Association of Antioxidative Enzymes Polymorphisms with Efficacy of Platin and Fluorouracil-Based Adjuvant Therapy in Gastric Cancer.

BACKGROUND/AIMS: Imbalance of oxidative/antioxidative enzymes in cells is associated with carcinogenesis and cancer cell chemoresistance. The aim of this study was to examine the clinical significance of potentially functional single nucleotides polymorphisms (SNPs) in antioxidative enzymes, GPxs and CAT, in stages II and III gastric cancer patients. METHODS: A total of 591 gastric cancer patients who had radical gastrectomy were recruited. 207 patients received platinum and fluorouracil-based (PF-based) adjuvant chemotherapy and 384 patients were untreated. GPx1 rs1050450, GPx2 rs4902346, GPx3 rs736775, rs3828599 and CAT rs769218 were genotyped in the DNA samples extracted from paraffin-embedded tumor tissue. RESULTS: CAT rs769218 was significantly correlated with the overall survival (OS) in the dominant model (P = 0.014). Multivariate analysis revealed that CAT rs769218 GA/AA (HR, 0.715; 95%CI, 0.562-0.910, P = 0.006) was an independent prognostic marker indicating improved survival. After adjustments, GPx3 rs736775 TC/CC was significantly associated with improved OS (HR, 0.621; 95%CI, 0.399-0.965; P=0.034) in patients treated with PF-based adjuvant chemotherapy, and CAT rs769218 GA/AA was significantly associated with improved OS (HR, 0.646; 95% CI, 0.482-0.864; P = 0.003) in the untreated patients. PF-based chemotherapy significantly decreased risk of death for patients carrying GPx3 rs736775 TC/CC and age ≤ 60 years or with diffused type adenocarcinoma compared to surgery alone. CONCLUSION: our findings suggested CAT rs769218 and GPx3 rs736775 may be considered as prognostic markers in gastric cancer. Patient stratification by GPx3 rs736775 and conventional pathological parameters may provide additional predictive information in treatment decision-making.

L-carnitine treatment of insulin resistance: A systematic review and meta-analysis.

BACKGROUND: L-carnitine has been used for several years as an adjuvant therapy in oxidative stress, blood sugar, high-sensitivity C-reactive protein (CRP), anemia, etc. However, the efficacy of L-carnitine treating insulin resistance (IR) remains controversial. Homeostasis model assessment of Insulin Resistance (HOMA-IR) is widely used in the clinical evaluation of patients with IR. OBJECTIVES: A meta-analysis, including randomized controlled trials (RCTs), was performed to assess the effect of L-carnitine on HOMA-IR patients. MATERIAL AND METHODS: The Cochrane Library, PubMed, and EMBASE databases were systematically searched to identify RCTs which evaluated the effects of L-carnitine on HOMA-IR patients. We screened relevant studies according to predefined inclusion and exclusion criteria. In the selected articles, we extracted the data: study design, sample size, age, L-carnitine dose and regimen, body mass index (BMI) of patients, mode of administration, study duration and study outcomes. RESULTS: A total of 5 studies were included for the meta-analysis. The result showed L-carnitine was useful in the treatment of IR (WMD -0.724, CI -0.959 -0.488, p < 0.0001). Evaluation at 3, 6, 9, 12 months, the p-values were 0.875, 0.165, 0.031, 0, 007, respectively. CONCLUSIONS: L-carnitine was useful in treating patients with IR. L-carnitine can treat IR more effectively with prolonging the medication time. However, more RCTs with long-term L-carnitine treatment of IR are needed to confirm the viewpoint.

Berberine Reverses Hypoxia-induced Chemoresistance in Breast Cancer through the Inhibition of AMPK- HIF-1α.

Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. Chemoresistance is common and inevitable after a variable period of time. Therefore, chemosensitization is a necessary strategy on drug-resistant breast cancer. In this study, MCF-7 breast cancer cell was cultured under hypoxia for a week to induce the resistance to doxorubincin (DOX). The effect of different doses of berberine, a traditional Chinese medicine, on DOX sensitivity to MFC-7/hypoxia cells was observed. We found that hypoxia increased DOX resistance on breast cancer cells with the AMPK activation. Low-dose berberine could resensitize DOX chemosensitivity in MCF-7/hypoxia cell, however, high-dose berberine directly induced apoptosis. The intriguing fact was that the protein expressions of AMPK and HIF-1α were down-regulated by berberine, either low dose or high dose. But the downstream of HIF-1α occurred the bifurcation dependent on the dosage of berberine: AMPK-HIF-1α-P-gp inactivation played a crucial role on the DOX chemosensitivity of low-dose berberine, while AMPK-HIF-1α downregulaton inducing p53 activation led to apoptosis in high-dose berberine. These results were consistent to the transplanted mice model bearing MCF-7 drug-resistance tumor treated by berberine combined with DOX or high-dose berberine alone. This work shed light on a potentially therapeutic attempt to overcome drug-resistant breast cancer.

High FAK combined with low JWA expression: clinical prognostic and predictive role for adjuvant fluorouracil-leucovorin-oxaliplatin treatment in resectable gastric cancer patients.

BACKGROUND: The multifunctional protein JWA was previously identified as a novel regulator of focal adhesion kinase (FAK/PTK2) in suppressing cancer cell adhesion, invasion and metastasis. JWA is downregulated in gastric cancer (GC) and a prognostic and predictive biomarker for resectable GC. However, the value of FAK combined with JWA for GC patients as a biomarker has not been studied. Here we evaluated the roles of FAK alone and combined with JWA in GC patients treated with surgery alone or combined with adjuvant platinum-based chemotherapy. METHODS: Two tissue microarrays were constructed of specimens from resected GC (n = 709 in total) for detection of FAK and JWA expression by immunohistochemistry. Correlations between both proteins and clinicopathological features as well as prognostic and predictive values were evaluated. RESULTS: Compared with adjacent non-cancerous tissues, FAK protein levels were remarkably up-regulated in GC lesions (P < 0.001). High FAK alone or combined with low JWA expression significantly correlated with worse overall survival (OS) (both P < 0.001 in two cohorts). Simultaneously, JWA plus FAK expression was a more valuable prognostic biomarker than JWA or FAK alone. Moreover, the patients with high FAK only or combined with low JWA had significant benefit from adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) therapy compared with those with surgery alone (P = 0.003); however, the cases with adjuvant fluorouracil-leucovorin-cisplatin (FLP) therapy did not show these effects. CONCLUSION: FAK plus JWA may serve as a more prognostic and predictive biomarker for GC than each separately with a potential clinical application.

MDM2 is a useful prognostic biomarker for resectable gastric cancer.

Expression of MDM2 protein appears to be increased in malignancy and correlated to prognosis of tumors, but its role in gastric cancer remains controversial. Our recent investigations indicated that JWA was a novel candidate biomarker for gastric cancer. To evaluate the impact of MDM2 protein expression alone, and in combination with JWA, on the prognostic and predictive of patients with resectable gastric cancer, expression of MDM2 and JWA were examined by immunohistochemistry in three large cohorts (total n = 1131) of patient with gastric cancer. We found that MDM2 protein levels were significantly upregulated in gastric cancer (70.4%, 57 of 81) compared with adjacent non-cancerous tissues. High tumoral MDM2 expression significantly correlated with clinicopathologic characteristics, as well as with shorter overall survival (OS; P < 0.001 for all cohorts) in patients without adjuvant treatment. The effect of adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) in improving OS compared with surgery alone was evident only in the high MDM2 group (hazard ratio = 0.57; 95% confidence interval, 0.37-0.89; P = 0.013). Furthermore, knockdown of MDM2 and overexpression of JWA had a synergistic effect on suppression of gastric cancer cell proliferation and migration. Patients with low MDM2 and high JWA expression had a better outcome of survival compared with the other groups (P < 0.001 for all cohorts). For the first time, our data suggest that MDM2 is a potent prognostic and predictive factor for benefit from adjuvant fluorouracil-leucovorin-oxaliplatin chemotherapy in resectable gastric cancer. The combination of MDM2 expression and JWA could serve as a more effective candidate prognostic biomarker for gastric cancer.

Prognostic and predictive role of JWA and XRCC1 expressions in gastric cancer.

PURPOSE: To investigate the expression pattern and significance of DNA repair genes JWA and X-ray repair cross complement group 1 (XRCC1) in gastric cancer. EXPERIMENTAL DESIGN: Expressions of JWA and XRCC1 were assessed by immunohistochemistry in a training cohort and they went into a second testing cohort and finally to a validating cohort. Prognostic and predictive role of JWA and XRCC1 expression status in cases treated with surgery alone or combined with adjuvant chemotherapy was evaluated, respectively. RESULTS: JWA and XRCC1 protein levels were significantly downregulated in gastric cancer lesions compared with adjacent noncancerous tissues. Low tumoral JWA or XRCC1 expression significantly correlated with shorter overall survival (OS), as well as with clinicopathologic characteristics in patients without adjuvant treatment. Multivariate regression analysis showed that low JWA and XRCC1 expressions, separately and together, were independent negative markers of OS. Adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) significantly improved OS compared with surgery alone (log-rank test, P = 0.01). However, this effect was evident only in the JWA or XRCC1 low expression group (HR = 0.44; 95% CI: 0.26-0.73; P = 0.002, and HR = 0.44, 95% CI: 0.26-0.75; P = 0.002, respectively); Adjuvant fluorouracil-leucovorin-platinol (FLP) did not improve OS, except in the patients with low JWA and XRCC1 expressions (P = 0.010 for JWA and 0.024 for XRCC1, respectively). CONCLUSIONS: JWA and XRCC1 protein expressions in tumor are novel candidate prognostic markers and predictive factors for benefit from adjuvant platinum-based chemotherapy (FLO or FLP) in resectable human gastric carcinoma.