Licochalcone D exhibits cytotoxicity in breast cancer cells and enhances tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis through upregulation of death receptor 5.

Anticancer strategies using natural products or derivatives are promising alternatives for cancer treatment. Here, we showed that licochalcone D (LCD), a natural flavonoid extracted from Glycyrrhiza uralensis Fisch, suppressed the growth of breast cancer cells, and was less toxic to MCF-10A normal breast cells. LCD-induced DNA damage, cell cycle arrest, and apoptosis in breast cancer cells. Furthermore, LCD potentiated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cytotoxicity. Mechanistically, LCD was revealed to reduce survival protein expression and to upregulate death receptor 5 (DR5) expressions. Silencing DR5 blocked the ability of LCD to sensitize cells to TRAIL-mediated apoptosis. LCD increased CCAAT/enhancer-binding protein homologous protein (CHOP) expression in breast cancer cells. Knockdown of CHOP attenuated DR5 upregulation and apoptosis triggered by cotreatment with LCD and TRAIL. Furthermore, LCD suppressed the phosphorylation of extracellular signal-regulated kinase and promoted the phosphorylation of c-Jun amino-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Pretreatment with JNK inhibitor SP600125 or p38 MAPK inhibitor SB203580 abolished the upregulation of DR5 and CHOP, and also attenuated LCD plus TRAIL-induced cleavage of poly(ADP-ribose) polymerase. Overall, our results show that LCD exerts cytotoxic effects on breast cancer cells and arguments TRAIL-mediated apoptosis by inhibiting survival protein expression and upregulating DR5 in a JNK/p38 MAPK-CHOP-dependent manner.

Daurisoline inhibits proliferation, induces apoptosis, and enhances TRAIL sensitivity of breast cancer cells by upregulating DR5.

Daurisoline (DS) is an isoquinoline alkaloid that exerts anticancer activities in various cancer cells. However, the underlying mechanisms through which DS affects the survival of breast cancer cells remain poorly understood. Therefore, the present study was undertaken to investigate the potential anticancer effect of DS on breast cancer cells and reveal the mechanism underlying the enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by DS. Cell counting kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EdU) assay were used to evaluate the ability of cell proliferation. Flow cytometry was selected to examine the cell cycle distribution. TUNEL assay was used to detect the cell apoptosis. The protein expression was measured by Western blot analysis. DS was found to reduce the cell viability and suppress the proliferation of MCF-7 and MDA-MB-231 cells by causing G1 phase cell cycle arrest. DS could trigger apoptosis by promoting the cleavage of caspase-8 and PARP. The phosphorylation of ERK, JNK, and p38MAPK was upregulated clearly following DS treatment. Notably, SP600125 (JNK inhibitor) pretreatment significantly abrogated DS-induced PARP cleavage. DS inactivated Akt/mTOR and Wnt/ß-catenin signaling pathway and upregulated the expression of ER stress-related proteins. Additionally, DS amplified TRAIL-caused viability reduction and apoptosis in breast cancer cells. Mechanismly, DS upregulated the protein level of DR4 and DR5, and knockdown of DR5 attenuated the cotreatment-induced cleavage of PARP. Inhibition of JNK could block DS-induced upregulation of DR5. This study provides valuable insights into the mechanisms of DS inhibiting cell proliferation, triggering apoptosis, and enhancing TRAIL sensitivity of breast cancer cells.

6-Methoxydihydrosanguinarine exhibits cytotoxicity and sensitizes TRAIL-induced apoptosis of hepatocellular carcinoma cells through ROS-mediated upregulation of DR5.

6-methoxydihydrosanguinarine (6-MS), a natural benzophenanthridine alkaloid extracted from Macleaya cordata (Willd.) R. Br, has shown to trigger apoptotic cell death in cancer cells. However, the exact mechanisms involved have not yet been clarified. The current study reveals the underlying mechanisms of 6-MS-induced cytotoxicity in hepatocellular carcinoma (HCC) cells and investigates whether 6-MS sensitizes TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis. 6-MS was shown to suppress cell proliferation and trigger cell cycle arrest, DNA damage, and apoptosis in HCC cells. Mechanisms analysis indicated that 6-MS promoted reactive oxygen species (ROS) generation, JNK activation, and inhibits EGFR/Akt signaling pathway. DNA damage and apoptosis induced by 6-MS were reversed following N-acetyl-l-cysteine (NAC) treatment. The enhancement of PARP cleavage caused by 6-MS was abrogated by pretreatment with JNK inhibitor SP600125. Furthermore, 6-MS enhanced TRAIL-mediated HCC cells apoptosis by upregulating the cell surface receptor DR5 expression. Pretreatment with NAC attenuated 6-MS-upregulated DR5 protein expression and alleviated cotreatment-induced viability reduction, cleavage of caspase-8, caspase-9, and PARP. Overall, our results suggest that 6-MS exerts cytotoxicity by modulating ROS generation, EGFR/Akt signaling, and JNK activation in HCC cells. 6-MS potentiates TRAIL-induced apoptosis through upregulation of DR5 via ROS generation. The combination of 6-MS with TRAIL may be a promising strategy and warrants further investigation.

Scutebarbatine A induces ROS-mediated DNA damage and apoptosis in breast cancer cells by modulating MAPK and EGFR/Akt signaling pathway.

Scutebarbatine A (SBT-A), a diterpenoid alkaloid, has exerted cytotoxicity on hepatocellular carcinoma cells in our previous works. Here, the antitumor activity of SBT-A in breast cancer cells and the underlying mechanism were explored. The anti-proliferative effect of SBT-A was measured by trypan blue staining, 5-ethynyl-2'-deoxyuridine (EdU) incorporation and colony formation assay. DNA double-strand breaks (DSBs) were evaluated by observing the nuclear focus formation of γ-H2AX. Cell cycle distribution was assessed by flow cytometry. Apoptosis was determined by a TUNEL assay. Intracellular reactive oxygen species (ROS) generation and superoxide production were measured with 2', 7'-dichlorofluorescein diacetate (DCFH-DA) and dihydroethidium (DHE) staining, respectively. The results indicated that SBT-A showed a dose-dependent cytotoxic effect against breast cancer cells while revealing less toxicity toward MCF-10A breast epithelial cells. Moreover, SBT-A remarkably induced DNA damage, cell cycle arrest and apoptosis in both MDA-MB-231 and MCF-7 cells. SBT-A treatment increased the levels of ROS and cytosolic superoxide production. Pretreatment with N-acetyl cysteine (NAC), a ROS scavenger, was sufficient to block viability reduction, DNA damage, apoptosis and endoplasmic reticulum (ER) stress caused by SBT-A. By exposure to SBT-A, the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) was upregulated, while the phosphorylation of extracellular signal-regulated kinase (ERK) was downregulated. In addition, SBT-A inhibited the EGFR signaling pathway by decreasing EGFR expression and phosphorylation of Akt and p70S6K. As mentioned above, SBT-A has a potent inhibitory effect on breast cancer cells through induction of DNA damage, apoptosis and ER stress via ROS generation and modulation of MAPK and EGFR/Akt signaling pathway.

Development and Validation of Nomograms Predicting the 5- and 8-Year Overall and Cancer-Specific Survival of Bladder Cancer Patients Based on SEER Program.

BACKGROUND: Bladder cancer is often prone to recurrence and metastasis. We sought to construct nomogram models to predict the overall survival (OS) and cancer-specific survival (CSS) of bladder cancer patients. METHODS: A reliable random split-sample approach was used to divide patients into two groups: modeling and validation cohorts. Uni-variate and multivariate survival analyses were used to obtain the independent prognostic risk factors based on the modeling cohort. A nomogram was constructed using the R package, "rms". Harrell's concordance index (C-index), calibration curves and receiver operating characteristic (ROC) curves were applied to evaluate the discrimination, sensitivity and specificity of the nomograms using the R packages "hmisc", "rms" and "timeROC". A decision curve analysis (DCA) was used to evaluate the clinical value of the nomograms via R package "stdca.R". RESULTS: 10,478 and 10,379 patients were assigned into nomogram modeling and validation cohorts, respectively (split ratio ≈ 1:1). For OS and CSS, the C-index values for internal validation were 0.738 and 0.780, respectively, and the C-index values for external validation were 0.739 and 0.784, respectively. The area under the ROC curve (AUC) values for 5- and 8-year OS and CSS were all greater than 0.7. The calibration curves show that the predicted probability values of 5- and 8-year OS and CSS are close to the actual OS and CSS. The decision curve analysis revealed that the two nomograms have a positive clinical benefit. CONCLUSION: We successfully constructed two nomograms to forecast OS and CSS for bladder cancer patients. This information can help clinicians conduct prognostic evaluations in an individualized manner and tailor personalized treatment plans.

Licochalcone B induces DNA damage, cell cycle arrest, apoptosis, and enhances TRAIL sensitivity in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is a highly fatal disease recognized as a growing global health crisis. Traditional Chinese herbal medicines have been used to treat patients with cancer for many years in China. This study investigated the effects of licochalcone B (LCB), a flavonoid compound isolated from the root of Glycyrrhiza uralensis Fisch., on cell proliferation, DNA damage and TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in HCC cells. Our results showed that LCB inhibited cell proliferation and induced DNA damage, cell cycle arrest and apoptosis. Treatment with LCB significantly inhibited the Akt/mTOR pathway and activated endoplasmic reticulum (ER) stress and mitogen-activated protein kinase (MAPK) signaling pathway. Moreover, combined treatment with LCB and TRAIL yielded evident enhancements in the viability reduction and apoptosis. LCB upregulated death receptor 4 (DR4) and death receptor 5 (DR5) protein in a concentration- and time-dependent manner. The knockdown of DR5 significantly suppressed TRAIL-induced cleavage of PARP, which was enhanced by LCB. Treatment with an extracellular-regulated kinase (ERK) inhibitor (PD98059) or c-Jun N-terminal kinase (JNK) inhibitor (SP600125) markedly reduced the LCB-induced upregulation of DR5 expression and attenuated LCB-mediated TRAIL sensitization. In summary, LCB exhibits cytotoxic activity through modulation of the Akt/mTOR, ER stress and MAPK pathways in HCC cells and effectively enhances TRAIL sensitivity through the upregulation of DR5 expression in ERK- and JNK-dependent manner. Combination therapy with LCB and TRAIL may be an alternative treatment strategy for HCC.

Nickel-Catalyzed, Manganese-Assisted Denitrogenative Cross-Electrophile-Coupling of Benzotriazinones with Alkyl Halides for ortho-Alkylated Benzamides.

A nickel-catalyzed denitrogenative cross-electrophile-coupling of benzotriazinones with unactivated alkyl halides (X = Cl, Br, I) in the presence of manganese powder as a reductant has been developed. The reaction furnishes ortho-alkylated secondary benzamides in modest to good yields under mild conditions. The scope of the reaction is demonstrated with 25 examples, showing good tolerance of steric hindrance and common functional groups, thus providing an efficient protocol to ortho-alkylated benzamide derivatives without the use of preprepared organometallic reagents.

Nomogram predicting long-term overall and cancer-specific survival of patients with buccal mucosa cancer.

BACKGROUND: Few models about the personalized prognosis evaluation of buccal mucosa cancer (BMC) patients were reported. We aimed to establish predictive models to forecast the prognosis of BMC patients. METHODS: The complete clinicopathological information of BMC patients from the surveillance, epidemiology and end results program was collected and reviewed retrospectively. Two nomograms were established and validated to predict long-term overall survival (OS) and cancer-specific survival (CSS) of BMC patients based on multivariate Cox regression survival analysis. RESULTS: 1155 patients were included. 693 and 462 patients were distributed into modeling and validation groups with 6:4 split-ratio via a random split-sample method. Based on the survival analysis, independent prognostic risk factors (variables that can be used to estimate disease recovery and relapse chance) influencing OS and CSS were obtained to establish nomograms. Then, we divided the modeling group into high- and low-risk cohorts. The low-risk cohort had improved OS and CSS compared to the high-risk cohort, which was statistically significant after the Log-rank test (p < 0.05). Furthermore, we used the concordance index (C-index), calibration curve to validate the nomograms, showing high accuracy. The decision curve analyses (DCA) revealed that the nomograms had evident clinical value. CONCLUSIONS: We constructed two credible nomogram models, which would give the surgeons reference to provide an individualized assessment of BMC patients.

Knockdown of LncRNA PANDAR by CRISPR-dCas9 Decreases Proliferation and Increases Apoptosis in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common malignant epithelial tumor in the oral cavity. Emerging evidence has demonstrated the important function roles of long noncoding RNAs (lncRNAs) in human cancers. LncRNA promoter of CDKN1A antisense DNA damage activated RNA (PANDAR) functions as an oncogene in multiple carcinomas, whereas its function in OSCC has not been investigated yet. The aim of our study is to investigate the possible regulatory mechanism of PANDAR in OSCC. First of all, PANDAR was highly expressed in OSCC cells and loss-of-function assays mediated by CRISPR-dCas9 observed that PANDAR silencing restrained cell proliferation and promoted cell apoptosis. Then we found and confirmed the interaction between PANDAR and serine and arginine rich splicing factor 7 (SRSF7). Subsequently, serine/threonine-protein kinase pim-1 (PIM1) was proved to be regulated by PANDAR in SRSF7-dependant way. Rescue experiments validated that PANDAR modulated the proliferation and apoptosis in OSCC through PIM1. In conclusion, PANDAR bound with SRSF7 to increase PIM1 expression, hence promoting the development of OSCC. These data shed new lights into the seeking for effective diagnostic biomarkers and therapeutic targets for OSCC patients.

A single-dose mRNA vaccine provides a long-term protection for hACE2 transgenic mice from SARS-CoV-2.

The rapid expansion of the COVID-19 pandemic has made the development of a SARS-CoV-2 vaccine a global health and economic priority. Taking advantage of versatility and rapid development, three SARS-CoV-2 mRNA vaccine candidates have entered clinical trials with a two-dose immunization regimen. However, the waning antibody response in convalescent patients after SARS-CoV-2 infection and the emergence of human re-infection have raised widespread concerns about a possible short duration of SARS-CoV-2 vaccine protection. Here, we developed a nucleoside-modified mRNA vaccine in lipid-encapsulated form that encoded the SARS-CoV-2 RBD, termed as mRNA-RBD. A single immunization of mRNA-RBD elicited both robust neutralizing antibody and cellular responses, and conferred a near-complete protection against wild SARS-CoV-2 infection in the lungs of hACE2 transgenic mice. Noticeably, the high levels of neutralizing antibodies in BALB/c mice induced by mRNA-RBD vaccination were maintained for at least 6.5 months and conferred a long-term notable protection for hACE2 transgenic mice against SARS-CoV-2 infection in a sera transfer study. These data demonstrated that a single dose of mRNA-RBD provided long-term protection against SARS-CoV-2 challenge.

Applying nomograms based on the surveillance, epidemiology and end results database to predict long-term overall survival and cancer-specific survival in patients with oropharyngeal squamous cell carcinomas: A case-control research.

Few models regarding to the individualized prognosis assessment of oropharyngeal squamous cell carcinoma (OPSCC) patients were documented. The purpose of this study was to establish nomogram model to predict the long-term overall survival (OS) and cancer-specific survival (CSS) of OPSCC patients. The detailed clinical data for the 10,980 OPSCC patients were collected from the surveillance, epidemiology and end results (SEER) database. Furthermore, we applied a popular and reasonable random split-sample method to divide the total 10,980 patients into 2 groups, including 9881 (90%) patients in the modeling cohort and 1099 (10%) patients in the external validation cohort. Among the modeling cohort, 3084 (31.2%) patients were deceased at the last follow-up date. Of those patients, 2188 (22.1%) patients died due to OPSCC. In addition, 896 (9.1%) patients died due to other causes. The median follow-up period was 45 months (1-119 months). We developed 2 nomograms to predict 5- and 8- year OS and CSS using Cox Proportional Hazards model. The nomograms' accuracy was evaluated through the concordance index (C-index) and calibration curves by internal and external validation. The C-indexes of internal validation on the 5- and 8-year OS and CSS were 0.742 and 0.765, respectively. Moreover, the C-indexes of external validation were 0.740 and 0.759, accordingly. Based on a retrospective cohort from the SEER database, we succeeded in constructing 2 nomograms to predict long-term OS and CSS for OPSCC patients, which provides reference for surgeons to develop a treatment plan and individual prognostic evaluations.

CCT128930 induces G1-phase arrest and apoptosis and synergistically enhances the anticancer efficiency of VS5584 in human osteosarcoma cells.

Osteosarcoma is a highly invasive primary malignant bone tumor. PI3K/mTOR pathway plays a key role in tumor progression, and inhibition of PI3K/mTOR pathway represents a novel strategy in therapy of osteosarcoma. CCT128930 and VS5584 are both inhibitors of PI3K/mTOR, but the anticancer mechanism of CCT128930 or/and VS5584 against human osteosarcoma cells remains unclear. Herein, U2OS and MG63 human osteosarcoma cells were cultured, and the anticancer effects of CCT128930 alone and the combined effect of CCT128930 and VS5584 against human osteosarcoma cells were explored. The results showed that CCT128930 as PI3K/mTOR inhibitor effectively inhibited p-p70 and p-AKT expression and dose-dependently inhibited U2OS cells and MG63 human osteosarcoma cells growth. Further studies found that CCT128930 triggered significant G-1 phase arrest and apoptosis, as convinced by the dysfunction of p27, Cyclin B1, Cyclin D1 and Cdc2, and PARP cleavage and caspase-3 activation. Moreover, CCT128930 treatment obviously enhanced VS5584-induced growth inhibition and apoptosis in human osteosarcoma cells, followed by enhanced PARP cleavage and caspase-3 activation. Taken together, CCT128930 alone or combined treatment with CCT128930 and VS5584 both effectively inhibited human osteosarcoma cells growth by induction of G1-phase arrest and apoptosis through regulating PI3K/mTOR and MAPKs pathways.

VS-5584 Inhibits Human Osteosarcoma Cells Growth by Induction of G1- phase Arrest through Regulating PI3K/mTOR and MAPK Pathways.

BACKGROUND: Activation of the PI3K/mTOR signaling pathway plays a key role in the progression of human osteosarcoma. Studies have confirmed that VS-5584 was a novel inhibitor of the PI3K/mTOR pathway, and displayed potential anticancer activity. OBJECTIVE: To explore the anticancer effect and underlying mechanism of VS-5584 against the growth of human osteosarcoma cells. METHODS: U2OS and MG-63 human osteosarcoma cells were cultured and the cytotoxicity, cell apoptosis in VS-5584-treated cells were explored by the CCK8 assay, flow cytometric analysis and western blot. Cell migration and tube formation were also employed to examine the anticancer potential. RESULTS: The results showed that VS-5584 treatment dose-dependently inhibited the growth of U2OS and MG-63 cells by induction of G1-phase arrest through regulating p21, p27, Cyclin B1 and Cdc2. Further investigation revealed that VS-5584 treatment effectively inhibited the PI3K/mTOR signaling pathway and triggered MAPK phosphorylation. Moreover, VS-5584 treatment dramatically suppressed cell migration and tube formation of HUVECs, followed by the down-regulation of HIF-1α and VEGF. CONCLUSION: Our findings validated that VS-5584 may be a promising anticancer agent with potential application in the chemotherapy and chemoprevention of human osteosarcoma.

MiR-148a inhibits oral squamous cell carcinoma progression through ERK/MAPK pathway via targeting IGF-IR.

OBJECTIVE: The current study aimed to investigate the functional roles and clinical significance of microRNA-148a (miR-148a) in the progression of oral squamous cell carcinoma (OSCC). METHODS: Relative expression of miR-148a in OSCC cells and tissues were detected using quantitative real-time polymerase chain reaction (qRT-PCR). Chi-square test was performed to estimate the relationship between miR-148a expression and clinical characteristics of OSCC patients. Cell transfection was carried out using Lipofectamine® 2000. Biological behaviors of tumor cells were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and transwell assays. Bioinformatics analysis and luciferase reporter assay were used to identify the target genes of miR-148a. Protein expression was detected through Western blot analysis. RESULTS: MiR-148a expression was obviously decreased in OSCC tissues and cells, and such down-regulation was closely correlated with lymph node metastasis (P=0.027) and tumor node metastasis (TNM) stage (P=0.001) of OSCC patients. miR-148a overexpression could significantly impair OSCC cell proliferation, migration and invasion in vitro (P<0.05 for all). Insulin-like growth factor-I receptor (IGF-IR) was a potential target of miR-148a. MiR-148a could inhibit ERK/MAPK signaling pathway through targeting IGF-IR. CONCLUSION: MiR-148a plays an anti-tumor role in OSCC and inhibits OSCC progression through suppressing ERK/MAPK pathway via targeting IGF-IR.

CUDC-907 enhances TRAIL-induced apoptosis through upregulation of DR5 in breast cancer cells.

CUDC-907 is a novel dual-acting inhibitor of phosphoinositide 3-kinase (PI3K) and histone deacetylase (HDAC). In this study, we aimed to explore the anticancer effects of CUDC-907 on human breast cancer cells. Our results showed that CUDC-907 effectively inhibited breast cancer cell proliferation. Flow cytometry analysis revealed that CUDC-907 induced cell cycle arrest and apoptosis in breast cancer cells. The combined treatment of CUDC-907 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in a marked increase in apoptosis and cleavage of caspase-8, -9 and poly (ADP-ribose) polymerase (PARP) in breast cancer cells. CUDC-907 enhanced expressions of death receptor 5 (DR5), reduced the levels of anti-apoptotic molecules XIAP, Bcl-2 and Bcl-xL. Knockdown of DR5 abrogated apoptosis induced by the combination of CUDC-907 and TRAIL in breast cancer cells. CUDC-907 increased the phosphorylation of JNK and p38 MAPK. JNK inhibitor pretreatment attenuated CUDC-907-induced upregulation of DR5. In summary, CUDC-907 shows potent cytotoxicity against breast cancer cells and facilitates TRAIL-mediated apoptosis through DR5 upregulation. The combination of CUDC-907 and TRAIL may be a promising therapeutic approach in the treatment of breast cancer.

Nomogram predicting long-term overall survival and cancer-specific survival of lip carcinoma patients based on the SEER database: A retrospective case-control study.

Our study was designed to construct nomograms to predict the overall survival (OS) and cancer-specific survival (CSS) of lip carcinoma patients.A search of the Surveillance, Epidemiology, and End Results (SEER) database provided us with detailed clinical data of the 1780 lip carcinoma patients. On the basis of the credible random split-sample method, the 1780 patients were placed into 2 groups, with 890 patients in the modeling group and 890 patients in the counterpart's group (proportion = 1:1). By employing Kaplan-Meier univariate and Cox multivariate survival analyses based on the modeling cohort, the nomograms were developed and then used to divide the modeling cohort into low-risk cohort and high-risk cohort. The survival rates of the 2 groups were calculated. Internal and external evaluation of nomogram accuracy was performed by the concordance index (C-index) and calibration curves.With regard to 5- and 8-year OS and CSS, the C-indexes of internal validation were 0.762 and 0.787, whereas those of external validation reached 0.772 and 0.818, respectively. All the C-indexes were higher than 0.7. The survival curves of the low-risk cohort were obviously better than those of the high-risk cohort.Credible nomograms have been established based on the SEER large-sample population research. We believe these nomograms can contribute to the design of treatment plans and evaluations of individual prognosis.

Caudatin potentiates the anti-tumor effects of TRAIL against human breast cancer by upregulating DR5.

BACKGROUND: The ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to preferentially induce apoptosis in transformed cells while sparing most normal cells is well established. However, the intrinsic and acquired resistance of tumors to TRAIL-induced apoptosis limits its therapeutic applicability. PURPOSE: We investigated the effect of caudatin, a species of C-21 steroidal glycosides isolated from the roots of Cynanchum auriculatum, on TRAIL-induced apoptosis in human breast cancer cells. METHODS: Cell growth inhibition was evaluated by the CCK-8 assay. The cell cycle distribution was assessed by propidium iodide flow cytometry. Apoptosis was determined by TUNEL staining. Protein expression was detected by western blotting analysis. RESULTS: Caudatin enhanced TRAIL-induced apoptosis in human breast cancer cells. This sensitization was achieved by upregulating death receptor 5 (DR5). Knockdown of DR5 abolished the enhancing effect of caudatin on TRAIL responses. The caudatin-induced upregulation of DR5 was accompanied by increased expression of CHOP and phosphorylation of p38 MAPK and JNK. CHOP knockdown blocked caudatin-upregulated DR5 expression. Moreover, cotreatment of breast cancer cells with p38 MAPK and JNK inhibitors significantly counteracted the caudatin-induced expression of DR5. CONCLUSION: Our results showed that caudatin sensitized breast cancer cells to TRAIL-induced apoptosis through activation of CHOP, p38 MAPK and JNK-mediated upregulation of DR5 expression. The combination of TRAIL and caudatin may be a promising therapeutic approach for the treatment of breast cancer.

Nomograms forecasting long-term overall and cancer-specific survival of patients with oral squamous cell carcinoma.

Our aim was to establish a "nomogram" model to forecast the overall survival (OS) and cancer-specific survival (CSS) of oral squamous cell carcinoma (OSCC) patients. The clinicopathological data for the 10,533 OSCC patients were collected from the Surveillance, Epidemiology and End Results (SEER) database. We used a credible random split-sample method to divide 10,533 patients into two cohorts: 7046 patients in the modeling cohort and 3487 patients in the external validation cohort (split-ratio = 2:1). The median follow-up period was 32 months (1-119 months). We developed nomograms to predict 5- and 8-year OS and CSS of OSCC patients with a Cox proportional hazards model. The precision of the nomograms was assessed by the concordance index (C-index) and calibration curves through internal and external validation. The C-indexes of internal validation regarding 5- and 8-year OS and CSS were 0.762 and 0.783, respectively. In addition, the external validation's C-indexes were 0.772 and 0.800. Based on a large-sample analysis targeting the SEER database, we established two nomograms to predict long-term OS and CSS for OSCC patients successfully, which can assist surgeons in developing a more effective therapeutic regimen and conducting personalized prognostic evaluations.