Autophagy represents an alternative tumor-suppressing mechanism that overcomes the dramatic resistance of malignant gliomas to radiotherapy and proapoptotic-related chemotherapy. This study reports that valproic acid (VPA), a widely used anti-epilepsy drug, induces autophagy in glioma cells. Autophagy, crucial for VPA-induced cell death, is independent of apoptosis, even though apoptotic machinery is proficient. Oxidative stress induced by VPA occurs upstream of autophagy. Oxidative stress also activates the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, whereas blocking this pathway inhibits autophagy and induces apoptosis. VPA-induced autophagy cannot be alleviated by inositol, suggesting a mechanism different from that for lithium. Moreover, VPA potentiates autophagic cell death, but not apoptosis, when combined with other autophagy inducers such as rapamycin, Ly294002, and temozolomide in glioma cells both in vitro and in vivo, which may warrant further investigation toward possible clinical application in patients with malignant gliomas.

Overexpression of ERCC1 mRNA is associated with drug resistance to cisplatin in human gliomas, but the role of the ERCC1 promoter in drug resistance has not been demonstrated. We have used sodium bisulfite sequencing to compare ERCC1 promoter methylation patterns in cisplatin-sensitive and cisplatin-resistant glioma cells. The levels of ERCC1 DNA methylation, mRNA and protein in 32 human glioma samples were examined by methylation specific PCR, real-time RT-PCR and immunohistochemistry, respectively. Meanwhile, cisplatin sensitivities to these human glioma samples were tested by histoculture drug response assay. Hypermethylation was observed in the upstream 5Kb region of the ERCC1 promoter of cisplatin-sensitive glioma cell lines. ERCC1 DNA methylation levels were highly variable in 32 human glioma samples ranging from 0.1 to 0.87, which have shown significant difference between cisplatin-sensitive samples and cisplatin-resistant samples (p < 0.05). The relative expression levels of ERCC1 mRNA in 32 glioma samples were also variable from 0.01 to 5.71. No detectable or low expression of ERCC1 protein was shown in 7 glioma samples. ERCC1 promoter methylation was inversely correlated to mRNA expression (r 5 20.903 p 5 0.001) as well as protein expression (r 5 20.884 p 5 0.001). Moreover, ERCC1 mRNA expression was significantly associated with protein levels (r 5 0.840 p 5 0.001). In summary, the aberrant CpG island methylation in ERCC1 promoter region exists in human glioma cell lines as well as clinical glioma samples. ERCC1 DNA methylation could regulate the expression of downstream mRNA and protein, and was associated with cisplatin chemosensitivity.

Pretreatment determination of DNA-PK/Ku86 activities might be helpful in identifying patients who will actually benefit from platinum-based treatment.

ABSTRACT. We aimed to evaluate the toxicity of long-term exposure to different cadmium (Cd) doses in rats and expression profiles of DNA repair-related genes. The model rats were exposed to different concentrations of CdCl 2 for 3 months, and 5 DNA repair-related genes -hMSH2, MLH1, XRCC1, hOGG1, ERCC1 -were cloned in different tissues, including the liver, kidney, heart, and lung. Accumulated amounts of Cd were detected in the tissues. Gene and protein detections were conducted via fluorescence quantitative realtime polymerase chain reaction and Western blotting, respectively. Methylated sequences of the 5 DNA repair-related gene promoters were used to investigate whether the low expression levels of the genes were related to methylation of the promoter. In the Cd-exposed group, 3 DNA repair genes (i.e., XRCC1, hOGG1, and ERCC1) significantly decreased in the rat liver, kidney, heart, and lung according to the β-actin internal standard (P < 0.01). Western blotting indicated the same trend for the different tissues. Each of the DNA repair genes had special characteristics; for example, hOGG1 gene expression decreased by 75% in the kidney, and XRCC1 gene expression decreased by 5% in the liver and heart when compared to the control group (P < 0.01). A negative correlation between the DNA repair gene expression levels and the cumulative levels of Cd was also suggested by malignancy pathology. The expression levels of 3 DNA repair genes (i.e., ERCC1, XRCC1, and hOGG1) played an important role in the rat response to Cd exposure but not DNA methylated protection.

Background: Colorectal cancer (CRC) remains one of the leading contributors to cancer-related mortality and morbidity worldwide. Traditional Chinese medicines have been widely employed to treat various types of cancer in China. This investigation aims to determine the association between Chinese herbal medicine (CHM) therapy and survival outcomes in CRC patients with liver-limited metastases. Methods: A retrospective cohort study was performed among patients with colorectal liver metastases at the First Affiliated Hospital of Guangzhou University of Chinese Medicine in Guangzhou, China. Data from a series of consecutive patients were collected via an electronic medical record system or telephone follow-up. We defined high exposure as a period of CHM therapy lasting more than 6 months. The primary outcome was overall survival. Results: The study included the data of 191 patients from January 2008 to December 2017; 126 patients (65.97%) met the inclusion criteria of high exposure to CHM. Multivariate analyses revealed that high exposure to CHM was associated with better overall survival (hazard ratio = 0.444, 95% confidence interval = [0.213, 0.926], P = .030). The association was further confirmed by a subgroup exploratory analysis. Conclusion: Long-term CHM therapy is correlated with improved survival outcomes in CRC patients with liver-limited metastases.

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Background. Colorectal cancer liver metastasis (CRLM) is a high degree of malignancy with rapid disease progression and has a poor prognosis. Both serum apolipoprotein A-I (ApoA-I) and neutrophil-to-lymphocyte ratio (NLR) play key roles in anti-inflammation and antitumor. This study is aimed at evaluating the implication of serum ApoA-I level in combination with NLR in the prognosis of CRLM. Methods. We retrospectively analyzed the serum ApoA-I level and NLR in 237 patients with CRLM. Cox regression analyses were used to identify the independent prognostic significance of these indicators. Kaplan-Meier method and Log-rank test were applied to compute overall survival (OS). Both the ApoA-I and NLR were divided into three levels, according to their medians. A risk-stratified prediction model was established to evaluate the prognosis of patients with CRLM. The ROC curve AUC values were applied to evaluate the capability of the model. Results. Higher levels of ApoA-I and lower NLR were strongly associated with prolonged OS (Log-rank test, P < 0.05 ). The patients were then grouped into three queues according to the ApoA-I level and NLR. There was a crucial diversity in the OS ( P < 0.001 ) between the high-risk ( ApoA − I ≤ 1.03  g/L and NLR > 3.24 ), medium-risk ( ApoA − I > 1.03   g/L or NLR ≤ 3.24 ) and low-risk groups ( ApoA − I > 1.03   g/L and NLR ≤ 3.24 ). The AUC value of the prediction model ( AUC = 0.623 , 95% CI: 0.557-0.639, P = 0.001 ) was higher than other individual indicators (including ApoA-I, NLR, cT classification, and cN classification). Additionally, the association of the prediction model and cTN classification ( AUC = 0.715 , 95% CI: 0.606-0.708, P < 0.001 ) was better than the model and cTN classification alone. Conclusion. The combination of ApoA-I level and NLR could be a prognostic indicator for CRLM.

Our results confirm that GP has an adverse impact on the renal function of patients with UUT-UC who retain a solitary kidney, but it can be safely administered to the majority of these patients without inducing SNT. In specific patients, GC is an alternative to GP that has comparable efficacy and favourable renal toxicity.