Search

Background: Cancer recurrence following surgical resection is a major cause of treatment failure. Finding effective methods to prevent postoperative recurrence and wound infection is an important component of successful surgery. With the development of new nanotechnology, more treatment options have been provided for postoperative adjuvant therapy. This study presents an innovative hydrogel system that stimulates tumoricidal immunity after surgical resection of non-small cell lung cancer (NSCLC) and prevents cancer relapse., Results: The hydrogel system is based on the excellent photothermal conversion performance of single-atom platinum (CN-Pt) along with the delivery and release of the chemotherapy drug, gemcitabine (GEM). The system is coated onto the wound surface after tumor removal with subsequent near-infrared (NIR) photothermal therapy, which efficiently induces necroptosis of residual cancer cells, amplifies the levels of damage-associated molecular patterns (DAMPs), and increases the number of M1 macrophages. The significantly higher levels of phagocytic macrophages enhance tumor immunogenicity and sensitize cancer cells to CD8 + T-cell immunity to control postoperative recurrence, which has been verified using an animal model of postoperative lung cancer recurrence. The CN-Pt-GEM-hydrogel with NIR can also inhibit postoperative wound infection., Conclusions: These findings introduce an alternative strategy for supplementing antitumor immunity in patients undergoing resection of NSCLC tumors. The CN-Pt-GEM-hydrogel with the NIR system also exhibits good biosafety and may be adaptable for clinical application in relation to tumor resection surgery, wound tissue filling, infection prevention, and recurrence prevention., (© 2024. The Author(s).)

NRF2 (NFE2L2) is a transcription factor mainly for regulating cellular antioxidant response and therefore promotes tumor progression. The target genes of NRF2 also play important roles in cellular processes including glucose metabolism, de novo serine synthesis, iron metabolism, etc. Here, by modulating NRF2 expression in lung adenocarcinoma (LUAD) cells, we showed that NRF2 regulated EGF expression at protein level. Furthermore, EGF was identified as a ubiquitinated protein. We predicted three deubiquitinases of EGF, and OTUD4 had the highest correlation with NRF2 in LUAD among the three. OTUD4 expression was reduced upon NRF2 knocking-down and recovered upon NRF2 rescuing in A549 cells. Then a potential binding site for NRF2 in OTUD4 promoter was searched out. By binding with OTUD4 promoter, NRF2 transcriptionally activated OTUD4, thus promoted EGF deubiquitination and enhanced its stability. More importantly, OTUD4 and NRF2 expression was found being correlated in LUAD patients. The data collectively revealed a novel mechanism of NRF2 regulating on EGF stability through OTUD4 in LUAD., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the prognostic impact of initial lung cancer (LC) on second primary breast cancer after LC (LC-BC) and further develop a nomogram for predicting the survival of patients., Methods: All patients diagnosed with LC-BC and first primary BC (BC-1) during 2000-2017 were collected from Surveillance, Epidemiology, and End Results database. Pathological features, treatment strategies and survival outcomes were compared between LC-BC and BC-1 before and after propensity score matching (PSM). Cox regression analysis was performed to identify the prognostic factors associated with LC in patients with LC-BC. Additionally, least absolute shrinkage and selection operator regression analysis was used to select clinical characteristics for nomogram construction, which were subsequently evaluated using the concordance index (C-index), calibration curve and decision curve analysis (DCA)., Results: 827 429 patients with BC-1 and 1445 patients with LC-BC were included in the analysis. Before and after PSM, patients with BC-1 had a better prognosis than individuals with LC-BC in terms of both overall survival (OS) and breast cancer-specific survival (BCSS). Furthermore, characteristics such as more regional lymph node dissection, earlier stage and the lack of chemotherapy and radiation for LC were found to have a stronger predictive influence on LC-BC. The C-index values (OS, 0.748; BCSS, 0.818), calibration curves and DCA consistently demonstrated excellent predictive accuracy of the nomogram., Conclusion: In conclusion, patients with LC-BC have a poorer prognosis than those with BC-1, and LC traits can assist clinicians estimate survival of patients with LC-BC more accurately., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aimed to investigate the relationship between complete pathological remission (PCR), tertiary lymphoid structure (TLS) maturation and expression and clinical outcomes of patients with resectable non-small cell lung cancer (NSCLC) receiving neoadjuvant chemoimmunotherapy. Totally 80 patients with resectable NSCLC (stage IB-IIIB) receiving neoadjuvant chemoimmunotherapy were analyzed. We used the Kaplan-Meier method to plot survival curves and the log-rank test to compare differences. Among all patients included, 45 patients (56.25%) achieved major pathological response (MPR), including 30 patients (37.50%) with PCR. The proportion of patients diagnosed with stage IB, II, IIIA and IIIB was 1.25%, 10.00%, 52.50% and 36.25%, respectively. We divided patients into PCR group and non-PCR group respectively according to whether they achieved PCR. We found that patients achieving PCR had significantly improved disease-free survival (DFS) (mDFS: NR vs. 20.24 months, P  = .020). TLS expression was low in 43 cases (53.75%) and high in 37 cases (46.25%). TLS maturation was low in 55 cases (68.75%) and high in 25 cases (31.25%). The DFS of patients with TLS high-maturation (34.07 vs. 22.30 months, P  = .024) and TLS high-expression (34.07 vs. 22.30 months, P  = .041) was significantly longer. In most subgroups, the PCR, TLS high-maturation and TLS high-expression group respectively achieved a better clinical outcome relative to the non-PCR, TLS low-maturation and TLS low-expression group. In patients with resectable NSCLC receiving neoadjuvant chemoimmunotherapy, the acquirement of PCR may predict better DFS. In addition, high expression and maturation of TLS may be prognostic factors.

Background: Whether patients with advanced non-small cell lung cancer (NSCLC) should choose an immune-combination therapy regimen after EGFR-tyrosine kinase inhibitors (EGFR-TKIs) resistance is currently unclear., Methods: We evaluated 118 NSCLC patients treated by immune checkpoint inhibitors (ICIs) + chemotherapy (I + C), ICIs + chemotherapy + antiangiogenic therapy (I + C + A), chemotherapy + antiangiogenic therapy (C + A) after inefficacy of EGFR-TKIs. We assessed the objective remission rate (ORR), disease control rate (DCR), and progression-free survival (PFS) of these treatments., Results: The ORR was 26.1% vs 38.2% vs 16.3% in the three groups (P = 0.093). The divergence in DCR was also statistically significant (65.2% vs 85.3% vs 74.4%, P = 0.209). The median PFS was no statistically significant difference in PFS (3.09 vs 6.31 vs 5.91 months, P = 0.809), but the Kaplan-Meier survival curve of 12-month-PFS indicated an apparent survival advantage in the I + C + A group (P = 0.001). In addition, the I + C/I + C + A group showed higher median PFS than the C + A group in patients with brain metastases (median PFS, 6.44 vs 4.21 months, P = 0.022). The divergence in ORR of patients in the brain group was also statistically significant (P = 0.045). The I + C + A group showed superior efficacy in patients with liver metastases (median PFS, 0.95 vs 6.44 vs 3.48 months, P < 0.0001). The Cox proportional hazard modeling analysis suggested that the age, brain metastases, and liver metastases were all connected with the prognosis., Conclusions: This study suggests that advanced NSCLC patients after resistance to EGFR-TKIs may achieve better outcomes from triple therapy. Patients with brain metastases favor ICIs-related combination therapies and patients with liver metastases prefer I + C + A therapy., (© 2023. The Author(s).)

Aims: The use of non-steroid anti-inflammatory drugs (NSAIDs) is conventional in management of postoperative pain in cancer patients, and further investigations have reported that some of these drugs correlated with the outcome in cancers. However, the prognostic value of the use of NSAIDs during surgery in non-small cell lung cancer (NSCLC) patients has been less addressed., Methods: NSCLC patients staged I-III are retrospectively enrolled, and the data of the use of NSAIDs during surgery are collected. Patients are divided into two subgroups according to the use intensity (UI) (low or high) of the NSAIDs, which was calculated by the accumulate dosage of all the NSAIDs divided by the length of hospitalization. The differences of the clinical features among these groups were checked. And the disease-free survival (DFS) and overall survival (OS) differences in these groups were compared by Kaplan-Meier analysis; risk factors for survival were validated by using a Cox proportional hazards model., Results: The UI was significant in predicting the DFS (AUC = 0.65, 95% CI: 0.57-0.73, P = 0.001) and OS (AUC = 0.70, 95% CI: 0.59-0.81, P = 0.001). Clinical features including type of resection (P = 0.001), N stages (P < 0.001), and TNM stages (P = 0.004) were significantly different in UI low (< 74.55 mg/day) or high (≥ 74.55 mg/day) subgroups. Patients in UI-high subgroups displayed significant superior DFS (log rank = 11.46, P = 0.001) and OS (log rank = 7.63, P = 0.006) than the UI-low ones. At last, the UI was found to be an independent risk factor for DFS (HR: 0.52, 95% CI: 0.28-0.95, P = 0.034)., Conclusions: The use of NSAIDs during radical resection in NSCLC patients correlated with the outcome and patients with a relative high UI has better outcome., (© 2023. The Author(s).)

Lung adenocarcinoma (LUAD) is the most common lung cancer, which accounts for about 35-40% of all lung cancer patients. Despite therapeutic advancements in recent years, the overall survival time of LUAD patients still remains poor, especially KRAS mutant LUAD. Therefore, it is necessary to further explore novel targets and drugs to improve the prognos is for LUAD. Ferroptosis, an iron-dependent regulated cell death (RCD) caused by lipid peroxidation, has attracted much attention recently as an alternative target for apoptosis in LUAD therapy. Ferroptosis has been found to be closely related to LUAD at every stage, including initiation, proliferation, and progression. In this review, we will provide a comprehensive overview of ferroptosis mechanisms, its regulation in LUAD, and the application of targeting ferroptosis for LUAD therapy.

Introduction: Lung cancer is one of primary cancer type with high incidence and mortality, non-small cell lung cancer (NSCLC) is the most common type of lung cncer. For advanced lung cancer, traditional chemotherapy and targeted therapy become difficult to solve the dilemma of further progress. In recent years, with the clinical application of immunotherapy, the therapeutic strategy of lung cancer has changed dramatically. At present, immunotherapy has shown conspicuous efficacy in NSCLC patients with high expression of programmed death-ligand 1 (PD-L1) and high tumor mutational burden (TMB). The discovery of driver mutations brings delightful hope for targeted cancer therapy. However, it remains controversial whether immunotherapy can be used in NSCLC patients with these specific driver mutations., Method: This article summarized the latest research progresses of immunotherapy in advanced NSCLC. We paid close attention to the relevance of various driver mutations and immunotherapy in NSCLC patients, and summarized the predictive effects of several driver mutations and immunotherapy., Results: The mutations of KRAS, KRAS+TP53, EPHA (especially EPHA5), ZFHX3, ZFHX3+TP53, NOTCH, BRAF and LRP1B+FAT3 have potential to be used as biomarkers to predict the positive effectiveness of immunotherapy. ZFHX3, ZFHX3+TP53, STKII/LKB1+KEAP1+SMARCA4+PBRM1 mutations in LUAD patients get more positive effect in immunotherapy. While the mutations of EGFR, KEAP1, STKII/LKB1+KRAS, EML4-ALK, MET exon 14 skipping mutation, PBRM1, STKII/LKB1+KEAP1+SMARCA4+PBRM1, ERBB2, PIK3CA and RET often indicate poor benefit from immunotherapy., Conclusion: Many gene mutations have been shown to be associated with immunotherapy efficacy. Gene mutations should be combined with PD-L1, TMB, etc. to predict the effect of immunotherapy., (© 2023. The Author(s).)

Lung cancer is the leading cause of cancer death, and non-small cell lung cancer (NSCLC) accounts for 85%. Immunotherapy has significantly improved the clinical prognosis of patients with NSCLC. However, because of the complexity and heterogeneousness of the tumor microenvironment, only a subset of individuals can benefit from immunotherapy. Therefore, it is necessary to explore effective predictive biomarkers for immunotherapy of NSCLC. Tertiary lymphoid structure (TLS) is an ectopic lymphoid organ that is highly similar to secondary lymphoid organs (SLO), and the presence of TLS has been found to be closely associated with a good prognosis in immunotherapy for a variety of solid tumors, including NSCLC. This article provides a review of the prognostic role of tertiary lymphoid structures in immunotherapy of NSCLC, in order to offer references for screening suitable candidates for immunotherapy of NSCLC and develop personalized and precise treatment plans.
.

Background: Programmed death receptor 1 (PD-1) inhibition has shown durable response and mild adverse events (AEs) in adult malignancies. However, data on the clinical activity of PD-1 inhibition in pediatric patients are lacking. We comprehensively assessed the efficacy and safety of PD-1 inhibitor-based regimens for pediatric malignancies., Methods: We conducted a real-world, multi-institutional, retrospective analysis of pediatric malignancies treated with PD-1 inhibitor-based regimens. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints included disease control rate (DCR), duration of response (DOR), and AEs. The Kaplan-Meier method was used to calculate PFS and DOR. The National Cancer Institute Common Toxicity Criteria for AEs (version 5.0) were used to grade toxicity., Results: A total of 93 and 109 patients were evaluated for efficacy and safety, respectively. For all efficacy-evaluable patients, PD-1 inhibitor monotherapy, combined chemotherapy, combined histone deacetylase inhibitor, and combined vascular endothelial growth factor receptor tyrosine kinase inhibitor cohorts, the ORR and DCR were 53.76%/81.72%, 56.67%/83.33%, 54.00%/80.00%, 100.00%/100.00%, and 12.50%/75.00%, respectively; the median PFS and DOR were 17.6/31.2 months, not achieved/not achieved, 14.9/31.2 months, 17.6/14.9 months, and 3.7/1.8 months, respectively; the incidence rate of AEs were 83.49%, 55.26%, 100.00%, 80.00%, and 100.00%, respectively. One patient in the PD-1 inhibitor-combined chemotherapy cohort discontinued treatment due to diabetic ketoacidosis., Conclusions: This largest retrospective analysis demonstrate that PD-1 inhibitor-based regimens are potentially effective and tolerable in pediatric malignancies. Our findings provide references for future clinical trials and practice of PD-1 inhibitors in pediatric cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.-, (Copyright © 2023 Hong, Song, Lan, Wang, Lu, Zhang, Zhu, Sun, Huang, Liu, Xu, Wu, Guo, Cai, Zhen, Que and Zhang.)

Context: Lung cancer is one of the most common forms of cancer. Autophagy and apoptosis play an important role in the development of lung cancer. Researchers have found upregulation of GRP78 expression in cancer cells of various types., Objective: The study intended to explore the mechanism of G protein-coupled receptor 78(GPR78) in regulating autophagy and drug resistance in non-small cell lung cancer (NSCLC)., Design: The research team performed a laboratory study., Setting: The study took place in the Department of Thoracic Surgery at Hainan General Hospital of the Hainan Affiliated Hospital of Hainan Medical University in Haikou, Hainan, China., Intervention: The research team cultured immortalized, normal, human bronchial epithelial cells C3 (HBEC3) lines and HBEC4 lines in a serum medium without keratinocytes and infected the expression of GPR78 in knockdown A549 cells using lentiviral agents. The team divided the cells into a control group and a shRNA-GPR78 group, the intervention group. The lentiviral silencing vector expressing shRNA targets human GPR78#1 and GPR78 #2aadam10., Outcome Measures: The research team analyzed the mRNA expression of GPR78 in the NSCLC cell lines H1975, H1299, and A549 and in HBEC3 and HBEC4 using a real time-polymerase chain reaction (RT-PCR) and measured the proliferation of A549 cells at 0h, 24h, 48h, 72h, and 96h using yellow tetrazolium salt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The team also analyzed the migration and invasion ability of cells using wound healing and Transwell tests as well as measured the protein expression of the autophagy-related factors Beclin-1, microtubule-associated protein light chain 3-I/II (LC3-I/LC3-II), ubiquitin-binding protein p62 and c-Jun N-terminal kinase (JNK) using a Western blot test. The team also analyzed the protein expressions of caspase-9, caspase-3, and caspase-12 related to apoptosis using a Western blot. To detect the cell viability induced by cisplatin, the team used a Cell Counting Kit 8 (CCK-8) at the concentrations of 1μM, 3μM and 10μM., Results: The mRNA expression of GPR78 in the H1975, H1299, and A549 cell lines was significantly higher than that in the HBEC3 and HBEC4 cell lines (P < .05). At 48h, 72h, and 96h, the A549 cell proliferation in the shRNA-GPR78 group was significantly lower than that of the control group (P < .05). The cell migration and invasion of cells in the shRNA-GPR78 group was significantly lower than that in the control group (P < .05), and the cell viability of the shRNA-GPR78 group was significantly lower than that of control group (P < .05). The expression of Beclin-1 and JNK protein in shRNA-GPR78 group was significantly higher than that in the control group (P < .05), and the expression of LC3-I/LC3-II and p62 protein in shRNA-GPR78 group was significantly lower than that in the control group (P < .05). The protein expressions of caspase-9, caspase-3, and caspase-12 in the shRNA-GPR78 group were significantly higher than those of the control group (P < .05), and the protein activities of RhoA and Rac1 in the shRNA-GPR78 group were significantly lower than those in the control group (P < .05)., Conclusion: NSCLC upregulated GPR78. The knockdown of GPR78 can attenuate the proliferation, migration, and invasion of NSCLC cells and increase the apoptosis and autophagy of NSCLC cells that cisplatin has induced. Therefore, targeting GPR78 may be a promising treatment strategy for NSCLC patients.

Lung cancer is one of the most threatening malignant tumors to human health. Epidermal growth factor receptor (EGFR)-targeted therapy is a common and essential means for the clinical treatment of lung cancer. However, drug resistance has always affected the therapeutic effect and survival rate in non-small cell lung cancer (NSCLC). Tumor heterogeneity is a significant reason, yielding various drug resistance mechanisms, such as EGFR-dependent or -independent extracellular signal-regulated kinase 1 and/or 2 (ERK1/2) activation in NSCLC. To examine whether this aberrant activation of ERK1/2 is related to the loss of function of its specific phosphatase, a series of in vitro and in vivo assays were performed. We found that F-box/SPRY domain-containing protein 1 (Fbxo45) induces ubiquitination of NP-STEP 46 , an active form of striatal-enriched protein tyrosine phosphatase, with a K6-linked poly-ubiquitin chain. This ubiquitination led to proteasome degradation in the nucleus, which then sustains the aberrant level of phosphorylated-ERK (pERK) and promotes tumor growth of NSCLC. Fbxo45 silencing can significantly inhibit cell proliferation and tumor growth. Moreover, NSCLC cells with silenced Fbxo45 showed great sensitivity to the EGFR tyrosine kinase inhibitor (TKI) afatinib. Here, we first report this critical pERK maintenance mechanism, which might be independent of the upstream kinase activity in NSCLC. We propose that inhibiting Fbxo45 may combat the issue of drug resistance in NSCLC patients, especially combining with EGFR-TKI therapy., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The syntheses and biological evaluation of GHRH antagonists of AVR series with high anticancer and anti-inflammatory activities are described. Compared to our previously reported GHRH antagonist 602 of MIAMI series, AVR analogs contain additional modifications at positions 0, 6, 8, 10, 11, 12, 20, 21, 29 and 30, which induce greater antitumor activities. Five of nineteen tested AVR analogs presented binding affinities to the membrane GHRH receptors on human pituitary, 2-4-fold better than MIA-602. The antineoplastic properties of these analogs were evaluated in vitro using proliferation assays and in vivo in nude mice xenografted with various human cancer cell lines including lung (NSCLC-ADC HCC827 and NSCLC H460), gastric (NCI-N87), pancreatic (PANC-1 and CFPAC-1), colorectal (HT-29), breast (MX-1), glioblastoma (U87), ovarian (SK-OV-3 and OVCAR-3) and prostatic (PC3) cancers. In vitro AVR analogs showed inhibition of cell viability equal to or greater than MIA-602. After subcutaneous administration at 5 μg/day doses, some AVR antagonists demonstrated better inhibition of tumor growth in nude mice bearing various human cancers, with analog AVR-353 inducing stronger suppression than MIA-602 in lung, gastric, pancreatic and colorectal cancers and AVR-352 in ovarian cancers and glioblastoma. Both antagonists induced greater inhibition of GH release than MIA-602 in vitro in cultured rat pituitary cells and in vivo in rats. AVR-352 also demonstrated stronger anti-inflammatory effects in lung granulomas from mice with lung inflammation. Our studies demonstrate the merit of further investigation of AVR GHRH antagonists and support their potential use for clinical therapy of human cancers and other diseases., (Published by Elsevier Inc.)

Bevacizumab (BV) has an inhibitory effect on tumor growth including lung adenocarcinoma. However, its efficacy is greatly affected by drug resistance. Astragaloside IV (AST-IV) is effective in combination with other drugs is effective to treat cancer. This study aimed to investigate the effect of AST-IV on enhancing the sensibility of lung adenocarcinoma cells to BV. A549 cells were treated by different concentrations of BV and AST-IV. Cell viability, cell cycle, and apoptosis were detected by thiazolyl blue tetrazolium bromide (MTT) and flow cytometry, respectively. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting were performed to detect the expression levels of autophagy- and apoptosis-related proteins, protein kinase B (AKT), and mammalian target of rapamycin (mTOR). The results showed that BV or AST-IV could inhibit the viability and promote the apoptosis of A549 cells in a concentration-dependent manner. Moreover, BV or AST-IV inhibited Bcl-2 expression and increased the expressions of Bax and Cleaved caspase-3, and promoted apoptosis. BV and AST-IV in combination acted synergistically on viability and apoptosis of A549 cells. However, BV alone down-regulated P62 expression, LC3I/LC3II level, the number of cells arrested at S phase and the phosphorylation levels of AKT and mTOR, but upregulated the number of cells arrested at G0/G1 phase and Beclin1 expression, whereas AST-IV alone could reverse the effect of BV on autophagy-related proteins, the phosphorylation levels of AKT and mTOR. This paper demonstrates that AST-IV enhances the effect of BV on inhibiting proliferation and promoting apoptosis of lung adenocarcinoma cells through inhibiting autophagy pathway., (© 2021 Wiley Periodicals, LLC.)

Objective: Telomere length-related genes (TLRGs) play an important role in multiple tumors; however, there is a lack of systematic reporting about their relevance in non-small cell lung cancer (NSCLC). This study investigated the relation between TLRG gene expression and the immunotherapeutic response of patients with NSCLC., Materials and Methods: Differentially expressed TLRGs in tumor tissues and normal tissues were screened using Gene Expression Omnibus (GEO) datasets. A univariate Cox regression analysis was performed to identify the optimal prognosis-related genes. A prognostic risk model was constructed by using least absolute shrinkage, selection operator, and multivariate Cox regression analysis results. The model was then evaluated by a Kaplan-Meier analysis, functional enrichment annotation, and a receiver operating characteristic curve analysis; after which, it was validated in the TCGA dataset. The model was used to predict immunotherapeutic response and drug sensitivity., Results: An 18-gene prognostic signature was developed and used to stratify NSCLC patients into a low- or high-risk group in GEO cohorts. Patients in the low-risk group had better survival possibilities than those in the high-risk group, and showed significantly higher overall survival times in the TCGA cohort. The risk score was identified as an independent prognostic factor, when compared with other clinical factors. ssGSEA scores showed that the risk model was mainly linked to cancer- and immune-related pathways. Importantly, the candidate risk model was linked to tumor immunity and predicted a patient's response to PDL-1 blockade immune therapy. Several potential drugs that might target this model were identified., Conclusions: This study provides broad molecular signatures that can be used in further functional and therapeutic studies of the telomere system, and also represents an integrated approach for characterizing key protein complexes when creating a prognosis and identifying new targets for cancer immunotherapy.

Purpose: Non-small cell lung cancer (NSCLC) is a high-risk type of lung cancer. Raddeanin A exerts anti-tumor activity by regulating cell proliferation and apoptosis, but its role in NSCLC remains to be elucidated. This study was to investigate the effect of raddeanin A in NSCLC and its mechanism., Methods: The effect of raddeanin A (2, 4, 8, 10 μmol/L) on the viability, proliferation and apoptosis of A549 and H1299 cells was determined by cell counting kit-8, colony formation and flow cytometry assays, respectively. Next, western blot was performed to examine the protein expressions of cleaved caspase-3, Bax, phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and STAT3. Subsequently, the intracellular reactive oxygen species (ROS) generation and mitochondrial membrane potential of NSCLC cells were detected by 2', 7'-dichlorofluorescein-diacetate (DCFH-DA) and JC-1 assay. Lastly, the effect of N-acetylcysteine (NAC) on the apoptosis, ROS generation, and STAT3 was evaluated by the above-mentioned assays again., Results: Raddeanin A treatment had no obvious effect on 16HBE cells viability, but it inhibited viability and proliferation of A549 and H1299 cells, promoted the apoptosis, increased the protein expressions of cleaved caspase-3 and Bax, generated intracellular ROS, as well as decreased mitochondrial membrane potential and the expressions of p-STAT3 and STAT3 in A549 and H1299 cells. After cells treated with NAC, the effect of raddeanin A was reversed, as evidenced by the apoptosis and ROS generation were suppressed, and the expression of p-STAT3 was promoted., Conclusion: Raddeanin A suppressed the proliferation and induced apoptosis of NSCLC cells via promoting the ROS-mediated STAT3 inactivation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Nuclear factor erythroid 2-related factor 2 (NRF2) is a crucial transcription factor for cell adaptation and defense against oxidative stress. NRF2 activation confers Kras / Lkb1 / Keap1 (KLK) mutant tumor cells with greater resistance to oxidative insults. We previously reported that SUMOylation at lysine residue 110 is important for the ability of NRF2 to promote reactive oxygen species (ROS) clearance in hepatocellular carcinoma. In this study, we investigated whether SUMOylation is necessary for the ability of NRF2 to inhibit KLK lung adenocarcinoma (LUAD) cell migration and invasion. Our experiments showed that mild oxidative stress reduced NRF2 SUMOylation, which promoted KLK LUAD cell migration and invasion. Mechanistically, NRF2 SUMOylation increased the antioxidant ability of NRF2 and reduced cellular ROS levels, mainly by transcriptionally activating Cat in KLK LUAD cells. With reduced NRF2 SUMOylation, increased ROS acted as signaling molecules to activate the JNK/c-Jun axis, which enhanced cell mobility and cell adhesion, to promote LUAD cell migration and invasion. Taken together, the results of this study reveal a novel signaling process in which reduced NRF2 SUMOylation permits increased KLK LUAD cell migration and invasion under mild oxidative stress., Competing Interests: The authors declare no competing interest., (Copyright © 2020 Jiaqian Xu et al.)

BACKGROUND Expression profiles of circular ribonucleic acids (circRNAs) have been recently reported in lung cancers including lung adenocarcinoma (LUAD). Hypoxia is a hallmark of lung cancers. However, the role of hsa&#95;circ&#95;0008193 (circ&#95;0008193) in LUAD under hypoxia remains to be illuminated. MATERIAL AND METHODS Gene expression levels were detected using real-time quantitative polymerase chain reaction and western blotting. Cell proliferation, migration, invasion, and Warburg effect were detected using 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide assay, transwell assays, special kits, and xenograft experiments. The relationship among circ&#95;0008193, micro (mi)RNA (miR)-1180-3p, and tripartite motif containing 62 (TRIM62) was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation. RESULTS Expression of circ&#95;0008193 was downregulated in human LUAD tumor tissues and cell lines (A549 and H1975), accompanied by miR-1180-3p upregulation and TRIM62 downregulation. Moreover, circ&#95;0008193 downregulation was correlated with tumor size and lymph node metastasis. Functionally, circ&#95;0008193 overexpression inhibited cell viability, glucose uptake, lactate production, migration, and invasion, as well as expression of hexokinase II, lactate dehydrogenase A, matrix metalloproteinase 2 (MMP2), and MMP9 in hypoxic LUAD cells in vitro. Furthermore, tumor growth of A549 cells in vivo was also hindered by circ&#95;0008193 overexpression. Mechanically, circ&#95;0008193 regulated TRIM62 expression via sponging miR-1180-3p, and TRIM62 was targeted by miR-1180-3p. Both miR-1180-3p upregulation and TRIM62 downregulation could abolish the suppressive role of circ&#95;0008193 in LUAD cells. CONCLUSIONS Upregulating circ&#95;0008193 inhibited LUAD cell proliferation, migration, invasion, and Warburg effect under hypoxia in vitro and in vivo through regulation of the miR-1180-3p/TRIM62 axis.

Objectives: The objective is to compare the efficacy of diffusion-weighted imaging (DWI) parameters of mean and minimum apparent diffusion coefficient (ADC mean and ADC min ) and intravoxel incoherent motion (IVIM) in the differentiation of benign and malignant lung nodules and masses., Methods: Lung lesions measured larger than 1.5 cm on CT were included between August 2015 and September 2018. DWI (10 b-values, 0-1000 s/mm 2 ) scans were performed, and the data were post-processed to derive the ADC mean , ADC min and IVIM parameters of true diffusion coefficient (D), pseudodiffusion coefficient (D*) and perfusion fraction (f). An independent sample t -test or Mann-Whitney U test was used to compare benign and malignant parameters. Receiver operating characteristic curves were generated and a Z test was used., Results: 121 patients were finally enrolled, each with one lesion. Examined 121 lesions were malignant in 88 (72.7%) and benign in 33 (27.3%). The ADC mean of malignant pulmonary nodules was significantly lower than that of benign pulmonary nodules ( t = 3.156, p = 0.006), whereas the other parameters revealed no significant differences ( p = 0.162-0.690). Receiver operating characteristic curve analysis revealed that an ADC mean threshold value of 1.43 × 10 -3 mm 2 /s yielded 88.57% sensitivity and 64.29% specificity. While for lung masses, the ADC mean , ADC min , D and D* values in malignant pulmonary masses were significantly lower ( P ﹤0.001-0.011). Among them, the D value exhibited the best diagnostic performance when the threshold of D was 1.23 × 10 -3 mm 2 /s, which yielded a sensitivity of 90.57% and a specificity of 89.47% ( Z = 2.230, 3.958, 2.877 and p = 0.026, ﹤0.001 and 0.004, respectively)., Conclusion: ADC is the most robust parameter to differentiate benign and malignant lung nodules, whereas D is the most robust parameter to differentiate benign and malignant lung masses., Advances in Knowledge: This is the first study to compare all the quantitative parameters of DWI and IVIM mentioned in the literatures for assessing lung lesions; Second, we divided the lesions into lung nodules and lung masses with the size of 3 cm as the boundary.

The ubiquitin system, known as a common feature in eukaryotes, participates in multiple cellular processes, such as signal transduction, cell-cycle progression, receptor trafficking and endocytosis, and even the immune response. In lung cancer, evidence has revealed that aberrant events in ubiquitin-mediated processes can cause a variety of pathological outcomes including tumorigenesis and metastasis. Likewise, ubiquitination on the core components contributing to the activity of cell signaling controls bio-signal turnover and cell final destination. Given this, inhibitors targeting the ubiquitin system have been developed for lung cancer therapies and have shown great prospects for clinical application. However, the exact biological effects and physiological role of the drugs used in lung cancer therapies are still not clearly elucidated, which might seriously impede the progress of treatment. In this work, we summarize current research advances in cell signal regulation processes mediated through the ubiquitin system during the development of lung cancer, with the hope of improving the therapeutic effects by means of aiming at efficient targets., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Lung cancer is the major cause leading to cancer mortality, and the 5-year survival rate for patients with lung cancer still remains low. It is urgent to fully understand the development and progression of lung cancer to discover new therapeutic targets and develop new therapeutic approaches. H19 was documented to be upregulated in lung cancer and related to cell proliferation. However, it is still unclear if H19 has other functions in lung cancer. The mRNA levels of genes were detected by qRT-PCR, and the cell proliferation rate and cell viability were measured through cell count assay and MTT assay. Transwell assays were applied to detect cell abilities to migration and invasion, while luciferase reporter assay and RNA pull-down assay were used to examine interaction between H19 and miR-200a. H19 expression was elevated in the lung cancer tissues and cell lines, while H19 overexpression promoted the lung cancer cell growth, cell migration and invasion, as well as the epithelial mesenchymal transition (EMT). Meantime, RNA pull-down assay showed that H19 interacted with miR-200a, and miR-200a inhibited the activity of H19-fused luciferase. Furthermore, H19 overexpression inhibited miR-200a function and thereby upregulated miR-200a target genes, ZEB1 and ZEB2.H19 sponged and inhibited miR-200a to de-repress expression of ZEB1 and ZEB2, and thereby enhanced lung cancer proliferation and metastasis.

When a nanomedicine is administrated into the human body, biomolecules in biological fluids, particularly proteins, form a layer on the surface of the nanoparticle known as a "personalized protein corona". An understanding of the formation and behavior of the personalized protein corona not only benefits the nanotherapy treatment efficacy but also can aid in disease diagnosis. Here we used Gd@C 82 (OH) 22 nanoparticles, a nanomedicine effective against several types of cancer, as a model nanomedicine to investigate the natural protein fingerprint of the personalized protein corona formed in 10 human lung squamous cell carcinoma patients. Our analysis revealed a specific biomarker, complement component C1q, in lung cancer personalized protein coronas, abundantly bound to Gd@C 82 (OH) 22 NPs. This binding altered the secondary structure of C1q protein and led to the activation of an innate immune response, which could be exploited for cancer immune therapy. On the basis of this finding, we provide a new strategy for the development of precision nanomedicine derived from opsonization of a unique protein fingerprint within patients. This approach overcomes the common pitfall of protein corona formation and exploits the corona proteins to generate a precision nanomedicine and diagnostic tool.

Anthropogenic carbon nanotubes, with a fibrous structure and physical properties similar to asbestos, have recently been found within human lung tissues. However, the reported carbon-nanotube-elicited pulmonary pathologies have been mostly confined to inflammatory or neoplastic lesions in the lungs or adjacent tissues. In the present study, we demonstrate that a single pulmonary exposure to multi-walled carbon nanotubes dramatically enhances angiogenesis and the invasiveness of orthotopically implanted mammary carcinoma, leading to metastasis and rapid colonization of the lungs and other organs. Exposure to multi-walled carbon nanotubes stimulates local and systemic inflammation, contributing to the formation of pre-metastatic and metastatic niches. Our study suggests that nanoscale-material-elicited pulmonary lesions may exert complex and extended influences on tumour progression. Given the increasing presence of carbon nanotubes in the environment, this report emphasizes the urgent need to escalate efforts assessing the long-term risks of airborne nanomaterial exposure in non-lung cancer progression.

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with exposure to asbestos, with poor prognosis and no effective therapies. The strong inhibitory activities of growth hormone-releasing hormone (GHRH) antagonists have been demonstrated in different experimental human cancers, including lung cancer; however, their role in MPM remains unknown. We assessed the effects of the GHRH antagonists MIA-602 and MIA-690 in vitro in MPM cell lines and in primary MPM cells, and in vivo in MPM xenografts. GHRH, GHRH receptor, and its main splice variant SV1 were found in all the MPM cell types examined. In vitro, MIA-602 and MIA-690 reduced survival and proliferation in both MPM cell lines and primary cells and showed synergistic inhibitory activity with the chemotherapy drug pemetrexed. In MPM cells, GHRH antagonists also regulated activity and expression of apoptotic molecules, inhibited cell migration, and reduced the expression of matrix metalloproteinases. These effects were accompanied by impairment of mitochondrial activity and increased production of reactive oxygen species. In vivo, s.c. administration of MIA-602 and MIA-690 at the dose of 5 μg/d for 4 wk strongly inhibited the growth of MPM xenografts in mice, along with reduction of tumor insulin-like growth factor-I and vascular endothelial growth factor. Overall, these results suggest that treatment with GHRH antagonists, alone or in association with chemotherapy, may offer an approach for the treatment of MPM., Competing Interests: Conflict of interest statement: A.V.S. and R.C. are listed as co-inventors on the patent for GHRH agonists, assigned to the University of Miami, Miami, FL, and the Veterans Affairs Medical Center, Miami, FL. The remaining authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Objectives: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor and is prevalent among children and adolescents. In recent years, following the emergence of high-throughput sequencing techniques, rearrangements in genes, such as ALK, ROS1, NTRK, RET, and PDGFRβ, have been detected in a considerable proportion of IMT patients. However, the practice of targeted therapy for those patients remains extremely limited. In this study, we report about a 14-year-old boy diagnosed with pulmonary IMT with a mass measuring 12 × 8 cm in the right lower lobe., Materials and Methods: Immunohistochemistry (IHC) assay and comprehensive next-generation sequencing (NGS) were performed on the biopsied tumor tissue., Results: The IHC assay revealed an ALK-negative tumor, while NGS detected aTFG-ROS1 rearrangement. The patient achieved continuous remission after treatment with crizotinib (250 mg, bid)., Conclusion: This case broadens the experience regarding targeted therapy forROS1-rearranged IMT and supports the use of broad molecular profiling testing for optimizing therapeutic options., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To explore the curative effect of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) combined with Traditional Chinese Medicine (TCM) versus single EGFR-TKIs for Advanced non-small-cell lung cancer (NSCLC)., Methods: A total of 59 NSCLC patients with EGFR mutation were divided (2:1) into treatment group and control group. Patients in treatment group (39 cases) take EGFR-TKIs plus TCM and control group (20 cases) take EGFR-TKIs. Analysis the progression-free survival (PFS), disease control rate (DCR) and treatment-related adverse events of two groups., Results: The DCR of the treatment group and control group was 94.1% and 84.2% respectively ( P =0.24). In the total population, PFS was 12.1 months in treatment group and 9.1 months in control group [hazard ratio ( HR ) 0.46; 95% CI 0.23-0.9; P =0.025]. Among patients with exon 19 deletion (19-del), PFS between treatment group and control group was 10.5 months and 9.5 months respectively ( P =0.17). For patients with exon Leu858Arg point mutation (L858R), PFS was significantly longer with treatment group than withcontrol group (median 13.2 months vs. 7.8 months; HR 0.32, 95% CI 0.10-0.97; P =0.046). Grade 3-4 treatment-related adverse events were less common withtreatment-group (8.33 %) than control group (15.00%) ( P =0.65)., Conclusion: For NSCLC patients with EGFR mutation, EGFR-TKIs combined with TCM has a certain effect to prolong PFS, especially for the patients with L858R., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)

Purpose: To prospectively evaluate the short-term reproducibility of intravoxel incoherent motion (IVIM) parameters and apparent diffusion coefficient (ADC) in lung cancer patients., Materials and Methods: In all, 50 patients (50 lesions) underwent free-breathing diffusion-weighted imaging (DWI) (b = 0, 300, 800 s/mm 2 ) and IVIM (10 b-values, 0-1000 s/mm 2 ) scans twice (0.5-1-hour interval) at 3T. Regions of interests (ROIs) were drawn on ADC maps and IVIM images to derive the mean ADC value and IVIM parameters D, D*, and f. Intra- and interobserver, test-retest reproducibility were assessed with intraclass correlation coefficients (ICCs), within coefficient-of-variations (WCVs), and Bland-Altman analysis. The effects of type, size, and location of lung lesions were compared with WCVs., Results: D and ADC showed good intraobserver reproducibility and interobserver agreement, while D* and f showed relatively larger variability (WCV 20.89-34.97%). The test-retest reproducibility of D and ADC were good (ICC 0.763-0.837; WCV 11.12-12.55%), while those of D* and f were relatively poor (ICC 0.604-0.842; WCV 36.54-72.62%). D and ADC had decreased reproducibility for lesions <2 cm (WCV 14.20%, 16.34%, respectively) and for lesions in the lower lung zones (WCV 16.52%, 14.78%, respectively). f had decreased reproducibility in central lung cancers (WCV 50.11%) and lesions >2 cm (WCV 42.64%). D* had even worse reproducibility in peripheral lung cancers (WCV 84.11%) and lesions in the lower lung zones (WCV 80.84%)., Conclusion: If the change in ADC, D, D*, and f values is less than ∼31%, 34%, 170%, and 130%, respectively, it may be caused by measurement error. The type, size, and location of lung lesions have an effect on measurement errors., Level of Evidence: 1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2018;47:1003-1012., (© 2017 International Society for Magnetic Resonance in Medicine.)

Objection: The aim of this study is to explain the significance and mechanism of miR-205 in the diagnosis and treatment of non-small cell lung cancer., Methods: The 70 advanced NSCLC patients, treated in our hospital, were collected from 2011.10 to 2013.9, taking the tissues from cancer and adjacent tissues to measure the miR-205 expression, evaluate the AKT gene and protein expression of cancer and adjacent normal tissues by RT-PCR and Immunohistochemistry (IHC) assays and analyzing the correlation between miR-205 and AKT. Following up the patients for 2 years; Recording patients' survival time. In the cell experiment, Selecting A549 cell as research object, the cells were divided into three groups: Normal control group (NC), Blank control group (BL) and si-miR-205 transfection group (si-miR-205). Cell proliferation rate and apoptosis rate were detected by MTT method and flow cytometry; Measuring invasion and migration of difference groups by transwell and scratch testing, measured the Akt, mTOR,P21, MMP2 and MMP9 gene expression and detected Akt, p-Akt, mTOR, p-mTOR, P21, MMP2 and MMP 9 protein expression levels., Results: Compared with adjacent normal tissue, the miR-205 and AKT gene expression level was significantly increased in NSCLC tissues (P<0.05) and the AKT protein expression was stronger than that of healthy tissues, miR-205 was positive correlation with AKT; In the overall survival, MiR-205 high expression group was significantly higher than low expression group (P<0.05). In the cell experiment, Compared with NC and BL groups, si-miR-205 could significantly reduced the biological activity of A549 cells in proliferation, invasion and migration, and promoted the apoptosis of A549 cells (P<0.05, respectively). Akt, p-Akt, mTOR, p-mTOR, P21, MMP 2 and MMP 9 gene and protein expression of si-miR-205 group were significantly compared with NC and BL groups (P<0.05, respectively)., Conclusion: miRNA-205 might serve as a potential biomarker for the prognosis of advanced NSCLC, and inhibiting miR-205 expression could decrease A549 cells biological activity by regulating Akt/mTOR/P21 and Akt/MMP 2/MMP 9signaling pathway., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Sirt6 is a histone deacetylase with NAD(+)-dependent activity. Sirt6 has been shown as a tumor suppressor partially via inhibiting the expression of c-Myc target genes and ribosome biogenesis. However, how to regulate Sirt6 activity is largely unknown. In this study, we identify that Sirt6 can be modified by small ubiquitin-like modifier. Sirt6 SUMOylation deficiency specifically decreases its deacetylation of H3K56 but not H3K9 in vivo. Mechanistically, we find that SUMOylation deficiency decreases Sirt6 binding with c-Myc, decreasing Sirt6 occupancy on the locus of c-Myc target genes. Therefore, Sirt6 SUMOylation deficiency reduces its deacetylation of H3k56 and its repression of c-Myc target genes. Moreover, Sirt6 SUMOylation deficiency reduces its suppression of cell proliferation and tumorigenesis. Thus, these results reveal that SUMOylation has an important role in regulation of Sirt6 deacetylation on H3K56, as well as its tumor suppressive activity.

Objective: To compare the effect of first-line treatment with platinum-based chemotherapy and non-platinum-based chemotherapy in patients with lung metastases from triple negative breast cancer (TNBC)., Methods: Sixty-five eligible patients were divided into platinum-treated group and non-platinum-treated group according to the first-line therapy. Factors predicting the chemotherapeutic efficacy included overall survival (OS), progression-free survival (PFS) and objective response (OR)., Results: In the platinum-treated group of 32 patients, 2 cases (6.3%) achieved CR, 16 cases (50.0%) achieved PR, 11 (34.4%) cases achieved SD, and 3 patients (9.4%) achieved PD. In the non-platinum-treated group of 33 patients, 2 cases (6.1%) achieved CR, 6 cases (18.2%) achieved PR, 16 cases (48.5%) achieved SD, and 9 cases (27.3%) achieved PD. Median PFS was significantly longer in the platinum-treated group than in the non-platinum-treated group (10 months vs. 6.0 months, P = 0.012), and OS was also improved (32 months vs. 22 months, P = 0.006). Multivariate analysis of several factors including local-regional lymph node involvement, lung metastasis-related symptoms, first-line platinum-based chemotherapy, disease-free interval, size and number of lung lesions, showed that first-line platinum-based chemotherapy was an independent prognostic factor for TNBC patients with lung metastases., Conclusions: Compared with non-platinum-based chemotherapy, the first-line platinum-based chemotherapy can improve PFS and OS in TNBC patients with metastases confined to the lungs.

The role of platinum-based chemotherapy (PBCT) in the treatment of triple-negative breast cancer (TNBC) is still undetermined. The aim of this study was to compare the efficacy of PBCT versus non-PBCT in patients with lung metastasis from TNBC. Clinical data on patients diagnosed and treated for lung metastasis from TNBC between 2004 and 2012 at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences, were retrospectively analyzed. Of the 79 patients identified, 34 received PBCT and 45 received non-PBCT. The median progression-free survival was 10 months [95% confidence interval (CI) 6.6-13.4 months] in the platinum-based group and 5 months (95% CI 3.7-6.3 months) in the nonplatinum group (P=0.002); overall survival was also significantly improved (32 vs. 21 months, P=0.002). In the multivariate analysis for the entire cohort, first-line PBCT (hazard ratio 0.425; 95% CI 0.251-0.720; P=0.001) and presentation of symptoms related to lung metastasis (hazard ratio 2.237; 95% CI 1.180-4.240; P=0.014) were associated independently with survival. Our results support the use of PBCT in the first-line treatment of lung metastasis from TNBC.

Background and Objective: Platinum plus a third-generation agent doublet chemotherapy is the standard regimen and first-line chemotherapy for the treatment of advanced non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the efficacy and safety of docetaxel plus platinum (DP) compared with vinorelbine plus platinum (VP) regimens in patients with advanced NSCLC., Methods: We searched the PubMed, EMBASE, Cochrane Library, CNKI, CBM, VIP, and WanFang databases for randomized controlled trials (RCTs), in which DP regimen was compared with VP regimen. A quality assessment of qualified RCTs was performed according to Cochrane Handbook 5.1.0, and Stata 12.0 was used to perform meta-analysis., Results: Seven RCTs involving 2,318 patients were included. Meta-analysis results indicated that the DP regimen increased the two-year survival rate (HR=0.887, 95%CI: 0.810-0.972, P=0.010), response rate (RR=1.276, 95%CI: 1.107 -1.450, P=0.001), and diarrhea rate (RR=3.134, 95%CI: 1.918-5.121, P<0.001) compared with the VP regimen. Anemia rate was also reduced (RR=0.386, 95%CI: 0.311-0.478, P<0.001). No statistical differences were observed between DP and VP regimens in terms of one-year survival rate, leukopenia, neutropenia, thrombocytopenia, anorexia, nausea, and vomiting., Conclusions: DP regimen reduced the rate of anemia and increased the rate of diarrhea, two-year survival rate, and response rate. Therefore, DP regimen may be a more effective option as a first-line treatment for advanced NSCLC compared with VP regimen.

HDAC inhibitors are promising antitumor drugs with several HDAC inhibitors already in clinical trials. LAQ824, a potent pan-HDAC inhibitor, has been shown to induce cell cycle arrest and cell death. However, the mechanism of its antitumor effects and specially its tumor selectivity are still poorly understood. The focus of this study is to elucidate LAQ824 mediated anti-proliferative effects in lung carcinoma cells and the mechanism underlying the different sensitivity of LAQ824 to cancer and normal cells. In this study, LAQ824 mediated apoptosis was found to occur mainly via activation of the mitochondrial death pathway by inducing Apaf1 and caspase 9 and promoting mitochondrial release of key proapoptotic factors in lung cancer cells, but not in normal fibroblast cells. Using chromatin immunoprecipitation assay, we found that RNA Pol II binding and histone H3 acetylation levels at Apaf1 promoter were increased following LAQ824 treatment, explaining LAQ824 induced expression of Apaf1 in lung cancer cells. Furthermore, we showed that LAQ824 only triggered the release of mitochondrial proapoptotic factors such as cytochrome C (Cyto C) and apoptosis inducing factor (AIF) in lung cancer cells but not in normal blast cells. In addition, LAQ824 was found to induce Bax translocation in lung cancer cell, which may play important role in the induction of the release of mitochondrial proapoptotic factors. These data provide insight into the mechanism underlying the selective induction of apoptosis by LAQ824 in cancer cells.

The dynamic balance between histone acetylation and deacetylation plays a significant role in the regulation of gene transcription. Much of our current understanding of this transcriptional control comes from the use of HDAC inhibitors such as trapoxin A (TPX), which leads to hyperacetylated histone, alters local chromatin architecture and transcription and results in tumor cell death. In this study, we treated tumor cells with TPX and HDAC1 antisense oligonucleotides, and analysed the transcriptional consequences of HDAC inhibition. Among other genes, the small GTPase RhoB was found to be significantly upregulated by TPX and repressed by HDAC1. The induction of RhoB by HDAC inhibition was mediated by an inverted CCAAT box in the RhoB promoter. Interestingly, measurement of RhoB transcription in approximately 130 tumor-derived cell lines revealed low expression in almost all of these samples, in contrast to RhoA and RhoC. Accumulating evidence indicates that the small GTPase Rho proteins are involved in a variety of important processes in cancer, including cell transformation, survival, invasion, metastasis and angiogenesis. This study for the first time demonstrates a link between HDAC inhibition and RhoB expression and provides an important insight into the mechanisms of HDAC-mediated transcriptional control and the potential therapeutic benefit of HDAC inhibition.

We investigated the effects of our synthetic bombesin/gastrin-releasing peptide (GRP) antagonists and somatostatin analogue RC-160 on the growth of human small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (non-SCLC) lines in nude mice. Athymic nude mice bearing xenografts of the SCLC NCl-H69 line or non-SCLC NCl-H157 line were treated for 5 and 4 weeks, respectively, with somatostatin analogue RC-160 or various bombesin/GRP antagonists. RC-160, administered s.c. peritumorally at a dose of 100 micrograms per animal per day, inhibited the growth of H69 SCLC xenografts as shown by more than 70% reduction in tumour volumes and weights, as compared with the control group. Bombesin/GRP antagonists, RC-3440, RC-3095 and RC-3950-II, given s.c. peritumorally at a dose of 20 micrograms per animal per day, also inhibited the growth of H69 SCLC tumours. RC-3950-II had the greatest inhibitory effect and decreased tumour volume and weights by more than 80%. The growth of H-157 non-SCLC xenografts was significantly reduced by treatment with RC-160, but not with bombesin/GRP antagonist RC-3095. In mice bearing either tumour model, administration of RC-160 significantly decreased serum growth hormone and gastrin levels. Specific high-affinity receptors for bombesin and somatostatin were found on membranes of SCLC H69 tumours, but not on non-SCLC H157 tumours. Receptor analyses demonstrated high-affinity binding sites for epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) on the membranes of H69 and H157 tumours. EGF receptors were down-regulated on H69 tumours after treatment with RC-160 and bombesin/GRP antagonists. The concentration of binding sites for EGF and IGF-I on the H157 tumours was decreased after treatment with RC-160, but bombesin/GRP antagonist RC-3095 had no effect. These results demonstrate that bombesin/GRP antagonists inhibit the growth of H-69 SCLC, but not of H-157 non-SCLC xenografts in nude mice, whereas somatostatin analogue RC-160 is effective in both tumour models. This raises the possibility that these peptide analogues could be used selectively in the treatment of various subclasses of lung cancer.