas detected by using the methylthiazoltetrazlium dye uptake method. RNAiwas used to knockout iron-responsive element binding protein 2, and polymerase chain reaction, western blot was used to evaluate the efficiency. Intracellular reduced glutathione level and glutathione peroxidases activitywere determined by related assay kit. Intracellularreactive oxygen species levelswere determined by flowcytometry. Electron microscopywas used to observe ultrastructure changes in cell. RESULTS: Among five chemotherapeutic drugs screened in this study, cisplatin was found to be an inducer for both ferroptosis and apoptosis in A549 and HCT116 cells. The depletion of reduced glutathione caused by cisplatin and the inactivation of glutathione peroxidase played the vital role in the underlying mechanism. Besides, combination therapy of cisplatin and erastin showed significant synergistic effect on their anti-tumor activity. CONCLUSION: Ferroptosis had great potential to become a new approach in anti-tumor therapies and make up for some classic drugs, which open up a new way for their utility in clinic.
Subject(s)
Apoptosis , Blotting, Western , Carrier Proteins , Cell Death , Cisplatin , Drug Therapy , Glutathione , Glutathione Peroxidase , HCT116 Cells , Methods , Oxygen , Peroxidases , Polymerase Chain ReactionABSTRACT
Objective To study the relationship between plasma TGF-β, TNF-α, IL-10 levels and radiation pneumonitis (RP) in patients received thoracic irradiation with 3DCRT. Methods Sixty-nine patients of lung cancer stage Ⅲ or esophageal carcinoma were evaluated prospectively by EUSA for plasma TNF-α, TGF- β, IL-10 levels and IL-10/TNF-α before 3DCRT, after 40 - 50 Gy and after 3DCRT. Results Twenty-eight patients had RP. In RP patients, the plasma TGF-β, TNF-α, IL-10 levels and IL-10/TNF-α was (15.2 ± 13.4) μg/L, (28.4 ± 13.4), (24. 1 ± 17. 1) ng/L and 1.01 ± 0.86 before 3DCRT, respectively;TNF-α increased to (36.1 ± 15.5) ng/L(t = 2.01, P = 0.040), IL-10 and IL-10/TNF-α decreased to (18.8 ± 10.8) ng/L (t =1.40, P = 0.166) and 0.62 0.55 (t = 1.90, P = 0.063)after 40-50 Gy. After 3DCRT TNF-α was higher (36.9 ± 15.5) ng/L than that before 3DCRT(t = - 2.20, P = 0.032) ,but IL-10 and IL-10/TNF-α were lower than that before 3DCRT [(13.7 ± 6.2) ng/L, t = 3.03, P = 0.005 ;0.41 ± 0.21, t = 3.60, P = 0.001]. TGF-β was not change in three times(P > 0.05) .In non-RP patients, TGF-β,TNF-α, IL-10 and IL-10/TNF-α was not yet change in three times(P > 0.05) respectively. TGF-β was not yet change between RP and non-RP patients before 3DCRT (t = 0.54, P = 0.594), and TNF-α was higher in RP group than that in non-RP group after 40-50 Gy(t = 2.02, P = 0.048), but IL-10 and IL-10/TNF-α was less in RP group than that in non-RP group after 3DCRT(t=2.50,P=0.015;t=4.63,P=0.000). Conclusions The levels of TNF-α and IL-10 are closely related to the occurrence of RP. Monitoring the changes in dynamic state could predict the generation of RP, which could be employed as a sensitive index for indicating risks for acute RP.
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Objective To research the early effects and side-effects of the local advanced nasopharyngeal carcinoma patients using intensity-modulated radiotherapy(IMRT)combined with concurrent chemotherapy.Methods From January 2005 to January 2007,60 patients with nasopharyngeal carcinoma of stage m-IV b were received IMRT combined with concurrent chemotherapy in our center.Sixty patients were divided into paclitaxel concurrent group(32 patients)and cisplatin concurrent group(28 patients).The prescribing doses of the primary tumor were 68-72 Gy for each group.The patients of paclitaxel concurrent group patients of the cisplatin concurrent group got earlier radiodennatitis and radiation-induced mucositis but also got significantly higher rate of radiodermatitis,radiation-induced mucositis,radiation-induced leucopenia and gastrointestinal toxicity,as well as the loss of weight.No significant difference was found on liver and renal funcfons between two groups.Four patients(12.5%)of the paclitaxel concurrent group were broken-off,which was much better than the cisplatin concurrent group.There was no significant difference on the specific length of break-off time,the 2-year overall survival rate and the 2-year diseaee-free survival rate between two groups.Conclusions IMRT combined with concurrent chemotherapy of paclitaxel liposome for local advanced nasopharyngeal carcinoma results in less side-effects and better tolerance than IMRT combined with concurrent cisplatin chemotherapy.
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The low dose hyper-radiosensitivity (HRS) in human lung cancer cell line A549 was investigated, the changes of ATM kinase, cell cycle and apoptosis of cells at different doses of radiation were observed, and the possible mechanisms were discussed. A549 cells in logarithmic growth phase were irradiated with (60)Co gamma-rays at doses of 0-2 Gy. Together with flow cytometry for precise cell sorting, cell survival fraction was measured by means of conventional colony-formation assay. The expression of ATM1981Ser-P protein was examined by Western blot 1 h after radiation. Apoptosis was detected by Hoechst 33258 fluorescent staining, and Annexin V-FITC/PI staining flow cytometry 24 h after radiation. Cell cycle distribution was observed by flow cytometry 6, 12 and 24 h after radiation. The results showed that the expression of ATM1981Ser-P protein was observed at 0.2 Gy, followed by an increase at >0.2 Gy, and reached the peak at 0.5 Gy, with little further increase as the dose exceeded 0.5 Gy. Twenty-four h after radiation, partial cells presented the characteristic morphological changes of apoptosis, and the cell apoptosis curve was coincident with the survival curve. As compared with control group, the cell cycle almost had no changes after exposure to 0.1 and 0.2 Gy radiation (P>0.05). After exposure to 0.3, 0.4 and 0.5 Gy radiation, G(2)/M phase arrest occurred 6 and 12 h after radiation (P<0.05), and the ratio of G(2)/M phase cells was decreased 24 h after radiation (P<0.05). It was concluded that A549 cells displayed the phenomenon of HRS/IRR. The mode of cell death was mainly apoptosis. The activity of ATM and cell cycle change may take an important role in HRS/IRR.