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Background/aim: Non-small cell lung cancer is known for its rapid growth and immune evasion, demanding effective therapies targeting both tumor cells and the microenvironment. Magnolol has shown promising anti-tumor effects in various cancers., Materials and Methods: CL1-5-F4-bearing mice were divided into control, 40 mg/kg, and 60 mg/kg magnolol groups, once tumors reached 100 mm 3 Tumor growth and body weight were monitored biweekly, and after 13 days, mice were euthanized for tumor and organ collection for subsequent staining. Histopathology and serum biochemistry assessed organ toxicity., Results: Magnolol dose-dependently suppressed NSCLC progression, with no pathology alterations observed in normal organs. Magnolol-induced apoptosis and cell cycle arrest, evidenced by increased cleaved caspase-3 and decreased cyclin D1/CDK4 levels. It also down-regulated VEGF, FOXP3, and IDO-1 in tumors, implicating tumor microenvironment modulation., Conclusion: Magnolol exhibits significant antitumor effects in NSCLC by inducing apoptosis, inhibiting proliferation, and modulating the tumor microenvironment. These results support further investigation of magnolol as a therapeutic adjuvant to enhance NSCLC treatment outcomes., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer worldwide, and treatment outcomes are still poor. Magnolol, a hydroxylated biphenyl isolated from Magnolia officinalis, was found to be effective against hepatocellular carcinoma via inactivating nuclear-factor-kappa B (NF-B) signaling. However, whether magnolol targets not only NF-B but also other factors in NSCLC and may contribute to the suppression of tumor progression is unclear., Materials and Methods: Cell viability, flow cytometry, and western blotting assays were used to identify the mechanism of magnolol action in human lung adenocarcinoma cell lines A549 and CL1-5-F4., Results: Our results indicated that magnolol induced cytotoxicity through extrinsic/intrinsic apoptosis signaling and suppressed phosphorylation of signal transducer and activator of transcription 3 (STAT3)/NF-B and expression of their downstream proteins., Conclusion: Magnolol not only induced extrinsic and intrinsic apoptosis signaling but also inactivated STAT3/NF-B and attenuated their signaling of epithelial-mesenchymal transition and metastasis-related protein expression in NSCLC., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The combination of regorafenib with cisplatin/pemetrexed has indicated controllable safety and encouraging antitumor activity in non-small cell lung cancer (NSCLC) patients. However, the anti-NSCLC effects and action mechanisms of regorafenib combined with cisplatin is ambiguous. The major goal of the study was to study the inhibitory effects and action mechanisms of regorafenib combined with cisplatin in NSCLC cells., Materials and Methods: Cell viability, flow cytometry, immunofluorescence staining, western blotting, migration, and invasion assays were employed to verify the anti-NSCLC effects and mechanisms of regorafenib in combination with cisplatin., Results: Cisplatin-induced epidermal growth factor receptor (EGFR)/nuclear factor κB (NF-κB) signaling was effectively inhibited by regorafenib treatment. Regorafenib, erlotinib (EGFR inhibitor) and QNZ (NF-κB inhibitor) may all enhance the cytotoxicity effect of cisplatin. The invasion ability was effectively decreased by combination treatment. Caspase-dependent and -independent apoptosis was activated by cisplatin combined with regorafenib., Conclusion: Apoptosis induction and EGFR/NF-κB inactivation correlate with regorafenib-enhanced anti-NSCLC efficacy of cisplatin. This study provides evidence of the therapeutic efficacy of regorafenib in combination with cisplatin on NSCLC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with poor prognosis. Lenvatinib is a multi-kinase inhibitor that has the potential to suppress tumor progression. Our previous study suggested that lenvatinib induces cytotoxicity and apoptosis in CL-1-5-F4 cells in vitro. However, whether lenvatinib suppresses NSCLC progression in vivo remains unclear., Materials and Methods: Tumor growth inhibition and normal tissue toxicity evaluation following lenvatinib treatment were performed on CL-1-5-F4-bearing mice., Results: Tumor growth calculated by caliper and living cell intensity decreased by lenvatinib treatment as analysed by bioluminescence imaging. Phosphorylation of AKT, NF-κB, and NF-κB downstream proteins involved in tumor progression were reduced by lenvatinib in the tumor tissue. No pathological changes were found in the liver, kidney, and spleen after lenvatinib treatment., Conclusion: Induction of apoptosis and suppression of AKT/NF-κB were associated with lenvatinib-induced inhibition of the progression of NSCLC in vivo., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Non-small cell lung cancer (NSCLC) is a malignant lung cancer type with poor prognosis. NF-κB, the oncogenic transcription factor, has been recognized as an important mediator in progression of NSCLC. Regorafenib, a multikinase inhibitor, was demonstrated to inhibit tumor progression through suppression of ERK/NF-κB signaling in hepatocellular carcinoma cells in vitro and in vivo. However, whether regorafenib inhibit progression of NSCLC is ambiguous. Thus, the major purpose of present study was to evaluate anticancer efficacy and underlying mechanism of regorafenib on tumor progression in NSCLC in vitro and in vivo. CL-1-5-F4 cells were treated with regorafenib, NF-κB (QNZ) or AKT (LY294002) inhibitor for 24 or 48 h. Then, we performed cell viability assay, NF-κB reporter gene assay, transwell invasion assay and apoptosis related flow cytometry assay on cellular level to verify anti-cancer effect and mechanism of regorafenib. CL-1-5-F4 bearing animal model was treated with vehicle or regorafenib for 28 days. The therapeutic efficacy and mechanism of regorafenib in CL-1-5-F4 bearing animal model were investigated by tumor size evaluation, whole body computer tomography (CT) scan, Haemotoxylin and Eosin (H&E) stain and immunohistochemistry (IHC) stain. Our results demonstrated regorafenib significantly inhibited tumor growth and induced apoptosis through extrinsic/intrinsic pathways in NSCLC in vitro and in vivo. Furthermore, we also found the suppression of AKT/NF-κB signaling was required for regorafenib inhibited expression of progression-related and invasion-related proteins. Our finding indicated apoptosis induction and suppression of AKT/NF-κB signaling were associated with regorafenib-inhibited progression of NSCLC in vitro and in vivo., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background/aim: The aim of present study was to verify the effect of fluoxetine on DNA repair and metastatic potential in non-small cell lung cancer (NSCLC) in vitro., Materials and Methods: Highly metastatic NSCLC CL1-5-F4 cells were used in this study. Cells were treated with different concentrations of fluoxetine or QNZ (NF-ĸB inhibitor) for 48 h. After treatment, cell viability, apoptotic signaling, NF-ĸB activation, expression of DNA repair and metastasis-associated proteins, and cell migration/invasion were evaluated by (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay, flow cytometry, NF-ĸB reporter gene, western blotting, and cell migration/invasion assay, respectively., Results: Fluoxetine induced apoptosis and reduced cell viability, NF-ĸB activation, expression of DNA repair and metastasis-associated proteins, and cell migration/invasion in CL1-5-F4 cells. Also, NF-ĸB activation was the critical factor in fluoxetine-inhibited metastatic potential., Conclusion: Fluoxetine induced apoptosis and inhibited DNA repair and metastatic potential in NSCLC CL1-5-F4 cells., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Overexpression of ribonucleotide reductase M2 (hRRM2) and p53-dependent RR small subunit (p53R2) has been correlated with tumor malignancy and progression in several types of cancer. The aim of this study was to determine the association of p53R2/hRRM2 expression with clinicopathological characteristics of stage I and II non-small cell lung cancer (NSCLC). Immunohistochemistry was conducted on a tissue array that included 92 samples. Correlations between hRRM2 and p53R2 expression and clinicopathological factors, recurrence/metastasis, and outcomes were analyzed. The analyses revealed that there was no correlation between p53R2 expression and clinicopathological factors; hRRM2 was only positively related to poor tumor differentiation (p=0.006). Regarding overall survival during the follow-up period, patients with p53R2+/hRRM2- tumors had the best outcomes (p<0.01). Multivariant Cox analysis revealed that p53R2 (risk=0.232, 95% CI=0.086-0.626, p=0.004) not only served as a prognostic biomarker to predict survival, but also as an independent biomarker to predict disease-free survival (risk=0.545, 95% CI=0.301-0.987, p=0.045) of patients with NSCLC. Therefore, we consider that the expression of p53R2 can be used not only as a biomarker for overall survival, but also as an indicator for tumor recurrence. Based on our finding, p53R2 expression seems more important than that of hRRM2 in prognosis of early-stage lung cancer.

Purpose: Inhibitors of antiapoptosis protein (IAP) have been implicated in the resistance to cisplatin. Therefore, verifying which pathway is involved in cIAP2 upregulation may be helpful in finding a feasible pathway inhibitor to increase the chemotherapeutic efficacy in human papillomavirus (HPV)-infected lung cancer., Experimental Design: Specific inhibitors of different pathways were used to verify which pathway is involved in cIAP2 transcription. cIAP2 promoter fragments with various deletions and/or mutations were constructed by site-directed mutagenesis. cIAP2, epidermal growth factor receptor (EGFR), and phospho-AKT (p-AKT) expressions in 136 lung tumors were evaluated by immunohistochemistry., Results: Our data show that two NF-κB (-209 to -200 and -146 to -137) and one CREB (cyclic AMP-responsive element binding protein; -52 to -42) binding sites in cIAP2 promoter region were responsible for cIAP2 upregulated by E6 in TL-1 cells. Moreover, CREB was phosphorylated by EGFR/phosphatidylinositol 3-kinase (PI3K) pathway. To test the involvement of cIAP2 on cisplatin resistance, IC(50) was lowered to 8.6 μmol/L in TL-1 cells with cIAP2 short hairpin RNA (shRNA) transfection and compared with 39.7 μmol/L in TL-1 cells with nonspecific shRNA. Pretreatment with EGFR or PI3K inhibitor in TL-1 cells diminished the resistance to cisplatin. Among the tumor groups, cIAP2 expression correlated significantly with HPV16/18 E6, EGFR, and p-AKT. We followed up 46 of 136 patients who had tumor recurrence and/or metastasis and underwent chemotherapy. Tumors with cIAP2-positive immunostaining were associated with a poorer tumor response to chemotherapy compared with those with negative immunostaining., Conclusions: cIAP2 upregulated by E6 via EGFR/PI3K/AKT cascades may contribute to cisplatin resistance, revealing that the EGFR or PI3K inhibitor combined with cisplatin may improve the chemotherapeutic efficacy in HPV-infected lung cancer., (©2010 AACR.)

Background: O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation has been demonstrated to associate with the G:C-->A:T transition mutation in the p53 gene of lung tumors. The purpose of this study is to clarify whether MGMT promoter methylation is not only associated with the shift from the G:C-->A:T mutation in the p53 gene but also whether MGMT increases other mutation patterns in lung tumors., Materials and Methods: To further verify whether a different prevalence of MGMT promoter methylation is observed in lung tumors with a different tumor histology, gender, and smoking status, 220 lung tumors were collected to evaluate the status of MGMT promoter methylation and p53 mutation using methylation-specific PCR (MSP) and direct sequencing, respectively., Results: The data shows that a higher prevalence of MGMT promoter methylation was observed in tumors with the G:C-->A:T transition or other p53 mutation patterns compared with those with p53 wild-type (P < 0.001 for G:C-->A:T; P = 0.015 for other mutation patterns), and this prevalence was more pronounced in tumors from male than from female patients. MGMT promoter methylation in p53 mutation patterns had a different effect on squamous cell carcinomas (SCC) and adenocarcinomas (ADC). Interestingly, the highest prevalence of MGMT promoter methylation was found in male nonsmokers followed by male smokers and female nonsmokers. This may be a partial explanation for the reason why male nonsmokers had a higher p53 mutation occurrence than female nonsmokers., Conclusions: MGMT promoter methylation may associate with increased occurrence of p53 mutation including the G:C-->A:T transition and other p53 mutation patterns in lung cancer, especially among male nonsmokers.

Background: Inconsistency in the prevalence of infection by human papillomavirus (HPV) in lung cancer patients was found between different countries with racial and geographic variations. Our previous reports have indicated that a high-risk HPV 16/18 DNA was frequently detected in Chinese lung cancer patients living in Taichung, Taiwan (Cheng et al. Cancer Res. 2001;61:2799-803). Thus, we conducted this study to verify whether there was a similar HPV 16/18 infection prevalence in lung cancer patients from Wuhan, China., Methods: To reduce the false positive HPV detection, the paraffin sections of 73 lung tumors and 34 non-cancer controls from Wuhan, China were collected for detection of the presence of HPV 16/18 DNA by in situ hybridization (ISH)., Results: Our results showed that the rates of HPV 16 and/or 18 infections in patients with lung tumors were significantly higher than in 34 non-cancer control subjects (26.0 versus 2.8% for HPV 16, P = 0.030; 23.3 versus 5.7% for HPV 18, P = 0.031; 27.7 versus 5.9% for HPV 16 or 18, P = 0.003) with a similar infection frequency of HPV 16 and 18 types in lung tumors. This result indicated that HPV 16/18 infection may be associated with lung cancer development in Chinese patients from Wuhan, China. Further statistical analyses revealed that HPV 16 or 18 infection was not correlated with any clinico-pathological parameter studied, including age, gender, smoking status, tumor type, tumor stage and tumor grades. Interestingly, smoking and male patients had a higher prevalence of HPV 16, although not reaching a statistical significance, compared with non-smoking and female patients, respectively (33.3% for smokers versus 20.0% non-smokers; 33.3% for male versus 17.6% for female). As compared with the HPV 16/18 infection in Taiwan, Chinese patients with lung cancer from Wuhan had a different HPV 16/18 infection prevalence., Conclusion: Difference in HPV 16/18 infection in lung cancer patients from Wuhan, China and Taichung, Taiwan suggests that HPV 16/18 might play a different role in lung cancer development among Chinese living in different areas.