|Year : 2018 | Volume
| Issue : 7 | Page : 1540-1548
Selenocystine inhibits JEG-3 cell growth in vitro and in vivo by triggering oxidative damage-mediated S-phase arrest and apoptosis
Ming Zhao1, Yajun Hou2, Xiaoting Fu2, Dawei Li2, Jingyi Sun2, Xiaoyan Fu2, Zhigang Wei3
1 Department of Orthopaedics, Taishan Hospital Affiliated to Taishan Medical University, Taian, Shandong, China
2 Department of Biochemistry, School of Basic Medicine, Taishan Medical University, Taian, Shandong, China
3 Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
|Date of Web Publication||19-Dec-2018|
324 Jingwuweiqi, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong
Source of Support: None, Conflict of Interest: None
Background: Selenocystine (SeC) is a nutritionally available selenoamino acid presenting novel anticancer potential against human cancers. However, neither the effects nor mechanism of SeC against choriocarcinoma growth has been clarified yet. This study investigated the anticancer effects and mechanism of SeC against JEG-3 human choriocarcinoma growth in vitro and in vivo.
Materials and Methods: The in vitro anticancer efficiency was evaluated with cell viability, apoptosis, and oxidative stress. JEG-3 cell viability was determined with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Cell cycle distribution and apoptosis were examined by flow cytometric analysis. Oxidative damage was detected with immunofluorescence and western blotting. The in vivo anticancer efficiency was evaluated in immunodeficient mouse model of choriocarcinoma. The mechanism was also investigated.
Results: SeC dose and time dependently inhibited the viability of JEG-3 cells in vitro. The result of flow cytometry (FCM) analysis showed that obvious S-phase arrest and cell apoptosis were initiated by SeC in JEG-3 cells, which was further convinced by the decreased levels of cyclin A, poly-ADP-ribose polymerase cleavage, and activation of caspase-3,-7, and-9. In addition, SeC resulted in significant generation of reactive oxygen species (ROS) and superoxide anion, followed by the activation of DNA damage. However, SeC-induced oxidative damage and apoptosis were effectively blocked after ROS inhibition. Further investigation indicated that SeC effectively suppressed JEG-3 choriocarcinoma tumor xenograft growth in vivo. The mechanism may be the induction of cell apoptosis and oxidative damage through inhibiting cell proliferation (Ki-67) and angiogenesis (CD-31).
Conclusions: Our findings supported that human choriocarcinoma growth could be inhibited by SeC in vitro and in vivo through triggering oxidative damage-mediated S-phase arrest and apoptosis. Thus, SeC may be promising in the treatment of human choriocarcinoma.
Keywords: Apoptosis, choriocarcinoma, reactive oxygen species, selenocystine, S-phase arrest
|How to cite this article:|
Zhao M, Hou Y, Fu X, Li D, Sun J, Fu X, Wei Z. Selenocystine inhibits JEG-3 cell growth in vitro and in vivo by triggering oxidative damage-mediated S-phase arrest and apoptosis. J Can Res Ther 2018;14:1540-8
|How to cite this URL:|
Zhao M, Hou Y, Fu X, Li D, Sun J, Fu X, Wei Z. Selenocystine inhibits JEG-3 cell growth in vitro and in vivo by triggering oxidative damage-mediated S-phase arrest and apoptosis. J Can Res Ther [serial online] 2018 [cited 2019 Aug 19];14:1540-8. Available from: http://www.cancerjournal.net/text.asp?2018/14/7/1540/247731
| > Introduction|| |
Choriocarcinoma has been derived from trophoblastic tissue, which was one of the most common malignant tumors in women, with high incidence and metastasis rate.,, Patients with choriocarcinoma often suffered from anemia, infertility, cachexia, and even death. Due to the aggressiveness of choriocarcinoma, surgical treatment has always been not appropriate., Hence, chemotherapy has been accepted as one of the most effective treatments for human choriocarcinoma., Therefore, exploring novel agents with high efficacy and low toxicity for the therapy of human choriocarcinoma is urgently needed.
Selenium (Se) is a trace element, which is significant for human and animal health. Increasing epidemiological studies and clinical trials have reported the novel chemoprevention and chemotherapeutic effects of Se-containing compounds on human cancers, heart diseases, hypertension, diabetes, senile diseases, cataracts, liver and pancreatic diseases, infertility, Keshan disease, and anemia., Se intake in diet and serum Se level were negatively associated with the incidence of human lung cancer, prostate cancer, colorectal cancer, leukemia, and ovarian cancer.,,,, Many evidences supported that Se-containing compounds could be applied as chemosensitizer for improving the therapeutic effects of chemotherapy drugs and reducing relevant side effects.,,,, Selenocystine (SeC) has been a natural available selenoamino acid showing novel anticancer activities against human cancers., Multiple mechanisms were reported to contribute to the anticancer potential of SeC, including the induction of cell apoptosis and/or cell cycle arrest, the modulation of redox state, the detoxification of carcinogen, and the inhibition of angiogenesis.,, However, the anticancer effects and mechanism of SeC against human choriocarcinoma have not been clarified yet.
In the present study, the anticancer activities and molecular mechanism of SeC against human choriocarcinoma were evaluated in vitro and in vivo. The results revealed that human choriocarcinoma cell growth could be significantly inhibited with SeC treatment both in vitro and in vivo. The mechanism may be the induction of S-phase arrest and apoptosis through triggering ROS-mediated DNA damage. Se-containing compounds may be promising in the chemoprevention and chemotherapy of human choriocarcinoma.
| > Materials and Methods|| |
SeC, propidium iodide (PI), 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), and other reagents were all purchased from Sigma-Aldrich (St. Louis, MO, USA). BCA assay kit was obtained from Beyotime Company (Beijing, China). Dulbecco's Modified Eagle's medium (DMEM), fetal bovine serum (FBS), and penicillin–streptomycin were purchased from Invitrogen (Carlsbad, CA, USA). All the solvents involved were of high-performance liquid chromatography grade. The water applied in this study was supplied with a Milli-Q water purification system from Millipore. All antibodies, including cyclin A (cat. no. 4656S), cleaved poly-ADP-ribose polymerase (PARP) (cat. no. 9541), active caspase-3 (cat. no. 9664), active caspase-7 (cat. no. 9491), active caspase-9 (cat. no. 9501), Ser1981-ataxia telangiectasia mutated (ATM) (cat. no. 5883), Ser428-ataxia telangiectasia Rad3-related (ATR) (cat. no. 2853), Ser15-p53 (cat. no. 9284), total-p53 (cat. no. 9282), and β-actin (cat. no. 4970), were all obtained from Cell Signaling Technology (Beverly, MA, USA).
JEG-3 human choriocarcinoma cells were obtained from American Type Culture Collection (cat. no. HTB-36, ATCC, USA) and cultured in DMEM supplemented with 10% FBS, penicillin (100 U/ml), and streptomycin (100 U/ml) at 37°C in a humidified incubator under 5% CO2 atmosphere.
Detection of cell viability
Cell viability was detected with MTT assay. Briefly, JEG-3 cells (6 × 103 cells/well) were seeded in a 96-well plate and treated with SeC (0–40 μM) for 72 h, or cells were treated with 20 μM SeC for 12, 24, 48, and 72 h. After treatment, 20 μl MTT (5 mg/ml) was added and incubated for another 4 h. Then, the medium was removed, and 150 μl/well dimethyl sulfoxide was added to dissolve the formazan. Then, the absorbance at 570 nm was detected for indicating cell growth status. Cell viability was expressed as percentage of control (as 100%). Cell morphology was observed by a phase microscope (with a magnification of ×200).
Analysis of cell cycle and cell apoptosis
FCM was employed to analyze cell cycle distribution and cell apoptosis. Briefly, JEG-3 cells seeded in cell culture dishes were treated with 10, 20, and 40 μM SeC for 72 h. After treatment, cells were trypsinized and harvested by centrifugation. Then, cells were fixed with 70% ethanol overnight at −20°C and stained with PI solution. Labeled cells were washed and analyzed by FCM. The cell cycle proportions of G0/G1, S, and G2/M phases were analyzed by ModFit LT 4.0 software. The sub-G1 peak (hypodiploid DNA contents) was used to quantify the apoptotic cell death. About 104 cells/sample was recorded.
Detection of reactive oxygen species and superoxide anion
Intracellular ROS and superoxide anion levels were determined with dichlorodihydrofluorescein diacetate (DCFH-DA) and dihydroethidium (DHE) probes, respectively. In brief, JEG-3 cells (5 × 104 cells/well) were seeded in 6-cm plate and treated with 20 μM SeC for 0, 10, 30, and 60 min. After treatment, cells were incubated with 10 μM DCFH-DA or DHE for 15 min at 37°C in the dark. Then, cells were washed with PBS and imaged under a fluorescence microscope (with a magnification of ×100).
JEG-3 cells were seeded in 9-cm culture dishes and treated with indicated concentrations of SeC for 72 h. After treatment, cells were washed and lysed with RIPA lysis buffer. Total protein was extracted and quantified with BCA assay kit according to the manufacturer's instructions. The protein expression in JEG-3 cells was determined with western blotting. Briefly, protein was boiled for 10 min, loaded at 40 μg/lane, and separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The proteins were transferred to polyvinylidene difluoride (PVDF) membrane and blocked with 5% bovine serum albumin for 2 h at room temperature. The PVDF membrane was incubated with primary antibodies (1:1000) overnight at 4°C and then secondary antibodies (1:2000) for 2 h at room temperature. Protein bands were developed with X-ray film using an enhanced chemiluminescence system (Nikon). The band of β-actin was employed as positive control.
In vivo study
Thirty female nude mice were divided into three groups. After adaptation for 1-week, JEG-3 cells (107 cells in 100 μl serum-free medium) were subcutaneously injected into the left oxter of mice. After growing for 7 days (tumor volume was about 60 mm 3), the mice were administrated with SeC. Group 1 was set as the control group without treatment and Groups 2 and 3 were administrated with 5 and 10 mg/kg of SeC, respectively. SeC was injected from the caudal vein every other day for 14 days (a total of eight times). After administration was completed, tumors were harvested and measured with the following formula: volume = l × w2/ 2, thereinto l was the maximal length and w was the width. Part of the tumor tissue was cut into 4-μm slice and analyzed with immunohistochemical (IHC) staining. The part of tumors was applied for western blotting assay. The animal experiments were generally conducted according to the demonstration of previous report. All animal experiments were reviewed and approved by the Animal Experimentation Ethics Committee.
Statistical analysis was performed with the SPSS statistical package (SPSS 13.0 for Windows; SPSS, Inc., Chicago, IL USA). The difference between two groups was analyzed with a two-tailed Student's t-test. The difference between three or more groups was analyzed by one-way analysis of variance multiple comparison. Difference with P < 0.05 (*) or P < 0.01 (**) was considered statistically significant. Bars in the figures with different characters indicated statistically difference at the P < 0.05 level.
| > Results|| |
Selenocystine inhibits JEG-3 cell growth in vitro
The in vitro cytotoxicity of SeC toward JEG-3 cells was screened with MTT assay. The result suggested that JEG-3 cell growth could be dose and time dependently inhibited with SeC treatment [Figure 1]. Specifically, for the cells exposed to 10, 20, and 40 μM SeC for 72 h, the cell viability was significantly decreased from control (100%) to 63.5, 40.3, and 18.6%, respectively. For the cells treated with 20 μM SeC for 24, 48, and 72 h, the cell viability was significantly inhibited to 82.2, 57.4, and 39.2%, respectively. This cytotoxic effect of SeC on JEG-3 cells was further confirmed by the cell morphological changes, such as cell shrinkage, reduced cell number, and lost cell-to-cell contact. The results suggested that SeC could be applied as a cytotoxic agent in inhibiting growth of JEG-3 human choriocarcinoma.
|Figure 1: Selenocystine inhibits JEG-3 cell growth in vitro. (a) Dose-dependent inhibition of selenocystine against JEG-3 cell growth. Cells (6 × 103 cells/well) were seeded in 96-well plate and treated with 0–40 μM selenocystine for 72 h. (b) Time-dependent inhibition of selenocystine against JEG-3 cell growth. Cells were treated with 20 μM selenocystine for 12, 24, 48, and 72 h. Cell viability was detected with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. (c) Morphological changes. Cells were treated with 20 μM selenocystine for 72 h, and the cell morphology was observed under an inverted phase microscope (×200)|
Click here to view
Selenocystine induces S-phase arrest and apoptosis
To explore the cell death mechanism, cell cycle distribution and apoptosis in SeC-treated JEG-3 cells were examined with FCM. The results suggested that significant S-phase arrest and apoptosis were observed after SeC treatment [Figure 2]a. For instance, after treating JEG-3 cells with 10 and 20 μM SeC for 72 h, S-phase arrest could be obviously induced from 17.8% (control) to 39.5 and 48.2%, respectively. The SeC-induced S-phase arrest has also been convinced with statistical results of cell cycle distribution [Figure 2]b. Cyclin A was a key regulator of S-phase,, which was also examined. As shown in [Figure 2]c and [Figure 2]d, SeC treatment apparently inhibited cyclin A expression in dose- and time-dependent manner. These results clearly demonstrated that SeC caused S-phase arrest in JEG-3 human choriocarcinoma cells. In addition, 20 μM of SeC also triggered slight cell apoptosis (9.8%) as convinced by the increase of sub-G1 peak, which was usually employed to quantify the apoptotic cell death. However, SeC treatment (40 μM) resulted in markedly cell apoptosis to 88.7% [Figure 2]a and [Figure 2]e. The apoptotic mechanism induced by SeC was further investigated. PARP cleavage and caspase activation, two important apoptotic events, were detected in SeC-treated choriocarcinoma JEG-3 cells [Figure 2]f. SeC treatment obviously induced the PARP cleavage and the activation of caspase-3, caspase-7, and caspase-9 with a dose-dependent manner. The SeC-induced apoptosis in JEG-3 human choriocarcinoma cells could be further validated.
|Figure 2: Selenocystine induces S-phase arrest and apoptosis in JEG-3 cells. (a) Cell apoptosis and cell cycle distribution. Cells were seeded in 6-well plate and treated with 10, 20, and 40 μM selenocystine for 72 h. Then cells were collected, stained with propidium iodide solution, and examined by flow cytometry. (b) Statistic analysis of cell cycle distribution. Dose-dependent (c) and time-dependent (d) effects of selenocystine on cyclin A expression. The protein expression was detected by western blotting. (e) Statistic analysis of cell apoptosis. (f) Effects of selenocystine on cell apoptosis markers|
Click here to view
Selenocystine triggers oxidative damage in JEG-3 cells
Previous studies have demonstrated that human cancer cell apoptosis could be induced by SeC through triggering ROS-mediated oxidative damage. In the present study, the oxidative status in SeC-treated JEG-3 cells was also evaluated. First, the ROS and superoxide anion were measured by DCFH-DA and DHE probes, respectively. As shown in [Figure 3]a, treatment with SeC (20 μM) leads to time-dependent increase of intracellular ROS and superoxide anion, as indicated by the enhanced green and red fluorescence, respectively. The accumulation of ROS and superoxide anion was determined as early as within 10 min. This result supported the significant role of ROS as an early event in drug-induced apoptosis. To further clarify the SeC-induced oxidative damage, several DNA damage markers in the DNA damage-signaling axis were also determined.,, As shown in [Figure 3]b, SeC dose dependently triggered the phosphorylation activation of ATM (Ser1981), ATR, Ser15-p53, and Ser139-histone. Sec also time dependently activated Ser15-p53 and Ser139-histone, further confirming the SeC-induced oxidative damage [Figure 3]c. Taken together, above results indicated that ROS-mediated oxidative damage could be triggered by SeC in JEG-3 human choriocarcinoma cells in vitro.
|Figure 3: Selenocystine triggers oxidative damage in JEG-3 cells. (a) Selenocystine caused reactive oxygen species and superoxide anion production. Cells were seeded in 6-well plate and treated with 20 μM selenocystine for 10, 30, and 60 min. After treatment, cells were preincubated with 10 μM dichlorodihydrofluorescein diacetate or dihydroethidium probe for detection of reactive oxygen species and superoxide anion, respectively. (b) Dose-dependent effects of selenocystine on DNA damage markers. Cells were treated with 0–40 μM selenocystine for 72 h. (c) Time-dependent effects of selenocystine on DNA damage markers. The protein expression was examined by western blotting method|
Click here to view
Roles of reactive oxygen species in Selenocystine-induced apoptosis in JEG-3 cells
Based on the significant roles of ROS in SeC-induced apoptosis, ROS scavenger, glutathione (GSH) was applied for further confirmation. As shown in [Figure 4]a, SeC treatment (10 and 20 μM) both significantly inhibited JEG-3 cell growth. However, SeC-induced cell growth inhibition could be effectively attenuated after pretreatment of cells with 5 mM GSH for 2 h. This tendency was further confirmed with improved cell morphology [Figure 4]b. In addition, ROS inhibition by GSH also suppressed SeC-induced caspase-3 activation [Figure 4]c, indicating attenuated SeC-induced cell apoptosis. Moreover, the molecular mechanism after ROS inhibition was also explored. As shown in [Figure 4]d, GSH pretreatment dramatically suppressed SeC-induced PARP cleavage, caspase-3 activation, and Ser15-p53 phosphorylation. Meanwhile, the cyclin A expression was also recovered after the supplement of GSH. Taken together, these results powerfully proved that SeC induced cytotoxicity and apoptosis in JEG-3 cells with ROS-dependent manner.
|Figure 4: The inhibition of reactive oxygen species suppresses selenocystine-induced cytotoxicity and apoptosis in JEG-3 cells. (a) Reactive oxygen species inhibition attenuated selenocystine-induced cytotoxicity. (b) Reactive oxygen species inhibition improved cell morphology in selenocystine-treated JEG-3 cells. Cells were pretreated with 5 mM glutathione for 2 h before selenocystine treatment. (c) Glutathione supplement blocked selenocystine-induced apoptosis in JEG-3 cells. Cells were pretreated with 5 mM glutathione for 2 h before selenocystine treatment. Cell apoptosis was detected by flow cytometry. (d) Reactive oxygen species elimination attenuated selenocystine-induced oxidative damage, S-phase arrest, and apoptosis|
Click here to view
Selenocystine attenuates choriocarcinoma tumor xenograft growth in vivo
To validate the in vivo anticancer effects and mechanism, the immunodeficiency nude mice bearing JEG-3 human choriocarcinoma cells were employed. The results showed that SeC treatment in vivo significantly inhibited tumor growth [Figure 5]a and tumor weight [Figure 5]b. Mechanically, cell apoptosis and oxidative damage could also be triggered with SeC treatment in vivo, as convinced by the activation of casspase-3, Ser15-p53, and Ser139-histone [Figure 5]c. Then, the cell proliferation and angiogenesis in vivo were also evaluated by the IHC method, and the results indicated that SeC treatment apparently inhibited both cell proliferation (Ki-67 staining) and angiogenesis (CD-31 staining) in vivo [Figure 5]d. These results all revealed that SeC was able to inhibit JEG-3 cell growth in vivo by triggering oxidative damage-mediated apoptosis involving antiproliferation and antiangiogenesis.
|Figure 5: Selenocystine attenuates the growth of choriocarcinoma tumor xenografts in vivo. Selenocystine inhibits tumor volume (a) and tumor weight (b). JEG-3 cells (107 cells) were injected subcutaneously in nude mice. After growing for 1 week, the mice were administrated selenocystine at 5 and 10 mg/kg. The tumor volume and weight were measured at the end of the experiment. (c) Selenocystine induced apoptosis and oxidative damage in vivo. The protein expression was assayed by western blotting. (d) Selenocystine abolished the cell proliferation and angiogenesis in vivo. The Ki-67 and CD-31 expressions in vivo were examined with immunohistochemical method|
Click here to view
| > Discussion|| |
Human choriocarcinoma has been one common malignant tumor in female, with high aggressiveness and recurrence rate. Current treatment strategies were mainly based on cytotoxic drugs, which also made obvious cytotoxic effects on healthy cells., Exploring novel and efficient drugs to inhibit the growth of choriocarcinoma have been an urgent problem in clinic., SeC is a nutritionally available selenoamino acid, showing novel anticancer activities against human cancers, such as lung cancer, breast cancer, and glioma.,, However, the ability of SeC for choriocarcinoma has not been elucidated. Hence, the anticancer effects and mechanism of SeC against JEG-3 cells in vitro and in vivo were investigated. The results indicated that SeC could inhibit JEG-3 cell growth in vitro and in vivo. The mechanism was the induction of S-phase arrest and apoptosis through triggering ROS-mediated oxidative damage.
Apoptosis is a programmed cell death involving multiple apoptotic pathways, through which the aging and dead cells would be removed to maintain and stabilize the homeostasis.,,, Induction of cancer cell apoptosis with cytotoxic drugs is the most important way in treating human tumors. Mitochondrial pathway, endoplasmic reticulum pathway, and death receptor pathway all contributed to drug-induced cancer cell apoptosis., Furthermore, drug-induced cell cycle arrest has also one of the most effective strategies for blocking cell cycle. Cyclin is a kind of key molecules that control the coordinated DNA synthesis, chromosome separation, and cell division. Cyclin A functioned as a positive regulator of the cell cycle, which was mainly detected in the S and M phases. Cyclin A can form a complex with CDK2 to regulate cells to enter the mitosis.,, In the present study, SeC could induce S-phase arrest by blocking cyclin A expression in JEG-3 cells. Moreover, JEG-3 cells exposed to SeC also showed significant apoptotic features, such as cell shrinkage, apoptotic body formation, PARP cleavage, and caspase activation. These results indicated that induction of S-phase arrest and apoptosis both contributed to SeC-induced cell growth inhibition against JEG-3 cells.
The balance of redox status would be disturbed by the overproduced ROS and superoxide, which would make negative effects on the normal life activities.,, ROS-mediated DNA damage belonged to oxidative damage, which has been supported by many previous publications.,, Induction of oxidative damage in cancer cells was accepted as one of the effective treatment strategies. ROS, including hydrogen peroxide, hydroxyl radical, superoxide anion, and so on, all played important roles in inducing cancer cell apoptosis, regulating cell signaling and maintaining cell homeostasis., The intracellular level of ROS has been maintained by the balance of the anti-antioxidant and pro-antioxidant system. It is well known that ROS was one of the main mechanisms of cellular damage, which was involved in cancer, inflammation, and so on., Therefore, induction of cell apoptosis by promoting ROS accumulation has been one important mechanism for treating human cancers.
Many chemotherapy drugs inhibit tumor growth by inducing ROS a cumulation and further DNA damage. In the present study, significant ROS and superoxide accumulation was observed in JEG-3 cells treated with SeC. As expected, ROS generation subsequently leads to DNA damage, as demonstrated by the phosphorylation activation of Ser1981-ATM, Ser428-ATR, Ser15-p53, and Ser139-histone. The p53 was a cell cycle checkpoint protein which can block DNA synthesis, arrest cell cycle progress, and inhibit cell division to maintain genetic stability.,, ATM was the main switch molecules that directly identify DNA double-strand breaks and initiate DNA damage signaling pathways.,,, ATR was a serine-threonine protein kinase that responded to DNA damage, and some proteins would be phosphorylated to initiate DNA repair signals.,, However, GSH supplement effectively inhibited ROS-mediated DNA damage, attenuated S-phase arrest, and apoptosis. We speculated that Se may be incorporated into the peptides of Se-containing enzymes, such as GSH peroxidase and thioredoxin reductase. Therefore, the antioxidant system would be disturbed and then induced ROS-mediated oxidative damage and cancer cell apoptosis. Hence, ROS, as the upstream apoptosis-inducing factor, plays important roles in triggering cell apoptosis. The inhibition of ROS accumulation by GSH could effectively inhibit SeC-induced DNA damage and apoptosis. Therefore, SeC-inhibited JEG-3 cell growth by induction of S-phase arrest and cell apoptosis was believed to a ROS-dependent manner.
| > Conclusions|| |
Our results revealed that SeC could inhibit human choriocarcinoma growth in vitro and in vivo by induction of S-phase arrest and apoptosis through trigging ROS-mediated DNA damage.
Financial support and sponsorship
The study was supported by Natural Science Foundation of Shandong No. ZR2015HL050 to D.-W. Li.
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Samantaray S, Rout N, Kakkar S, Pattanayak L. Choriocarcinoma presenting as a vaginal nodule: A rare presentation diagnosed by fine needle aspiration cytology. Acta Cytol 2009;53:364-5.
Francischetti IM, Cajigas A, Suhrland M, Farinhas JM, Khader S. Incidental primary mediastinal choriocarcinoma diagnosed by endobronchial ultrasound-guided fine needle aspiration in a patient presenting with transient ischemic attack and stroke. Diagn Cytopathol 2017;11:237-9.
Prouillac C, Videmann B, Mazallon M, Lecoeur S. Induction of cells differentiation and ABC transporters expression by a myco-estrogen, zearalenone, in human choriocarcinoma cell line (BeWo). Toxicology 2009;263:100-7.
Gleizal A, Torossian JM, Geha H, Lebreton F, Beziat JL. Testicular choriocarcinoma presenting as cutaneous metastasis. A case report and review of the literature. Ann Chir Plast Esthet 2005;50:237-41.
Kösem M, Cankaya H, Kaya Z. Choriocarcinoma metastatic to mandibular gingiva: Case report and review of metastatic gingival tumours. J Otolaryngol 2004;33:310-4.
Suradji EW, Hatabu T, Kobayashi K, Yamazaki C, Abdulah R, Nakazawa M, et al.
Selenium-induced apoptosis-like cell death in Plasmodium falciparum.
Long M, Wu J, Hao J, Liu W, Tang Y, Li X, et al.
Selenocystine-induced cell apoptosis and S-phase arrest inhibit human triple-negative breast cancer cell proliferation. In Vitro
Cell Dev Biol Anim 2015;51:1077-84.
Wang H, Chen B, He M, Yu X, Hu B. Selenocystine against methyl mercury cytotoxicity in HepG2 cells. Sci Rep 2017;7:147.
Bai Y, Qin B, Zhou Y, Wang Y, Wang Z, Zheng W, et al.
Preparation and antioxidant capacity of element selenium nanoparticles sol-gel compounds. J Nanosci Nanotechnol 2011;11:5012-7.
Liu C, Liu Z, Li M, Li X, Wong YS, Ngai SM, et al.
Enhancement of auranofin-induced apoptosis in MCF-7 human breast cells by selenocystine, a synergistic inhibitor of thioredoxin reductase. PLoS One 2013;8:e53945.
Zhu LZ, Hou YJ, Zhao M, Yang MF, Fu XT, Sun JY, et al.
Caudatin induces caspase-dependent apoptosis in human glioma cells with involvement of mitochondrial dysfunction and reactive oxygen species generation. Cell Biol Toxicol 2016;32:333-45.
Fan L, Cao X, Yan H, Wang Q, Tian X, Zhang L, et al
. Morigen the synthetic antihyperlipidemic drug potassium piperate selectively kills breast cancer cells through inhibiting G1-S-phase transition and inducing apoptosis. Oncotarget 2017;12:168-72.
Li HL, Ma Y, Li Y, Li Y, Chen XB, Dong WL, et al
. The design of novel inhibitors for treating cancer by targeting CDC25B through disruption of CDC25B-CDK2/Cyclin A interaction using computational approaches. Oncotarget 2017;27:166-70.
He Z, Pu L, Yuan C, Jia M, Wang J. Nutrition deficiency promotes apoptosis of cartilage endplate stem cells in a caspase-independent manner partially through upregulating BNIP3. Acta Biochim Biophys Sin (Shanghai) 2017;49:25-32.
Suvorova II, Kozhukharova IV, Nikol'skiĭ NN, Pospelov VA. ATM/ATR signaling pathway activation in human embryonic stem cells after DNA damage. Tsitologiia 2013;55:841-51.
Chiu YT, Liu J, Tang K, Wong YC, Khanna KK, Ling MT, et al.
Inactivation of ATM/ATR DNA damage checkpoint promotes androgen induced chromosomal instability in prostate epithelial cells. PLoS One 2012;7:e51108.
Klusmann I, Rodewald S, Müller L, Friedrich M, Wienken M, Li Y, et al.
P53 activity results in DNA replication fork processivity. Cell Rep 2016;17:1845-57.
Simpson L, Sundaresan R, Vohra M, Sheagren J, Cougar D, August C, et al.
Invasive choriocarcinoma involving the major duodenal papilla. Gastrointest Endosc 2005;61:926-8.
Yang C, Lim W, Bazer FW, Song G. Myricetin suppresses invasion and promotes cell death in human placental choriocarcinoma cells through induction of oxidative stress. Cancer Lett 2017;399:10-9.
Shorbagi A, Aksoy S, Kilickap S, Güler N. Successful salvage therapy of resistant gestational trophoblastic disease with ifosfamide and paclitaxel. Gynecol Oncol 2005;97:722-3.
Kawamoto Y, Morinaga Y, Kimura Y, Kaku N, Kosai K, Uno N, et al.
TNF-α inhibits the growth of Legionella pneumophila
in airway epithelial cells by inducing apoptosis. J Infect Chemother 2017;23:51-5.
Mondal A, Bennett LL. Resveratrol enhances the efficacy of sorafenib mediated apoptosis in human breast cancer MCF7 cells through ROS, cell cycle inhibition, caspase 3 and PARP cleavage. Biomed Pharmacother 2016;84:1906-14.
Pawlak A, Gładkowski W, Mazur M, Henklewska M, Obmińska-Mrukowicz B, Rapak A, et al.
Optically active stereoisomers of 5-(1-iodoethyl)-4-(4'-isopropylphenyl) dihydrofuran-2-one: The effect of the configuration of stereocenters on apoptosis induction in canine cancer cell lines. Chem Biol Interact 2017;261:18-26.
Shen L, Lou Z, Zhang G, Xu G, Zhang G. Diterpenoid tanshinones, the extract from Danshen (Radix Salviae miltiorrhizae
) induced apoptosis in nine human cancer cell lines. J Tradit Chin Med 2016;36:514-21.
Yasuda J, Okada M, Yamawaki H. T3 peptide, an active fragment of tumstatin, inhibits H2O2-induced apoptosis in H9c2 cardiomyoblasts. Eur J Pharmacol 2017;807:64-70.
Roskoski R Jr. Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs. Pharmacol Res 2016;107:249-75.
Luo X, Zhong B, Hong X, Cui Y, Gao Y, Yin M, et al.
Puerarin exerts a delayed inhibitory effect on the proliferation of cardiomyocytes derived from murine ES cells via slowing progression through G2/M phase. Cell Physiol Biochem 2016;38:1333-42.
Hein JB, Nilsson J. Interphase APC/C-cdc20 inhibition by cyclin A2-cdk2 ensures efficient mitotic entry. Nat Commun 2016;7:10975.
Miftakhova R, Hedblom A, Semenas J, Robinson B, Simoulis A, Malm J, et al.
Cyclin A1 and P450 aromatase promote metastatic homing and growth of stem-like prostate cancer cells in the bone marrow. Cancer Res 2016;76:2453-64.
Fan CD, Li Y, Fu XT, Wu QJ, Hou YJ, Yang MF, et al.
Reversal of beta-amyloid-induced neurotoxicity in PC12 cells by curcumin, the important role of ROS-mediated signaling and ERK pathway. Cell Mol Neurobiol 2017;37:211-22.
Jani NV, Ziogas J, Angus JA, Schiesser CH, Macdougall PE, Grange RL, et al.
Dual action molecules: Bioassays of combined novel antioxidants and angiotensin II receptor antagonists. Eur J Pharmacol 2012;695:96-103.
Ma K, Zhang C, Huang MY, Li WY, Hu GQ. Cinobufagin induces autophagy-mediated cell death in human osteosarcoma U2OS cells through the ROS/JNK/p38 signaling pathway. Oncol Rep 2016;36:90-8.
Qiu M, Chen L, Tan G, Ke L, Zhang S, Chen H, et al.
JS-K promotes apoptosis by inducing ROS production in human prostate cancer cells. Oncol Lett 2017;13:1137-42.
Yeh CC, Li KT, Tang JY, Wang HR, Liu JR, Huang HW, et al.
Butanol-partitioned extraction from aqueous extract of Gracilaria tenuistipitata
inhibits cell proliferation of oral cancer cells involving apoptosis and oxidative stress. DNA Cell Biol 2016;35:210-6.
Yang J, Zhao X, Tang M, Li L, Lei Y, Cheng P, et al.
The role of ROS and subsequent DNA-damage response in PUMA-induced apoptosis of ovarian cancer cells. Oncotarget 2017;8:23492-506.
Maj MA, Ma J, Krukowski KN, Kavelaars A, Heijnen CJ. Inhibition of mitochondrial p53 accumulation by PFT-μ prevents cisplatin-induced peripheral neuropathy. Front Mol Neurosci 2017;10:108.
Park JB. Javamide-I-O-methyl ester increases p53 acetylation and induces cell death via activating caspase 3/7 in monocytic THP-1 cells. Phytomedicine 2016;23:1647-52.
Joyce EF, Pedersen M, Tiong S, White-Brown SK, Paul A, Campbell SD, et al.
Drosophila ATM and ATR have distinct activities in the regulation of meiotic DNA damage and repair. J Cell Biol 2011;195:359-67.
Knobel PA, Kotov IN, Felley-Bosco E, Stahel RA, Marti TM. Inhibition of REV3 expression induces persistent DNA damage and growth arrest in cancer cells. Neoplasia 2011;13:961-70.
Song L, Lin C, Wu Z, Gong H, Zeng Y, Wu J, et al.
MiR-18a impairs DNA damage response through downregulation of ataxia telangiectasia mutated (ATM) kinase. PLoS One 2011;6:e25454.
Subhash VV, Tan SH, Yeo MS, Yan FL, Peethala PC, Liem N, et al.
ATM expression predicts veliparib and irinotecan sensitivity in gastric cancer by mediating P53-independent regulation of cell cycle and apoptosis. Mol Cancer Ther 2016;15:3087-96.
Sousa MM, Zub KA, Aas PA, Hanssen-Bauer A, Demirovic A, Sarno A, et al.
An inverse switch in DNA base excision and strand break repair contributes to melphalan resistance in multiple myeloma cells. PLoS One 2013;8:e55493.
Zhang L, Chen H, Gong M, Gong F. The chromatin remodeling protein BRG1 modulates BRCA1 response to UV irradiation by regulating ATR/ATM activation. Front Oncol 2013;3:7.
Zhao Q, Fan J, Hong W, Li L, Wu M. Inhibition of cancer cell proliferation by 5-fluoro-2'-deoxycytidine, a DNA methylation inhibitor, through activation of DNA damage response pathway. Springerplus 2012;1:65.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]