Tumor-derived exosomal PD-L1: a new perspective in PD-1/PD-L1 therapy for lung cancer.

Exosomes play a crucial role in facilitating intercellular communication within organisms. Emerging evidence indicates that a distinct variant of programmed cell death ligand-1 (PD-L1), found on the surface of exosomes, may be responsible for orchestrating systemic immunosuppression that counteracts the efficacy of anti-programmed death-1 (PD-1) checkpoint therapy. Specifically, the presence of PD-L1 on exosomes enables them to selectively target PD-1 on the surface of CD8+ T cells, leading to T cell apoptosis and impeding T cell activation or proliferation. This mechanism allows tumor cells to evade immune pressure during the effector stage. Furthermore, the quantification of exosomal PD-L1 has the potential to serve as an indicator of the dynamic interplay between tumors and immune cells, thereby suggesting the promising utility of exosomes as biomarkers for both cancer diagnosis and PD-1/PD-L1 inhibitor therapy. The emergence of exosomal PD-L1 inhibitors as a viable approach for anti-tumor treatment has garnered significant attention. Depleting exosomal PD-L1 may serve as an effective adjunct therapy to mitigate systemic immunosuppression. This review aims to elucidate recent insights into the role of exosomal PD-L1 in the field of immune oncology, emphasizing its potential as a diagnostic, prognostic, and therapeutic tool in lung cancer.

Use of the prognostic nutrition index as a predictive biomarker in small-cell lung cancer patients undergoing immune checkpoint inhibitor treatment in the Chinese alpine region.

Background: Whether the prognostic nutritional index (PNI), which is suggested to reflect systemic inflammation and nutritional status of patients, could be used as an effective prognostic factor for small-cell lung cancer (SCLC) has not yet been clarified. The purpose of this study was to verify the prognostic value of the PNI in SCLC patients treated with programmed cell death ligand-1/programmed cell death 1 (PD-L1/PD-1) inhibitors in the alpine region of China. Methods: SCLC patients treated with PD-L1/PD-1 inhibitors monotherapy or combined with chemotherapy between March 2017 and May 2020 were included. Based on the values of serum albumin and total lymphocyte count, the study population was divided into two groups: high and low PNI. The Kaplan-Meier method was used to compute the median survival time and the log-rank test was used to compare the two groups. To evaluate the prognostic value of the PNI, univariable and multivariable analyses of progression-free survival (PFS) and overall survival (OS) were performed. The correlations between PNI and DCR or ORR were calculated by Point biserial correlation analysis. Results: One hundred and forty patients were included in this study, of which, 60.0% were high PNI (PNI > 49.43) and 40.0% were low PNI (PNI ≤ 49.43). Results indicated that the high PNI group had better PFS and OS than the low PNI group in the patients who received PD-L1/PD-1 inhibitors monotherapy (median PFS: 11.0 vs. 4.8 months, p < 0.001 and median OS: 18.5 vs. 11.0 months, p = 0.004). Similarly, better PFS and OS were associated with an increase in PNI level in the patients who accepted PD-L1/PD-1 inhibitors combined with chemotherapy (median PFS: 11.0 vs. 5.3 months, p < 0.001 and median OS: 17.9 vs. 12.6 months, p = 0.005). Multivariate Cox-regression model showed that high PNI was significantly related to better PFS and OS in patients who accepted PD-L1/PD-1 inhibitors monotherapy or combined with chemotherapy (PD-L1/PD-1 inhibitors monotherapy: PFS: HR = 0.23, 95% CI: 0.10-0.52, p < 0.001 and OS: HR = 0.13, 95% CI: 0.03-0.55, p = 0.006; PD-L1/PD-1 inhibitors combined with chemotherapy: PFS: HR = 0.34, 95% CI: 0.19-0.61, p < 0.001 and OS: HR = 0.53, 95% CI: 0.29-0.97, p = 0.040, respectively). Additionally, Point biserial correlation analysis between PNI and disease control rate (DCR) showed that PNI status was positively correlated with DCR in SCLC patients receiving PD-L1/PD-1 inhibitors or combined with chemotherapy (r = 0.351, p < 0.001; r = 0.285, p < 0.001, respectively). Concussions: PNI may be a promising biomarker of treatment efficacy and prognosis in SCLC patients treated with PD-L1/PD-1 inhibitors in the alpine region of China.

Phage nanoparticle as a carrier for controlling fungal infection.

A mass of nanocarriers have been exploited and utilized for prevention of fungi, including organic nanomaterials, inorganic nanoparticles, polypeptides, and viruses. Due to biological safety and flexible genetic engineering property, bacteriophages, as bionanoparticles, are widely used in the diagnosis and treatment of microorganisms, which can be easily loaded with proteins and drugs. In particular, random DNAs can be inserted into the genome of phage by phage display technology, and it is possible to obtain the peptide/antibody targeting fungi from phage library. Meanwhile, phages displaying specific peptides are able to conjugate with other nanoparticles, which have both characteristics of peptides and nanomaterials, and have been used for precise detection of fungi. Additionally, phage nanomaterials as carriers can reduce the toxicity of drugs, increase the time of drug circulation, stimulate the immune response, and have an anti-fungal effect by itself. In this review, we summarize the recent applications of bacteriophages on the study of fungi. The improvement of our understanding of bacteriophage will supply new tools for controlling fungal infections. These phage libraries were used to pan the specific peptides for diagnosis, prevention, and treatment of fungi. KEY POINTS: • System fungal infection has no significant clinical symptoms; it is important to develop vaccine, diagnosis, and therapeutic agents to reduce mortality; phage is an ideal carrier for vaccine and drug to stimulate immune response and improve the efficiency of drug, and also can improve the sensitivity of detection • This review summarized recent studies on phage-based fungal vaccine and threw light on the developing therapeutic phage in the treatment of fungal infection.

Collagen type 1 alpha 1 chain is a novel predictive biomarker of poor progression-free survival and chemoresistance in metastatic lung cancer.

Background: Collagen type 1 alpha 1 chain (COL1A1) is an extracellular matrix protein comprising two alpha 1 chains and one alpha 2 chain. Our previous study identified that COL1A1 is the key gene during the development and progression of lung adenocarcinoma by multi-omics analysis. However, the clinical significance of COL1A1 expression in lung cancer samples remains largely unknown. Here, we aimed to evaluate the level of COL1A1 in lung cancer samples and correlate its level with the clinical outcome. Methods: COL1A1 gene expression in lung cancer samples was analyzed using the Oncomine database (www.oncomine.org). A total of 308 lung cancer samples (208 formalin-fixed paraffin-embedded tissues and 100 blood samples) were assessed for protein expression of COL1A1. Immunohistochemistry staining and enzyme-linked immunosorbent assay were used to detect COL1A1 expression in tissues and serum, respectively. Results: We identified an elevation of COL1A1 in mRNA level and gene amplification in lung cancer tissues compared with normal lung tissues. High COL1A1 expression was observed in lung cancer tissues and serum (P < 0.05), it was significantly correlated with the peripheral type tumor, the larger diameter of the tumor, the occurrence of lymph node metastases and distant metastases, a higher TNM stage, and smoking (P < 0.05). High COL1A1 expression was associated with poor progression-free survival (PFS) and chemoresistance in lung cancer patients (P < 0.05). Multivariable Cox-regression analysis showed that COL1A1 expression was an independent prognostic factor (P < 0.05). Furthermore, the area under the receiver operating characteristic (AUC) curve was 0.909 for the combined COL1A1 and carcinoembryonic antigen (CEA) measurement. Conclusion: Our findings revealed that COL1A1 could be used as a novel diagnostic, prognostic, and chemoresistance biomarker of human lung cancer, and these results provide a potential therapeutic strategy for lung cancer patients.

IL-24 inhibits the malignancy of human glioblastoma cells via destabilization of Zeb1.

Glioblastoma (GBM) is the most common and fatal type of primary malignant tumours in the central nervous system. Cytokines such as interleukins (ILs) play an important role in GBM progression. Our present study found that IL-24 is down-regulated in GBM cells. Recombinant IL-24 (rIL-24) can suppress the in vitro migration and invasion of GBM cells while increase its chemo-sensitivity to temozolomide (TMZ) treatment. rIL-24 negatively regulates the expression of Zeb1, one well known transcription factors of epithelial to mesenchymal transition (EMT) of cancer cells. Over expression of Zeb1 can attenuate IL-24-suppressed malignancy of GBM cells. Mechanistically, IL-24 decreases the protein stability of Zeb1 while has no effect on its mRNA stability. It is due to that IL-24 can increase the expression of FBXO45, which can destabilize Zeb1 in cancer cells. Collectively, we reveal that IL-24 can suppress the malignancy of GBM cells via decreasing the expression of Zeb1. It suggests that targeted activation of IL-24 signals might be a potential therapy approach for GBM treatment.

Nutritional status in patients with advanced lung cancer undergoing chemotherapy: a prospective observational study.

Purpose: The consequences of malnutrition include increased risk of many complications. The assessment and management of nutritional problems are essential in supportive care of patients undergoing therapy. The primary objective of the present study was to assess changes in the nutritional status in lung cancer patients who had undergone chemotherapy.Patients and methods: Preliminary and post-chemotherapy assessments of patients' nutritional status and medical characteristics were conducted using the Patient-Generated Subjective Global Assessment (PG-SGA) from July 2014 to May 2016 at Harbin Medical University Cancer Hospital. Four hundred sixty-five advanced lung cancer patients (51.8% men and 48.2% women with a mean (SD) age of 60.2 ± 9.8 years) participated in the present study. PG-SGA was assessed prior to the initiation of chemotherapy and after four cycles of chemotherapy.Results: We found that 11.4% of the patients were severely malnourished and 65.6% of the patients were moderately malnourished prior to chemotherapy. After chemotherapy, 52.9% of the patients were considered moderately malnourished, whereas 33.8% were severely malnourished. The nutritional status had deteriorated in the majority of patients. After chemotherapy, there was a rise in the prevalence of nutrition impact symptoms.Conclusions: A deteriorated nutritional status was the result of the side effects caused by chemotherapy in the patients of the present study. These findings highlight that more attention should be paid to improve the nutritional status in patients with advanced lung cancer undergoing chemotherapy, and proper nutrition education and nutritional support should be provided to these patients.

Nutritional status and related factors of patients with advanced lung cancer in northern China: a retrospective study.

BACKGROUND: Mortality of lung cancer in northern China has been increasing at an alarming speed. The consequences of malnutrition may include an increased risk of many complications. However, the nutritional status in advanced lung cancer patients is still unknown. So the aims of this research are to report on the prevalence of malnutrition in our population, the proportion of participants requiring nutrition interventions, and the relationship between nutritional status at diagnosis and overall survival (OS). PATIENTS AND METHODS: We evaluated 495 patients with advanced lung cancer (stage IIIB and IV). Nutritional status was estimated by the Patient-Generated Subjective Global Assessment (PG-SGA). This study investigated the clinical significance of PG-SGA scores at admission by following OS. Kaplan-Meier survival analysis and the log-rank test were used to calculate OS. Univariate and multivariate analyses of the OS were performed using Cox analysis. RESULTS: Our results showed that 88.9% of the patients required nutrition intervention and 25.1% of the patients required improved nutrition-related symptom management and/or urgent nutritional support (PG-SGA score ≥9). Factors related to malnutrition were age, sex, pathology, TNM stage, smoking condition, anemia, body mass index, pre-albumin, and albumin. The research outcomes indicated that PG-SGA score at admission was significantly associated with OS, which was still maintained when stratified by age and sex. CONCLUSION: Malnutrition was prevalent in patients with advanced lung cancer. Poor nutritional status was associated with worse clinical outcomes.

Robust analysis of novel mRNA-lncRNA cross talk based on ceRNA hypothesis uncovers carcinogenic mechanism and promotes diagnostic accuracy in esophageal cancer.

BACKGROUND: ceRNAs have emerged as pivotal players in the regulation of gene expression and play a crucial role in the physiology and development of various cancers. Nevertheless, the function and underlying mechanisms of ceRNAs in esophageal cancer (EC) are still largely unknown. METHODS: In this study, profiles of DEmRNAs, DElncRNAs, and DEmiRNAs between normal and EC tumor tissue samples were obtained from the Cancer Genome Atlas database using the DESeq package in R by setting the adjusted P<0.05 and |log2(fold change)|>2 as the cutoff. The ceRNA network (ceRNet) was initially constructed to reveal the interaction of these ceRNAs during carcinogenesis based on the bioinformatics of miRcode, miRDB, miRTarBase, and TargetScan. Then, independent microarray data of GSE6188, GSE89102, and GSE92396 and correlation analysis were used to validate molecular biomarkers in the initial ceRNet. Finally, a least absolute shrinkage and selection operator logistic regression model was built using an oncogenic ceRNet to diagnose EC more accurately. RESULTS: We successfully constructed an oncogenic ceRNet of EC, crosstalk of hsa-miR372-centered CADM2-ADAMTS9-AS2 and hsa-miR145-centered SERPINE1-PVT1. In addition, the risk-score model -0.0053*log2(CADM2)+0.0168*log2(SERPINE1)-0.0073*log2(ADAMTS9-AS2)+0.0905*log2(PVT1)+0.0047*log2(hsa-miR372)-0.0193*log2(hsa-miR145), (log2[gene count]) could improve diagnosis of EC with an AUC of 0.988. CONCLUSION: We identified two novel pairs of ceRNAs in EC and its role of diagnosis. The pairs of hsa-miR372-centered CADM2-ADAMTS9-AS2 and hsa-miR145-centered SERPINE1-PVT1 were likely potential carcinogenic mechanisms of EC, and their joint detection could improve diagnostic accuracy.

Multiomics analysis on DNA methylation and the expression of both messenger RNA and microRNA in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) poses a significant threat to public health worldwide, while the genetic and epigenetic abnormalities involved in the oncogenesis of LUAD remains unknown. This study aimed to identify and validate key genes during the development and progression of LUAD by multiomics analysis. First, Empirical Analysis of Digital Gene Expression Data in R (EdgeR) was used to identify differentially regulated genes between normal samples and LUAD samples. Then significance analysis of microarrays (SAM) was used to identify differentially methylated genes and regulated microRNAs (miRNAs) between normal samples and LUAD samples. Following that, Kyoto Encyclopedia of Genes and Genomes (KEGG)-enrichment analysis was used to analyze the function that these genes enriched in. A total of 4,816 genes, 419 miRNAs, and 4,476 methylated genes that were significantly differentially expressed corresponding to the normal tissues in LUAD were obtained, and some of the pathways these genes enriched in were the same. Moreover, 255 genes differentially methylated and expressed at the same time were also found, and these 255 genes were the target genes of the miRNAs differentially expressed in LUAD. Finally, nine genes (BRCA1, COL1A1, ESR1, FGFR2, HNF4A, IGFBP3, MET, MMP3, and PAK1) network analysis, and two of which were found to be related to the survival of LUAD patients. In summary, a total of nine genes that may play important roles in the development of LUAD were identified, and two (PAK1 and FGFR2) of them can be served as prognostic biomarkers for LUAD patients. The genes found in this study played different roles in the tumor progression of LUAD, indicating these genes may be considered as potential target genes for LUAD treatment.

CXCL12 suppresses cisplatin-induced apoptosis through activation of JAK2/STAT3 signaling in human non-small-cell lung cancer cells.

AIMS: Poor efficacy of chemotherapy drugs in non-small-cell lung cancer (NSCLC) is the key reason for the failure of treatment, but the mechanism of this remains largely unknown. Stromal cell-derived factor 1-alpha (SDF-1α/CXCL12) is a small chemotactic cytokine protein that plays an important role in tumor progression. In this study, we investigated the anti-apoptotic mechanism of the CXCL12/CXCR4 axis in response to cisplatin, a commonly used chemotherapeutic drug, in human lung adenocarcinoma A549 cells. METHODS: CXCL12 blocks cisplatin-induced apoptosis in A549, and the results were shown by propidium iodide/annexin V staining in vitro. The mechanism of CXCL12 stimulating phosphorylation of STAT3 through CXCR4/JAK2 was demonstrated by immunofluorescence and Western blotting. The expression of CXCL12 and p-STAT3 in clinical specimens was examined by immunohistochemistry. RESULTS: CXCL12 significantly decreased the ratio of apoptotic cells and stimulation of phospho-signal transducer and activator of transcription (p-STAT)-3 in a time-dependent manner through interaction with CXCR4. Among the signaling molecules downstream of CXCR4, the JAK2/STAT3 pathway plays a predominant role in the anti-apoptotic effect of CXCL12. Analysis of clinical specimens revealed that increased CXCL12 and p-STAT3 expression correlates with enhanced lung cancer progression. CONCLUSION: These data suggest that CXCR4 contributes to CXCL12-mediated anti-apoptosis by activating JAK2/STAT3 pathway in NSCLC cells. Therefore, targeting CXCL12/CXCR4 signaling pathway reveals a potential therapeutic approach for NSCLC.

The 50 Most-cited Articles in Gastroenterology and Hepatology from Mainland China.

OBJECTIVE: To identify and analyze the 50 most-cited gastroenterology and hepatology articles originating from mainland China. METHODS: We utilized the 2015 edition of Journal Citation Reports and PubMed to determine the 50 most-cited gastroenterology and hepatology articles from 75 professional journals and four leading journals in clinical medicine, which are The New England Journal of Medicine, The Lancet, The Journal of the American Medical Association, and The British Medical Journal. Then we excluded the articles written outside mainland China and collected the basic information, including the title, authors, year of publication, source journal, city, institution, number of citations, and topic of the research. RESULTS: The number of citations for the top 50 papers ranged from 279 to 89 (mean, 129). These articles were published between 2005 and 2012, in which 2009 was the year with the largest number of highly cited papers(13). All articles were published in 15 journals. The journal Hepatology published the largest number of articles(21), followed by Journal of Gastroenterology and Hepatology(4), Journal of Hepatology(4) and World Journal of Gastroenterology(4). The top 50 articles originated mainly from Shanghai(20), Guangzhou(13) and Beijing(6). Sun Yat-sen University produced most highly cited papers(10). The number of basic research was far more than clinical research, of which the ratio was about 1.78(32:18). In all these articles, hepatocellular carcinoma was the most-discussed topic(19), followed by hepatitis B virus(8) and endoscopic(5). CONCLUSIONS: Although a large gap remains between mainland China and the global community, the gastroenterology and hepatology research from China is gradually recognized by the world.

Multifunctional upconversion nanoparticles for targeted dual-modal imaging in rat glioma xenograft.

PURPOSE: Achieving a radiographic gross total resection in high-grade gliomas improves overall survival. Many technologies such as intraoperative microscope, intraoperative ultrasound, fluorescence imaging, and intraoperative magnetic resonance imaging have been applied to improve tumor resection. However, most commercial available magnetic resonance imaging contrast agents have limited permeability across the blood-brain barrier and are cleared rapidly from circulation. Fluorescence imaging discriminates tumor from normal tissue and provides a promising new strategy to maximize sage surgical resection of tumor. However, the penetration depth of fluorescence imaging is generally low. MATERIALS AND METHODS: In this study, a new type of magnetite NaGdF4:Yb(3+),Er(3+),Li(+)@NaGdF4 (UCNPs) core-shell nanoparticles, coated with SiO2 and further functionalized with glioma and blood-brain barrier targeting motifs, was prepared for dual-modal in vivo upconversion imaging and magnetic resonance imaging. RESULTS: The as-prepared multifunctional upconversion nanoparticles (UCNPs@SiO2-CX-Lf) were biocompatible, showed strong upconversion luminescence under excitation of 980 nm, and provided high signal-to-noise ratio in vivo. Moreover, UCNPs@SiO2-CX-Lf nanoparticles showed a high relaxivity of 1.25 S(-1 )mM(-1) and were successfully applied as contrast agent for magnetic resonance imaging in tumor xenograft rat model with prolonged tumor signal enhancement. In vivo and magnetic resonance imaging Upconversion Luminescence (UCL) imaging results indicated that these particles can across the blood-brain barrier, bind to glioma, gave bright UCL signal and T1 magnetic resonance imaging contrast. CONCLUSIONS: Targeted UCL and magnetic resonance imaging dual-modal in vivo imaging using Yb(3+)/Er(3+)/Li(+) codoped NaGdF4 core-shell nanostructure can serve as a platform technology for the next generation of intraoperative probes for image-guided tumor resection.

Differential expression of Notch1 intracellular domain and p21 proteins, and their clinical significance in gastric cancer.

Changes in the expression of the Notch1 intracellular domain (NICD) and p21 proteins have been shown to be closely associated with the development and progression of a number of cancers. The present study aimed to investigate the expression levels of the two proteins in gastric carcinoma and precancerous lesions, and to determine the clinical significance of this. A total of 109 gastric cancer, 57 precancerous gastric lesion, 50 chronic superficial gastritis and 17 normal gastric mucosa patients were recruited for immunohistochemical staining of NICD and p21 protein expression. The protein expression levels in the gastric cancer patient samples were associated with the clinicopathological and survival data. NICD protein levels were upregulated gradually from normal gastric mucosae through chronic superficial gastritis and precancerous gastric lesions to gastric cancer tissues (P<0.01), whereas p21 protein levels were downregulated accordingly (P<0.01). Increased NICD and a loss of p21 expression were closely associated with tumor dedifferentiation, depth of tumor invasion, lymph node metastasis, surface morphology and Lauren classification in gastric cancer. Thus, NICD expression was inversely associated with p21 expression. In addition, the overall survival rate was greater in NICD- and P21+ patients than in NICD+ and P21- patients, respectively (P<0.05). The COX regression multivariate analysis revealed that NICD+, p21-, depth of tumor invasion and lymph node metastasis were all independent prognostic factors for patients with gastric cancer. NICD and p21 proteins are differentially expressed in gastric cancer and the aberrant expression of these proteins is associated with an advanced tumor stage, tumor metastasis and overall patient survival. Future studies are required to further evaluate the two proteins as novel prognostic markers for patients with gastric cancer.

Transplantation of bone marrow stromal cells enhances nerve regeneration of the corticospinal tract and improves recovery of neurological functions in a collagenase-induced rat model of intracerebral hemorrhage.

The reorganization of brain structures after intracerebral hemorrhage (ICH) insult is crucial to functional outcome. Although the pattern of neuronal rewiring is well-documented after ischemic stroke, the study of brain plasticity after ICH has been focusing on the enhancement of dendritic complexity. Here we hypothesized that functional restoration after ICH involves brain reorganization which may be favorably modulated by stem cell transplantation. In this study, bone marrow stromal cells (BMSCs) were transplanted into the perilesional sites of collagenase-induced ICH in adult rats one day after ICH injury. Forelimb functional recovery was monitored with modified limb placing and vibrissae-elicited forelimb placement tests. Anterograde and retrograde tracing were used to assess the reorganization of bilateral forelimb areas of the sensorimotor cortex. We found that in rats transplanted with BMSCs after ICH injury, axonal sprouting occurred in the contralateral caudal forelimb area of the cortex, and was significantly higher than in ICH rat models that received only the vehicle (P < 0.01). The number of positive neurons in the ipsilateral rostral forelimb area of the cortex of the BMSC group was 1.5-to 4.5-fold greater than in the vehicle group (P < 0.05). No difference was found between the BMSC and vehicle groups in hemispheric atrophy or labeled neurons in the ipsilateral caudal forelimb area (P = 0.193). Scores for improved functional behavior in the BMSC group were in accord with the results from histology. Neuronal plasticity of the denervated corticospinal tract at bilateral forelimb areas of the cortex in the collagenase-induced ICH rat models was significantly enhanced by BMSC transplantation. BMSC transplantation may facilitate functional recovery after ICH injury.

Spinal duraplasty with two novel substitutes restored locomotor function after acute laceration spinal cord injury in rats.

A dural tear is a common complication after acute laceration spinal cord injury (ALSCI). An unrepaired dural tear is associated with poor locomotor functional recovery. Spinal duraplasty with biomaterials may promote functional recovery in ALSCI. However, an ideal dural substitute has not yet been found. In this work, we investigated the possibility of using a denuded human amniotic membrane (DHAM) or DHAM seeded on bone marrow stromal cells (DHAM-BMSCs) as duraplasty biomaterials. We patched broken dura with the two novel substitutes in an ALSCI rat model. At the end of the eighth week, we observed that the neural motor function was recovered according to the Basso-Beattie-Bresnahan scale, and the neural loop was successfully reestablished between the ends of the lesions by motor-evoked potentials in the duraplasty groups. Moreover, the DHAM-BMSCs repaired the dura and resulted in a significant reduction in the total lesion and cystic volumes by nearly 10-fold versus the control group (p < 0.01). The levels of neurotrophic factors and NF-200-positive fibers were also improved in the duraplasty groups, compared to the control group. Our data suggest that the two novel substitutes may be promising grafts for patching dural defects to improve locomotor function after ALSCI.

[Effects of mifepristone on the proliferation, apoptosis, and cis-platinum (DDP) sensitivity of chemo-resistant human ovarian cancer cells].

BACKGROUND & OBJECTIVE: Mifepristone is an effective progesterone receptor antagonist. It was reported that mifepristone can inhibit the growth of ovarian carcinoma cells either in vitro or in vivo, but the exact mechanism is unknown. The effect of mifepristone on the growth, apoptosis and cis-platinum (DDP)-sensitivity of chemo-resistant ovarian carcinoma cell lines have scarcely been reported. The purpose of this study was to investigate the effect and its mechanism of mifepristone on the proliferation, apoptosis and DDP sensitivity of DDP-resistant human ovarian carcinoma cells, and to give experimental basis for treating refractory ovarian carcinoma with mifepristone. METHODS: DDP-resistant human ovarian carcinoma cell line SK-OV-3 cells were cultured in vitro, and the MTT assay was used to examine the antiproliferative effect of mifepristone with or without DDP on SK-OV-3 cells. The cooperative effects between mifepristone and DDP in inhibiting the growth of SK-OV-3 cells were analyzed. TdT mediated dUTP nick end labeling (TUNEL) and flow cytometry (FCM) were used to examine the effects of mifepristone with or without DDP on the apoptosis and cell cycle of SK-OV-3 cells. RESULTS: Mifepristone produced concentration-dependent antiproliferative effect on SK-OV-3 cells at all experimental concentrations.Enhanced antiproliferative effects were found when SK-OV-3 cells were cultured with mifepristone at 0.625, 1.25, 2.5, 5, 10, and 20 microg/ml combined with 1.25 microg/ml or 2.5 microg/ml DDP (q >1.15). Only additive effects were found when the cells were cultured with mifepristone and 0.625 microg/ml or 5.0 microg/ml DDP (0.85< q< 1.15). Mifepristone induced concentration-dependent apoptosis in SK-OV-3 cells and arrested cells in the G(0)/G(1)-phase of cell cycle. The apoptosis rate were 14.52%, 36.14%, and 53.22%,respectively,when the cells were cultured with mifepristone at 1.25, 2.50, and 5.00 microg/ml. The percentage of G(0)/G(1)-phase cells was increased with the concentration of mifepristone. Synergic effect between mifepristone (at 1.25, 2.5, and 5 microg/ml) and 2.5 microg/ml DDP was found in inducing SK-OV-3 cells apoptosis (q >1.15) and G0/G1-phase stasis. CONCLUSION: Mifepristone can inhibit the growth of chemo-resistant human ovarian carcinoma cells,and enhance its DDP sensitivity. This may be associated with the synergic effect between mifepristone and DDP in inducing apoptosis and G(0)/G(1)-phase stasis.