Chemoresistance in hepatocellular carcinoma (HCC) is associated with multiple cellular responses to environmental stresses, such as nutrient deprivation and hypoxia. Nevertheless, whetherERstress resulting from nutrient deprivation and tumor hypoxia contributes to drug resistance remains unclear. Melatonin increased the efficacy of chemotherapeutic drugs in hepatocellular carcinoma in our previous studies. However, the effects of melatonin on endoplasmic reticulum (ER) stress‐induced resistance to chemotherapeutic agents inHCChave not been tested. The effect of the endoplasmic reticulum (ER) stress response during resistance of human hepatocellular carcinoma cells against doxorubicin was investigated in this study. Pretreatment of HepG2 andSMMC‐7721 cells (two human hepatocellular carcinoma cell lines) with tunicamycin, anERstress inducer, drastically decreased the rate of apoptosis generated by doxorubicin. Interestingly, co‐pretreatment with tunicamycin and melatonin significantly increased apoptosis induced by doxorubicin. Simultaneously, the expression of phosphorylatedAKT(p‐AKT) was elevated in HepG2 andSMMC‐7721 cells given tunicamycin but reduced in the presence of melatonin. Furthermore, consistent with inhibition ofAKTactivation by using thePI3K inhibitorLY294002, melatonin elevated the levels ofCHOP(C/EBP‐homologous protein) and reduced the levels of Survivin (a member of the inhibitor of apoptosis protein family)suggesting that inhibition of thePI3K/AKTpathway by melatonin‐reversedERstress‐induced resistance to doxorubicin in human hepatocellular carcinoma cells. These results demonstrate that melatonin attenuatesERstress‐induced resistance to doxorubicin in human hepatocellular carcinoma cells by down‐regulating thePI3K/AKTpathway, increasing the levels ofCHOPand decreasing the levels of Survivin.

Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients. We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria, or hand and foot syndrome (HFS) in the first 4 weeks. Time-to-event variables were assessed using Kaplan–Meier methods and Cox proportional hazard regression models. Binary endpoints were assessed using logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model was analyzed, and risk scores were calculated to predict overall survival. Presence of AEs in the first 4 weeks was associated with prolonged median overall survival (169 vs. 103 days, log-rank p = 0.0039; adjusted hazard ratio (HR) 0.64, 95% confidence interval [CI] 0.64–0.84, p = 0.001), prolonged median progression-free survival (86.5 vs. 62 days, log-rank p = 0.0309; adjusted HR 0.69, 95% CI 0.53–0.91, p = 0.007), and increased disease control rate (54.67 vs. 32.77%; adjusted odds ratio 2.67, p < 0.001). Results remained significant in landmark analyses. The onset of any single AE or any combinations of the AEs were all statistically significantly associated with prolonged OS, except for the presence of proteinuria. An AE-based prediction model and subsequently derived scoring system showed high calibration and discrimination in predicting overall survival. Presence of HTN, proteinuria, or HFS during the first cycle of apatinib treatment was a viable biomarker of antitumor efficacy in metastatic GC patients.

To detect the expression of COX-2 and HER-2 in colorectal cancer and to analyze their correlation and clinical significance. A total of 1026 colorectal cancer surgical specimens were collected from patients treated from December 2002 to December 2007 at the First Affiliated Hospital of Anhui Medical University. All specimens were made into 4-μm slices. The expression of COX-2 and HER-2 were detected by immunohistochemistry using the streptavidin-biotin-peroxidase method. The correlations between COX-2 and HER-2 expression and colorectal cancer clinical features were analyzed. The positive rates of COX-2 and HER-2 expression in colorectal cancer were 77.97% (800/1026) and 46.20% (474/1026), respectively. There was a significant correlation between COX-2 and HER-2 expression in colorectal cancer (P < 0.05). In patients with tumor size ≥ 5 cm, the positive rates of COX-2 and HER-2 expression were 81.48% (308/378) and 57.94% (219/378), respectively. In patients with serosal invasion, the positive COX-2 and HER-2 expression rates were 80.53% (612/760) and 49.21% (374/760), respectively. In patients with lymph node metastasis, the positive expression rates were 85.04% (506/595) and 54.62% (325/595), respectively, and the positive expression rates differed significantly between patients with lymph node metastasis and those without (P < 0.05). In patients with Duke's C and D colorectal cancer, the positive COX-2 and HER-2 expression rates were 82.80% (443/535) and 57.94% (310/535), respectively. In patients with poorly differentiated colorectal cancer, the positive expression rates were 74.49% (210/282) and 52.84% (149/282), respectively (P < 0.05). In patients with distant metastasis, the positive expression rates were 82.27% (116/141) and 53.90% (76/141), respectively (P < 0.05). These findings suggest that COX-2 and HER-2 have synergistic effects in colorectal cancer. COX-2 and HER-2 expression had no significant correlation with sex, age, or tumor location. COX-2 and HER-2 are important markers for invasion and metastasis of colorectal cancer, and they act together to regulate the invasion and metastasis of colorectal cancer.