Radiotherapy opens the blood-brain barrier and synergizes with anlotinib in treating glioblastoma.

BACKGROUND: Glioblastoma (GBM) has a poor prognosis and lacks effective treatment. Anlotinib is a multitargeted receptor tyrosine kinase inhibitor (TKI) that may have anti-tumor activity in the central nervous system (CNS). This study aimed to determine the therapeutic value of radiotherapy combined with anlotinib in GBM via preclinical research. METHODS: HPLC-MS/MS was used to assess the concentration of anlotinib in blood and brain samples. Cell proliferation assays, flow cytometry, and colony formation assays were performed in vitro. The potential value of anlotinib or in combination with radiotherapy for GBM treatment was estimated in vivo. Western blotting, immunohistochemistry, and immunofluorescent staining were performed to determine the underlying mechanism. RESULTS: Anlotinib effectively inactivated the JAK3/STAT3 pathway to inhibit growth and induce apoptosis in malignant glioma cells (MGCs) independent of MGMT expression. Meanwhile, anlotinib induces MGCs G2/M arrest and sensitizes MGCs to radiation. Radiation down-regulates claudin-5 and weakens the blood-brain barrier (BBB), which contributes to the increased distribution of anlotinib in the CNS by 1.0-2.9 times. Anlotinib restrains tumor growth (PCNA), inhibits tumor microvascular proliferation (CD31), and alleviated intratumor hypoxia (HIF 1α) in vivo. Anlotinib alone or in combination with radiation is effective and safe in vivo evaluation. CONCLUSIONS: We discovered that anlotinib, the original small molecule antiangiogenesis TKI, down-regulates JAK3/STAT3 axis with anti-cancer activity alone or in combination with radiation. Anlotinib combined with radiotherapy might be a promising treatment for newly diagnosed GBM in the clinic.

Acute Effects of Intravenous Sub-Anesthetic Doses of Ketamine and Intranasal Inhaled Esketamine on Suicidal Ideation: A Systematic Review and Meta-Analysis.

Purpose: Suicide is a major public health concern with currently no validated and efficacious treatments approved. Preliminary evidence suggests that intravenous ketamine has rapid and sustained antidepressant effects, making it a candidate with therapeutic potential for depressed patients at risk for suicide. We conducted a meta-analysis to evaluate the efficacy of ketamine and esketamine in reducing suicidal ideation (SI), as well as their respective onset and duration of action. Data Sources: We searched PubMed, Embase, Ovid, Cochrane, and Web of Science databases for studies published from inception to September 29, 2022. Study Eligibility Criteria: We conducted a systematic review of all parallel randomized controlled trials (RCTs) examining the effect and duration of ketamine or esketamine on SI. Our primary outcome measure was the Suicide Scale score, which was measured using the Scale for Suicidal Ideation (SSI), Beck Scale for Suicide Ideation (BSS), Beck Depression Inventory (BDI), or Modified Scale for Suicidal Ideation (MSSI). To obtain effect sizes (Cohen's d), we calculated the difference in Suicide Scale scores before and after administration in each group. Results: Our study showed that intravenous sub-anesthetic doses of ketamine and intranasal inhaled esketamine had a significant anti-SI effect. Specifically, ketamine produced a large degree of anti-SI effect within the 4-6 hours (Cohen's d = 1.16, 95% CI: 0.50, 1.81) and a medium-large degree in the 24 hours (Cohen's d = 0.95, 95% CI: 0.48, 1.41). Esketamine, on the other hand, produced a small-medium degree of anti-SI effect within the 4-6 hours timeframe (Cohen's d = 0.26, 95% CI: 0.09, 0.44) and the 24 hours (Cohen's d = 0.30, 95% CI: 0.17, 0.47). Conclusion: Intravenous sub-anesthetic doses of ketamine and intranasal inhaled esketamine could reduce SI within 4 hours and last for 24 hours.

The role of AMPK-Sirt1-autophagy pathway in the intestinal protection process by propofol against regional ischemia/reperfusion injury in rats.

Intestinal ischemia/reperfusion (II/R) is a clinical event associated with high morbidity and mortality. AMP-activated protein kinase (AMPK), a central cellular energy sensor, is associated with oxidative stress and inflammation. However, whether the AMPK is involved in the II/R-induced intestinal injury and the underlying mechanism is yet to be elucidated. Propofol has a protective effect on organs; yet, its specific mechanism of action remains unclear. This study explored the role of the AMPK-Sirt1-autophagy pathway in intestinal injury, and whether propofol could reduce intestinal injury and investigated the mechanisms in a rat model of II/R injury as well as a cell model (IEC-6 cells) of hypoxia/reoxygenation (H/R). Propofol, AMPK agonist (AICAR) and AMPK inhibitor (Compound C) were then administered, respectively. The histopathological changes, cell viability and apoptosis were detected. Furthermore, the levels of proinflammatory factors, the activities of oxidative stress, diamine oxidase, and signaling pathway were also analyzed. The results demonstrated that the AMPK-Sirt1-autophagy pathway of intestine was activated after II/R or H/R. Propofol could further activate the pathway, which reduced intestinal injury, inhibited apoptosis, reversed inflammation and oxidative stress, and improved the 24-hour survival rate in II/R rats in vivo, and attenuated H/R-induced IEC-6 cell injury, oxidative stress, and apoptosis in vitro, as fine as changes in AICAR treatment. Compound C abrogated the protective effect of propofol on II/R and H/R-induced injury. These results suggested a crucial effect of AMPK on the mechanism of intestinal injury and might provide a new insight into the mechanism of propofol reducing II/R injury.

Activation of LRP1 Ameliorates Cerebral Ischemia/Reperfusion Injury and Cognitive Decline by Suppressing Neuroinflammation and Oxidative Stress through TXNIP/NLRP3 Signaling Pathway in Mice.

Cerebral ischemia/reperfusion (I/R) injury is a clinical event associated with high morbidity and mortality. Neuroinflammation plays a crucial role in the pathogenesis of I/R-induced brain injury and cognitive decline. Low-density lipoprotein receptor-related protein-1 (LRP1) can exert strong neuroprotection in experimental intracerebral hemorrhage. However, whether LRP1 can confer neuroprotective effects after cerebral I/R is yet to be elucidated. The present study is aimed at investigating the effects of LRP1 activation on cerebral I/R injury and deducing the underlying mechanism involving TXNIP/NLRP3 signaling pathway. Cerebral I/R injury was induced in mice by bilateral common carotid artery occlusion. LPR1 ligand, apoE-mimic peptide COG1410, was administered intraperitoneally. To elucidate the underlying mechanism, overexpression of TXNIP was achieved via the hippocampal injection of AAV-TXNIP before COG1410 treatment. Neurobehavioral tests, brain water content, immunofluorescence, Western blot, enzyme-linked immunosorbent assay, HE, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. Our results showed that the expressions of endogenous LRP1, TXNIP, NLRP3, procaspase-1, and cleaved caspase-1 were increased after cerebral I/R. COG1410 significantly ameliorated cerebral I/R-induced neurobehavioral deficits, brain edema, histopathological damage, and poor survival rate. Interestingly, COG1410 inhibited microglia proinflammatory polarization and promoted anti-inflammatory polarization, decreased oxidative stress, attenuated apoptosis, and inhibited the expression of the TXNIP/NLRP3 signaling pathway. However, the benefits of COG1410 were abolished by TXNIP overexpression. Thus, our study suggested that LRP1 activation with COG1410 attenuated cerebral I/R injury at least partially related to modulating microglial polarization through TXNIP/NLRP3 signaling pathway in mice. Thus, COG1410 treatment might serve as a promising therapeutic approach in the management of cerebral I/R patients.

Thioredoxin-Interacting Protein (TXNIP) Knockdown Protects against Sepsis-Induced Brain Injury and Cognitive Decline in Mice by Suppressing Oxidative Stress and Neuroinflammation.

Sepsis-associated encephalopathy (SAE) is linked to increased morbidity and mortality rates in patients with sepsis. Increased cytokine production and neuronal apoptosis are implicated in the pathogenesis of the SAE. Neuroinflammation plays a major role in sepsis-induced brain injury. Thioredoxin-interacting protein (TXNIP), an inhibitor of thioredoxin, is associated with oxidative stress and inflammation. However, whether the TXNIP is involved in the sepsis-induced brain injury and the underlying mechanism is yet to be elucidated. Therefore, the present study was aimed at elucidating the effects of TXNIP knockdown on sepsis-induced brain injury and cognitive decline in mice. Lipopolysaccharide (LPS) was injected intraperitoneally to induce sepsis brain injury in mice. The virus-carrying control or TXNIP shRNA was injected into the lateral ventricle of the brain 4 weeks before the LPS treatment. The histological changes in the hippocampal tissues, encephaledema, and cognitive function were detected, respectively. Also, the 7-day survival rate was recorded. Furthermore, the alterations in microglial activity, oxidative response, proinflammatory factors, apoptosis, protein levels (TXNIP and NLRP3 inflammasome), and apoptosis were examined in the hippocampal tissues. The results demonstrated that the TXNIP and NLRP3 inflammasome expression levels were increased at 6, 12, and 24 h post-LPS injection. TXNIP knockdown dramatically ameliorated the 7-day survival rate, cognitive decline, brain damage, neuronal apoptosis, and the brain water content, inhibited the activation of microglia, downregulated the NLRP3/caspase-1 signaling pathway, and reduced the oxidative stress and the neuroinflammatory cytokine levels at 24 h post-LPS injection. These results suggested a crucial effect of TXNIP knockdown on the mechanism of brain injury and cognitive decline in sepsis mice via suppressing oxidative stress and neuroinflammation. Thus, TXNIP might be a potential therapeutic target for SAE patients.

Dexmedetomidine alleviates neuroinflammation, restores sleep disorders and neurobehavioral abnormalities in rats with minimal hepatic encephalopathy.

The occurrence and progress of minimal hepatic encephalopathy (MHE) is closely related to the inflammatory response; however, inflammation contributes to behavioral abnormalities and sleep disorders. Dexmedetomidine has anti-inflammatory effects against various diseases. Whether dexmedetomidine improves MHE and the underlying mechanism is yet unclear. The present study aimed to explore the effects of dexmedetomidine on sleep structure, neurobehavior, and brain morphology of MHE rats and investigate its underlying mechanism. A rat MHE model was established by intraperitoneal injection of thioacetamide (TAA). Dexmedetomidine or yohimbine was administered intraperitoneally to investigate the role of α2 adrenoreceptor in the protection conferred by dexmedetomidine. The 24-h sleep, neurobehavioral changes, the liver function, blood ammonia and morphological changes of the liver and brain were assessed. Also, the microglia, astrocytes, neurons, the expression of pro-inflammatory factors (IL-1ß, TNF-α, IL-18), and NLRP3 inflammasomes were detected. The results showed that marked sleep disorders, cognitive impairment, anxiety, abnormal liver function and pathological damage of liver and brain were detected in the MHE rats. The microglia in the prefrontal cortex was highly activated along with the increased expression of pro-inflammatory factors and NLRP3 inflammasomes. Interestingly, dexmedetomidine improved above indicators, however, yohimbine significantly abolished the protection of dexmedetomidine. These findings showed that dexmedetomidine restored the changes in the sleep disorders and neurobehavior in rats and reduced brain damage. The mechanism might be partially related to the activation of α2 adrenergic receptors, reduction of neuroinflammatory response, and inhibition of the activation of microglia and NLRP3/Caspase1 signaling pathway.

Melatonin alleviates intestinal injury, neuroinflammation and cognitive dysfunction caused by intestinal ischemia/reperfusion.

Intestinal ischemia/reperfusion (I/R) can cause multiple organ damage with extremely high morbidity and mortality. Melatonin has anti-inflammatory, anti-oxidative and anti-apoptotic effects against various diseases. This study aimed to explore whether melatonin had a protective effect against intestinal I/R-induced neuroinflammation and cognitive dysfunction, and investigate its potential mechanisms. In this study, melatonin was administered to the rats with intestinal I/R, then histological changes in intestine and brain (frontal cortex and hippocampal CA1 area) tissues and cognitive function were detected, respectively. The encephaledema and blood-brain barrier (BBB) permeability were observed. Moreover, the alterations of proinflammatory factors (tumor necrosis factor-α, interleukin-6 and interleukin-1ß), oxidative response (malondialdehyde, superoxide dismutase, and reactive oxygen species), apoptosis and proteins associated with inflammation,including Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and phosphorylated nuclear factor kappa beta (NF-κB), and apoptosis (cleaved caspase-3) in brain tissues were examined. Furthermore, the expressions of TLR4, Myd88, and microglial activity were observed by multiple immunofluorescence staining. The results showed that intestinal I/R-induced abnormal neurobehavior and cerebral damage were ameliorated after melatonin treatment, which were demonstrated by improved cognitive dysfunction and aggravated histology. Furthermore, melatonin decreased the levels of proinflammatory factors and oxidative stress in plasma, intestine and brain tissues, attenuated apoptotic cell, and inhibited the expressions of related proteins and the immunoreactivity of TLR4 or Myd88 in microglia in brain tissues. These findings showed that melatonin might relieve neuroinflammation and cognitive dysfunction caused by intestinal I/R, which could be, at least partially, related to the inhibition of the TLR4/Myd88 signaling in microglia.

Circulating guanylyl cyclase C (GCC) mRNA is a reliable metastatic predictor and prognostic index of colorectal cancer.

BACKGROUND: Currently, few specific biomarkers or standard cutoff values are available for circulating tumor cells (CTCs) detection and survival prediction in patients with early stage colorectal cancer (CRC). Guanylyl cyclase C (GCC) presents as a specific expression in intestinal tumor cells and during their metastases, indicating its potential application as a metastatic predictor of CRC. METHODS: The circulating GCC mRNA of 160 colorectal cancer patients at stage I-III was detected via quantitative real-time (qRT)-PCR in our study, and the correlation of GCC mRNA level with tumor metastasis and long-term survival was explored. RESULTS: GCC mRNA was found to be positive in 43 out of 160 CRC patients and negative in ten healthy controls. It was found that GCC mRNA over the baseline (>100 copies/µL and 200 copies/µL) showed a significant correlation with disease-free survival (DFS) and overall survival (OS) in the stage II subgroup. It was further revealed that GCC mRNA over 300 copies/µL or higher than the median value of copy numbers was significantly correlated with reduced OS and DFS in CRC patients. A nomogram model based on variables including GCC mRNA copy number was established for predicting the OS of CRC patients (AUC =0.98). CONCLUSIONS: Circulating GCC mRNA over baseline is a reliable predictor for tumor metastasis and can be a prognostic index in CRC patients.

Downregulation of LINC00515 in high-grade serous ovarian cancer and its relationship with platinum resistance.

Aim: To investigate the expression of long intergenic noncoding RNA 00515 (LINC00515) in high-grade serous ovarian cancer (HGSOC) and its potential correlation with platinum resistance. Patients & methods: Expression of LINC00515 in HGSOC (n = 115) and normal (n = 19) tissues was detected via quantitative real-time PCR (qRT-PCR). We further explored the statistical significance of the relationship between LINC00515 expression and platinum resistance in HGSOC. Results: LINC00515 was gradually downregulated in the order of normal > platinum-sensitive > platinum-resistant tissue (p < 0.05). Results demonstrated that LINC00515 downregulation was correlated with platinum resistance and relapse-free survival (RFS) of HGSOC (p < 0.05). Conclusion: LINC00515 downregulation is correlated with HGSOC development, platinum resistance and RFS, supporting its utility as a potential biomarker to predict platinum resistance and prognosis of RFS.

Prefrontal cortex miR-29b-3p plays a key role in the antidepressant-like effect of ketamine in rats.

Ketamine has a rapid, obvious, and persistent antidepressant effect, but its underlying molecular mechanisms remain unknown. Recently, microRNAs (miRNAs) have emerged as important modulators of ketamine's antidepressant effect. We investigated the alteration in miR-29b-3p in the brain of rats subjected to ketamine administration and chronic unpredictable mild stress (CUMS), and a sucrose preference test and forced swimming test were used to evaluate the rats' depressive-like state. We used recombination adeno-associated virus (rAAV) or lentivirus-expressing miR-29b-3p to observe the change in metabotropic glutamate receptor 4 (GRM4). Cell culture and electrophysiological recordings were used to evaluate the function of miR-29b-3p. Ketamine dramatically increased miR-29b-3p expression in the prefrontal cortex of the normal rats. The dual luciferase reporter test confirmed that GRM4 was the target of miR-29b-3p. The miR-29b-3p levels were downregulated, while the GRM4 levels were upregulated in the prefrontal cortex of the depressive-like rats. The ketamine treatment increased miR-29b-3p expression and decreased GRM4 expression in the prefrontal cortex of the depressive-like rats and primary neurons. By overexpressing and silencing miR-29b-3p, we further validated that miR-29b-3p could negatively regulate GRM4. The silencing of miR-29b-3p suppressed the Ca2+ influx in the prefrontal cortex neurons. The miR-29b-3p overexpression contributed to cell survival, cytodendrite growth, increases in extracellular glutamate concentration, and cell apoptosis inhibition. The overexpression of miR-29b-3p by rAAV resulted in a noticeable relief of the depressive behaviors of the CUMS rats and a lower expression of GRM4. The miR-29b-3p/GRM4 pathway acts as a critical mediator of ketamine's antidepressant effect in depressive-like rats and could be considered a potential therapeutic target for treating major depression disorder.

Myricetin induces apoptosis and enhances chemosensitivity in ovarian cancer cells.

Ovarian cancer is the most lethal type of gynecological cancer and is the fifth leading cause of cancer-associated mortality in females globally. The majority of patients with ovarian cancer suffer from recurrent, progressive disease, due to the acquisition of a resistance phenotype towards various conventional chemotherapy drugs. Although paclitaxel has been demonstrated to be effective against ovarian tumors, there have been reports of the development of a resistant phenotype against Taxol® treatment. The multidrug resistance (MDR)-1/P-glycoprotein has previously been demonstrated to be associated with the acquisition of paclitaxel resistance in certain ovarian tumors. Therefore, the screening of novel drug candidates able to target MDR-1 in ovarian cancer cells and increase the sensitivity to Taxol® is required in order to improve the treatment of this disease. In the present study, the underlying mechanisms by which the dietary flavonoid myricetin enhances the cytotoxic potential of paclitaxel in ovarian cancer cells, was investigated. It was observed that myricetin induced significant cytotoxicity in A2780 and OVCAR3 ovarian cancer cells, with the IC50 value obtained at 25 µM. Myricetin treatment also resulted in the induction of apoptosis in the two cell lines, accompanied by the modulation of certain pro- and anti-apoptotic markers. It was also determined that the pre-incubation of ovarian cancer cells with a lower dose of myricetin was able to increase the cytotoxicity of paclitaxel, due to the significant downregulation of MDR-1 in these cells.

Paris Saponins enhance radiosensitivity in a gefitinib-resistant lung adenocarcinoma cell line by inducing apoptosis and G2/M cell cycle phase arrest.

Acquired resistance to epidermal growth factor inhibitors has been reported to be associated with cross­resistance to radiation. Paris Saponins (PSs) exert a wide range of pharmacological activities, including cell apoptosis induction, multidrug resistance inhibition, angiogenesis inhibition and tumor cell migration by modulating various signaling pathways. The present study aimed to investigate the radiosensitization effects of PSII, PSVI and PSVII in a gefitinib­resistant PC­9­ZD lung adenocarcinoma cell line, and the possible mechanism underlying their function. A clonogenic assay was performed to determine the effects of PS radiosensitization on the PC­9­ZD cell line. The cell cycle was analyzed by flow cytometry, and cell apoptosis was analyzed with Annexin V/propidium iodide and Hoechst staining. Protein expression levels were detected by western blotting. The results of the present study revealed a significant increase in PC­9­ZD cell line radiosensitivity following treatment with PSs. PSs induced G2/M cell cycle phase arrest and apoptosis of the irradiated PC­9­ZD cells. Notably, the expression levels of B cell lymphoma 2 (Bcl­2) were downregulated, and those of caspase­3, Bcl­2­associated X protein (Bax) and p21/Waf1/Cip1 were upregulated following treatment with PSs. The present results demonstrated that PSs induced radiosensitivity in gefitinib­resistant cells by inducing G2/M phase arrest and by enhancing the apoptotic response via the modulation of caspase­3, Bax, Bcl­2 and p21/Waf1/Cip1 expression.

The genotype of ribonucleotidereductase M1 -269C > A is associated with the response to platinum-based chemotherapy and as a prognostic biomarker in advanced nonsmall cell lung cancer.

PURPOSE: Genetic polymorphisms of ribonucleotidereductase M1 (RRM1) was a DNA repair gene, which may affect patients' response to platinum-based chemotherapy or gemcitabine-based chemotherapy. We retrospectively assessed whether single nucleotide polymorphisms (SNPs) of RRM1 can be used to predict overall survival (OS), progression free survival and response in nonsmall cell lung cancer (NSCLC) patients treated with platinum-based regimens as first-line chemotherapy. SUBJECTS AND METHODS: The genotypes of four tagSNPs (RRM1 -316C > A, RRM1 -269C > A, RRM1 -702G > A and RRM1 -585T > G) were determined by SNaPshot detection technology and sequencing approaches in 184 advanced NSCLC patients by using peripheral blood. RESULTS: The overall response rate for 178 patients was 40.2% and the disease control rate was 90.2%. In patients who had ever smoked, a significant correlation was observed between the genotype of RRM1 -269C > A and response (P = 0.046). There was a significant difference in response according to the genotype of RRM1 -702G > A (P = 0.043). Using Log-rank test, we found that patients with the allelotype (CC) of RRM1 -269C > A had a shorter OS (P = 0.006) than the allelotype (CA + AA). CONCLUSION: The genotype of RRM1 -269C > A was significantly associated with platinum-based chemotherapy sensitivity in smoking patients and can be used to predict OS in advanced NSCLC patients who received platinum-based chemotherapy or gemcitabine-based chemotherapy. And the genotype of RRM1 -702G > A can serve as a biomarker for chemotherapy sensitivity in advanced NSCLC patients.

Establishment and characterization of GCSR1, a multi-drug resistant signet ring cell gastric cancer cell line.

Signet ring cell gastric cancer (SRCGC) has very poor prognosis worldwide, and studying its molecular characteristics is urgent for improving the outcome. However, few well-characterized SRCGC cell lines are available for research. Therefore, we established a novel cell line GCSR1, from a Chinese male SRCGC patient. Cell morphology of GCSR1 in culture, maintained in vitro for over 90 passages, is similar to the cells from the patient. GCSR1 cells proliferated in vitro with a doubling time of 67.65 h. Karyotyping showed they were aneuploid. Missense mutation occurred in codon 193 of P53 and deletion occurred in exons 1 and 3 of P16. Results of CCK8 assay revealed that GCSR1 was more resistant to 5-fluorouracil (5-FU) and mitomycin (MMC) than other gastric cancer cell lines. Stem cell marker assay by flow cytometry showed that GCSR1 had high proportion of CD44+ and/or CD133+ cells. It formed colonies easily in soft agar and generated xenograft tumors in nude mice. In conclusion, GCSR1 is a well-established, well-characterized multi-drug resistant cell line with abundant cancer stem cells.

The molecular mechanisms of Tanshinone IIA on the apoptosis and arrest of human esophageal carcinoma cells.

OBJECTIVE: To explore the possible mechanisms of Tanshinone IIA (TanIIA) on esophageal carcinoma cell lines. METHODS: Two human esophageal carcinoma cell lines (EC-1 cells and ECa-109 cells) were treated with different concentrations of TanIIA. Cell proliferation was measured by CCK-8, colony-forming efficiency was calculated, cell cycle and apoptosis were measured, and changes in cell cycle- and apoptosis-related gene expression were measured by Western blotting. RESULTS: The CCK-8 and colony formation assay indicated that TanIIA inhibited the cell proliferation of human esophageal cancer cells (IC50 below 1 µg/mL) at 48 h. Hoechst 33258 and flow cytometry showed that TanIIA induced apoptosis in both esophageal cancer cell lines. Flow cytometry showed that TanIIA arrested cell cycle in S phase and G2/M phase. Western blotting analysis showed that Akt1 and its phosphorylation were inhibited, the Bax/Bcl-2 ratio increased, and both caspase-9 and caspase-3 were activated after treatment with 1.3 µg/mL TanIIA at 48 h. Meanwhile, p53 and p21 protein levels increased, whereas cyclin B1, CDC2, and CDC2 phosphorylation were inhibited. CONCLUSION: TanIIA inhibits the growth of esophageal cancer cells and induces apoptosis in a time-dependent and concentration-dependent manner, possibly by affecting cell cycle- and apoptosis-related signaling pathways.

The impact of functional LIG4 polymorphism on platinum-based chemotherapy response and survival in non-small cell lung cancer.

DNA repair capacity is correlated with the sensitivity of cancer cells toward platinum-based chemotherapy. The aim of this study was to investigate whether single-nucleotide polymorphisms (SNPs) in DNA repair genes NBS1, LIG4, and RAD51 were correlated with tumor response in advanced non-small cell lung cancer (NSCLC) patients in a Chinese population who received platinum-based chemotherapy. The treatment outcomes of 146 advanced NSCLC patients who were treated with platinum-based chemotherapy were evaluated. The polymorphic status of three SNPs was determined by genotyping via the polymerase chain reaction-restriction fragment length polymorphism method. Forty-five patients in the group with the CC genotype (45/90) showed a good response to treatment, while only 18 patients in the CT+TT group (18/55) showed a good response, indicating a substantial differences in the chemotherapy response rate based on the LIG4 Thr9Ile polymorphism (P = 0.042). Patients with the GG genotype for the NSB1 Glu185Gln polymorphism were more sensitive to platinum-based chemotherapy compared with patients with either the CG or CC genotype (P = 0.001). Kaplan-Meier analysis of all patients showed a significant association between the LIG4 Thr9Ile CC polymorphism and superior progression-free survival and overall survival (log-rank P = 0.045 and 0.031, respectively). However, there were no significant differences in survival based on the LIG4 Thr9Ile or the RAD51 135G>C polymorphisms. Polymorphisms in the NSB1 and LIG4 genes may be a predictive marker for treatment response and for advanced NSCLC patients in stage IIIB + IV. The CC genotype of the LIG4 Thr9Ile polymorphism may also serve as an independent prognosis factor.