Search results for: non-small cell lung cancer (NSCLC)

Authors: Melliti Rihab, Zaeid Sonia, Khechine Wiem, Daldoul Amira

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Introduction: Lung cancer is the leading cause of cancer death. Its incidence is increasing, and its prognosis remains pejorative. We present the clinical, pathological, and therapeutic characteristics of bronchopulmonary cancer (BPC) in Tunisia. Methods: Retrospective study including patients followed in the oncology department of the University Hospital of Monastir between April 2014 and December 2021 suffering from lung cancer. Results: These are 117 patients, including 86.3% men and 13.7% women (sex ratio 6.3). The average age was 64 years ± 9 (37-83), with 95.7% being over 50 years old. Patients were smokers in 82% of cases. The clinical signs were dominated by chest pain (27.5%) and dyspnea in 21.1% of cases. In 6 patients, an episode of COVID-19 infection revealed the diagnosis. Half of the patients had a PS between 0 and 1. Small cell lung cancer was present in 18 patients (15.4%). The majority of non small cell lung cancer was of the adenocarcinoma type (68.7%). The diagnosis was late (stage IV) in 62.4% of cases. BPC was metastatic to bone (52%), contralateral lung (25.9%), and brain (27.3%). Patients were oligometastatic in 26% of cases. Surgery and radiotherapy were performed respectively in 14.5% and 23.1% of cases. Three-quarters of the patients had had nutrition (75.2%). The ROS1 mutation was present in 1 patient. PDL-1 expression was >40% in 2 patients. Survival was mean eight months ± 7.4. Conclusion: Lung cancer is diagnosed at a late stage in Tunisia. The lack of molecular study for non-small cell PBC and the lack of marketing authorization for tyrosine kinase inhibitors in Tunisia make the management incomplete.

Keywords: SCLC, NCSLC, ROS1, PDL1

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Authors: Vishnu Varthan Vaithiyalingam Jagannathan, Lakshmi Karunanidhi Santhanalakshmi, Srividya Ammayappan Rajam

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Formononetin is the O-Methoxy Flavonol that has many pharmacological activities, which belongs to the flavonoid family. In the current study, activity of this molecule was evaluated in lung cancer cell lines. In general, flavonoids possess certain anticancer mechanism. Being a flavonoid subfamily, this molecule was subjected to evaluate cytotoxicity assay by MTT ((3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide)) stain, mode of cell death assay stained by acridine orange and ethidium bromide and Evaluation of Apoptosis pathway (extrinsic or intrinsic) by Caspase 3/7 stain and Rhodamine-123 stain. From the results, we could able to confirm that the investigatory molecule formononetin has anticancer activity and in future, the study will propose to evaluate the formononetin action against genetic changes occurs during lung cancer progression.

Keywords: Caspase 3/7, formononetin, lung cancer, Rhodamine-123

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Authors: Rubab Z. Kahlon, Ibtisam Butt, Isma Younis, Aamer G. Mufti

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Worldwide lung cancer 1.61 million cases were seen in both genders. Lung carcinoma is the major cause of both morbidity and mortality in the world. Purpose of the present study was to describe the spatio- temporal trends of lung cancer in both genders. A retrospective study was conducted. Total 1498 patients of lung carcinoma were examined. Only lung cancer patients from all over the Punjab were included in the present study. MS Excel 2010 was used for data tabulation and calculation while the Arc GIS version 9.3 was used for geographical representation of the data. 1498 cases of Lung cancer were found from 2008-2012. The number of male patients was 1236 and female was 262. Majority of the patients were from Lahore districts with 807 patients. Lung cancer was more prevalent in male as compared to female in our region. Increase in the prevalence of lung cancer was prominently seen in the most populated and industrial areas of the Punjab province. Time trend of five years showed fluctuation in the lung cancer incidence during the study period.

Keywords: districts, gender, lung cancer trends, Punjab province of Pakistan

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Authors: Moiseenko F. V., Volkov N. M., Zhabina A. S., Stepanova E. O., Kirillov A. V., Myslik A. V., Artemieva E. V., Agranov I. R., Oganesyan A. P., Egorenkov V. V., Abduloeva N. H., Aleksakhina S. Yu., Ivantsov A. O., Kuligina E. S., Imyanitov E. N., Moiseyenko V. M.

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Analysis of ctDNA in patients with NSCLC is an emerging biomarker. Multiple research efforts of quantitative or at least qualitative analysis before and during the first periods of treatment with TKI showed the prognostic value of ctDNA clearance. Still, these important results are not incorporated in clinical standards. We evaluated the role of ctDNA in EGFR-mutated NSCLC receiving first-line TKI. Firstly, we analyzed sequential plasma samples from 30 patients that were collected before intake of the first tablet (at baseline) and at 6, 12, 24, 36, and 48 hours after the “starting point.” EGFR-M+ allele was measured by ddPCR. Afterward, we included sequential qualitative analysis of ctDNA with cobas® EGFR Mutation Test v2 from 99 NSCLC patients before the first dose, after 2 and 4 months of treatment, and on progression. Early response analysis showed the decline of EGFR-M+ level in plasma within the first 48 hours of treatment in 11 subjects. All these patients showed objective tumor response. 10 patients showed either elevation of EGFR-M+ plasma concentration (n = 5) or stable content of circulating EGFR-M+ after the start of the therapy (n = 5); only 3 of these patients achieved an objective response (p = 0.026) when compared to the former group). The rapid decline of plasma EGFR-M+ DNA concentration also predicted for longer PFS (13.7 vs. 11.4 months, p = 0.030). Long-term ctDNA monitoring showed clinically significant heterogeneity of EGFR-mutated NSCLC treated with 1st line TKIs in terms of progression-free and overall survival. Patients without detectable ctDNA at baseline (N = 32) possess the best prognosis on the duration of treatment (PFS: 24.07 [16.8-31.3] and OS: 56.2 [21.8-90.7] months). Those who achieve clearance after two months of TKI (N = 42) have indistinguishably good PFS (19.0 [13.7 – 24.2]). Individuals who retain ctDNA after 2 months (N = 25) have the worst prognosis (PFS: 10.3 [7.0 – 13.5], p = 0.000). 9/25 patients did not develop ctDNA clearance at 4 months with no statistical difference in PFS from those without clearance at 2 months. Prognostic heterogeneity of EGFR-mutated NSCLC should be taken into consideration in planning further clinical trials and optimizing the outcomes of patients.

Keywords: NSCLC, EGFR, targeted therapy, ctDNA, prognosis

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Authors: Emad A. Shalaby

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Cancer is a disease that causes abnormal cell proliferation and invades nearby tissues. Lung cancer is the second most frequent cancer worldwide. Natural anti-cancer drugs have been developed with low side effects and toxicity. Citrus peels and extracts have been demonstrated to have significant pharmacological and physiological effects as a result of the high concentration of phenolic compounds found in citrus fruits, particularly peels. Tangerine peels can serve as an effective source of bioactive substances such as phenolics, flavonoids, and catechins, which have antioxidant, antibacterial, anticancer, and anti-inflammatory properties. Consequently, this work aims to determine the anticancer activity of ethanol extract of Tangerine peels against the A549 cell line and identify the phenolic compound profile (19 compounds) by using HPLC. Anticancer and antioxidant potentials of the extract were evaluated by MTT assay and TLC- TLC-bioautography sprayed with DPPH reagent, respectively. The obtained results revealed that tangerine peel extract showed significant activity against the A549 cell line with IC50 of 97.66 μg/mL. HPLC analysis proved that the highest concentration is naringenin 464.05 mg/g. More studies indicate that naringenin has significant anticancer potential on A549 cancer cells. The results showed that naringenin binds t0 EGFR protein in A549 with high binding affinity and thus may reduce lung cancer cell migration and enhance the apoptosis of cancer cells. From the obtained results it could be concluded that tangerine peel extract is an effective anti-cancer agent that may potentially serve as a natural therapeutic option for lung cancer treatment.

Keywords: tangerine peel, A549 cell line, anticancer, naringenin, HPLC analysis, naringenin, TLC bioautography

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Authors: Shiva Shakori Poshteh

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Lung cancer is a highly prevalent and devastating disease, representing a significant global health concern with profound implications for healthcare systems and society. Its high incidence, mortality rates, and late-stage diagnosis contribute to its formidable nature. To address these challenges, nanoparticle-based drug delivery has emerged as a promising therapeutic strategy. Curcumin (CUR), a natural compound derived from turmeric, has garnered attention as a potential nanomedicine for lung cancer treatment. Nanoparticle formulations of CUR offer several advantages, including improved drug delivery efficiency, enhanced stability, controlled release kinetics, and targeted delivery to lung cancer cells. CUR exhibits a diverse array of effects on cancer cells. It induces apoptosis by upregulating pro-apoptotic proteins, such as Bax and Bak, and downregulating anti-apoptotic proteins, such as Bcl-2. Additionally, CUR inhibits cell proliferation by modulating key signaling pathways involved in cancer progression. It suppresses the PI3K/Akt pathway, crucial for cell survival and growth, and attenuates the mTOR pathway, which regulates protein synthesis and cell proliferation. CUR also interferes with the MAPK pathway, which controls cell proliferation and survival, and modulates the Wnt/β-catenin pathway, which plays a role in cell proliferation and tumor development. Moreover, CUR exhibits potent antioxidant activity, reducing oxidative stress and protecting cells from DNA damage. Utilizing CUR as a standalone treatment is limited by poor bioavailability, lack of targeting, and degradation susceptibility. Nanoparticle-based delivery systems can overcome these challenges. They enhance CUR’s bioavailability, protect it from degradation, and improve absorption. Further, Nanoparticles enable targeted delivery to lung cancer cells through surface modifications or ligand-based targeting, ensuring sustained release of CUR to prolong therapeutic effects, reduce administration frequency, and facilitate penetration through the tumor microenvironment, thereby enhancing CUR’s access to cancer cells. Thus, nanoparticle-based CUR delivery systems promise to improve lung cancer treatment outcomes. This article provides an overview of lung cancer, explores CUR nanoparticles as a treatment approach, discusses the benefits and challenges of nanoparticle-based drug delivery, and highlights prospects for CUR nanoparticles in lung cancer treatment. Future research aims to optimize these delivery systems for improved efficacy and patient prognosis in lung cancer.

Keywords: lung cancer, curcumin, nanomedicine, nanoparticle-based drug delivery

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Authors: Nilubon Kurubanjerdjit, Nattakarn Iam-On, Ka-Lok Ng

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MicroRNAs are small non-coding RNA found in many different species. They play crucial roles in cancer such as biological processes of apoptosis and proliferation. The identification of microRNA-target genes can be an essential first step towards to reveal the role of microRNA in various cancer types. In this paper, we predict miRNA-target genes for lung cancer by integrating prediction scores from miRanda and PITA algorithms used as a feature vector of miRNA-target interaction. Then, machine-learning algorithms were implemented for making a final prediction. The approach developed in this study should be of value for future studies into understanding the role of miRNAs in molecular mechanisms enabling lung cancer formation.

Keywords: microRNA, miRNAs, lung cancer, machine learning, Naïve Bayes, SVM

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Authors: Drashti G. Daraji, Rosa E. Moo-Puc, Hitesh D. Patel

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Substituted 2-Thioimidazole analogues have been synthesized and confirmed by advanced spectroscopic techniques. Among them, ten compounds have been selected and evaluated for their in vitro anti-cancer activity at the National Cancer Institute (NCI) for testing against a panel of 60 different human tumor cell lines derived from nine neoplastic cancer types. Furthermore, synthesized compounds were tested for their in vitro antiprotozoal activity, and none of them exhibited significant potency against antiprotozoans. It was observed that the tested all compounds seem effective on the UACC-62 melanoma cancer cell line as compared to other cancer cell lines and also exhibited the least potent in the Non-Small Cell Lung Cancer cell line in one-dose screening. In silico studies of these derivatives were carried out by molecular docking techniques and Absorption, Distribution, Metabolism, and Excretion (ADME) using Schrödinger software to find potent B-Raf kinase inhibitor (PDB ID: 3OG7). All the compounds have been performed for docking study; Compound D4 has a good docking score for melanoma cancer as compared with other.

Keywords: anticancer activity, cancer cell line, 2-thio imidazole, one-dose assay, molecular docking

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Authors: Fakhrosadat Sajjadian

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The majority of deaths in cancer patients are caused by distant metastasis. Breast cancer shows a unique spread pattern, often affecting bone, liver, lung, and brain. Breast cancer can be categorized into various subtypes according to gene expression patterns, and these subtypes exhibit specific preferences for organs where metastasis occurs. Breast tumors with luminal characteristics have a preference for spreading to the bone, whereas basal-like breast cancer (BLBC) shows a tendency to metastasize to the lungs. Still, the mechanisms behind this particular pattern of metastasis in organs have yet to be fully understood. In this evaluation, we will outline the latest progress in molecular signaling pathways and treatment methods for breast cancer lung metastasis.

Keywords: lung cancer, liver cancer, diagnosis, BLBC, metastasis

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Authors: Ipsita Biswas, Arnab Sarkar, Ashikur Rahaman, Gopeswar Mukherjee, Subhrangsu Chatterjee, Shamee Bhattacharjee, Deba Prasad Mandal

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One of the major reasons for the high mortality rate of lung cancer is the substantial delays in disease detection at late metastatic stages. It is of utmost importance to understand the detailed molecular signaling and detect the molecular markers that can be used for the early diagnosis of cancer. Several studies explored the emerging roles of long noncoding RNAs (lncRNAs) in various cancers as well as lung cancer. A long non-coding RNA LINC00273 was recently discovered to promote cancer cell migration and invasion, and its positive correlation with the pathological stages of metastasis may prove it to be a potential target for inhibiting cancer cell metastasis. Comparing real-time expression of LINC00273 in various human clinical cancer tissue samples with normal tissue samples revealed significantly higher expression in cancer tissues. This long intergenic noncoding RNA was found to be highly expressed in human liver tumor-initiating cells, human gastric adenocarcinoma AGS cell line, as well as human non-small cell lung cancer A549 cell line. SiRNA and shRNA-induced knockdown of LINC00273 in both in vitro and in vivo nude mice significantly subsided AGS and A549 cancer cell migration and invasion. LINC00273 knockdown also reduced TGF-β induced SNAIL, SLUG, VIMENTIN, ZEB1 expression, and metastasis in A549 cells. Plenty of reports have suggested the role of microRNAs of the miR200 family in reversing epithelial to mesenchymal transition (EMT) by inhibiting ZEB transcription factors. In this study, hsa-miR-200a-3p was predicted via IntaRNA-Freiburg RNA tools to be a potential target of LINC00273 with a negative free binding energy of −8.793 kcal/mol, and this interaction was verified as a confirmed target of LINC00273 by RNA pulldown, real-time PCR and luciferase assay. Mechanistically, LINC00273 accelerated TGF-β induced EMT by sponging hsa-miR-200a-3p which in turn liberated ZEB1 and promoted prometastatic functions in A549 cells in vitro as verified by real-time PCR and western blotting. The similar expression patterns of these EMT regulatory pathway molecules, viz. LINC00273, hsa-miR-200a-3p, ZEB1 and TGF-β, were also detected in various clinical samples like breast cancer tissues, oral cancer tissues, lung cancer tissues, etc. Overall, this LINC00273 mediated EMT regulatory signaling can serve as a potential therapeutic target for the prevention of lung cancer metastasis.

Keywords: epithelial to mesenchymal transition, long noncoding RNA, microRNA, non-small-cell lung carcinoma

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Authors: Rhea Kapoor

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Fractal dimension provides a way to characterize non-geometric shapes like those found in nature. The purpose of this research is to estimate Minkowski fractal dimension of human lung images for early detection of lung cancer. Lung cancer is the leading cause of death among all types of cancer and an early histopathological analysis will help reduce deaths primarily due to late diagnosis. A Python application program, PathoPy2.0, was developed for analyzing medical images in pixelated format and estimating Minkowski fractal dimension using a new box-counting algorithm that allows windowing of images for more accurate calculation in the suspected areas of cancerous growth. Benchmark geometric fractals were used to validate the accuracy of the program and changes in fractal dimension of lung images to indicate the presence of issues in the lung. The accuracy of the program for the benchmark examples was between 93-99% of known values of the fractal dimensions. Fractal dimension values were then calculated for lung images, from National Cancer Institute, taken over time to correctly detect the presence of cancerous growth. For example, as the fractal dimension for a given lung increased from 1.19 to 1.27 due to cancerous growth, it represents a significant change in fractal dimension which lies between 1 and 2 for 2-D images. Based on the results obtained on many lung test cases, it was concluded that fractal dimension of human lungs can be used to diagnose lung cancer early. The ideas behind PathoPy2.0 can also be applied to study patterns in the electrical activity of the human brain and DNA matching.

Keywords: fractals, histopathological analysis, image processing, lung cancer, Minkowski dimension

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Authors: Abraham J. Rizkalla, Joanne F. Irons, Christopher Q. Cao

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Purpose: Lobectomy was considered the standard of care for early-stage non-small lung cancer (NSCLC) after the Lung Cancer Study Group trial demonstrated increased locoregional recurrence for sublobar resections. However, there has been heightened interest in segmentectomies for selected patients with peripheral lesions ≤2cm, as investigated by the JCOG0802 and CALGB140503 trials. Minimally invasive robotic surgery facilitates segmentectomies with improved maneuverability and visualization of intersegmental planes using indocyanine green. We hereby present a patient who underwent robotic lingulectomy for an undiagnosed ground-glass opacity. Methodology: This video demonstrates a robotic portal lingulectomy using three 8mm ports and a 12mm port. Stereoscopic direct vision facilitated the identification of the lingula artery and vein, and intra-operative bronchoscopy was performed to confirm the lingula bronchus. The intersegmental plane was identified by indocyanine green and a near-infrared camera. Thorough lymph node sampling was performed in accordance with international standards. Results: The 18mm lesion was successfully excised with clear margins to achieve R0 resection with no evidence of malignancy in the 8 lymph nodes sampled. Histopathological examination revealed lepidic predominant adenocarcinoma, pathological stage IA. Conclusion: This video presentation exemplifies the standard approach for robotic portal lingulectomy in appropriately selected patients.

Keywords: lung cancer, robotic segmentectomy, indocyanine green, lingulectomy

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Authors: Ayeshmanthe Rathnayake, Ashutosh Hardikar

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Introduction: Lung cancer is the most common cause of cancer death in Australia, with more than 13000 cases per year. Until now, there has been a major deficiency of national comprehensive thoracic surgery data. The thoracic workload for surgeons as well as caseload per unit, is highly variable, with some centres performing less than 15 cases per annum, thus raising concerns about optimal care at low-volume sites. This is an attempt to review the outcomes of lung cancer surgery in Tasmania. Method: The objective of this study is to determine the surgical outcomes of lung cancer surgery at Royal Hobart Hospital (RHH) with the primary outcome of surgical mortality. Four hundred fifty-one cases were analysed retrospectively from 2010 to May 2022. Results: A total of 451 patients underwent thoracic surgery with a primary diagnosis of lung cancer. The primary outcome of 30-day mortality was <0.5%. The mean age was 65.3 years, with male predominance and a 4.2% prevalence of Indigenous Australians. The mean LOS was 7.5 days. The surgical approach was either VATS (50.3%) or Thoracotomy (49.7%), with a trend towards the former in recent years with an increase in the proportion of VATS from 18.2% to 51% (p<0.05) in complex resections since 2019. A corresponding reduction in conversion rate to open was observed (18% vs. 5.5%), and there were no deaths within this subgroup. Lung resections were divided into lobectomy (55.4%), wedge resection (36.8%), segmentectomy (2.9%) and pneumonectomy (4.9%). The RHH demonstrates good surgical outcomes for lung cancer and provides a sustainable service for Tasmania. Conclusion: This retrospective study reports the surgical outcomes of lung cancer surgery at the Royal Hobart Hospital, thereby providing insight into the surgical management of lung cancer in the state thus far. The state has been slow to catch up on the minimally invasive program, but the overall results have been comparable to most peers.

Keywords: lung cancer, thoracic surgery, lung resection, surgical outcomes

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Authors: Satoshi Furukawa, Satomu Morita, Katsuji Nishi, Masahito Hitosugi

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A 75-year-old woman took thyroidectomy forty years previously. Enlarged masses were seen at autopsy just above and below the left clavicle. We proved the diagnosis of papillary thyroid cancer (PTC) and lung metastasis by histological examinations. The prognosis of PTC is excellent; the 10-year survival rate ranges between 85 and 99%. Lung metastases may be found in 10% of the patients with PTC. We report an unusual case of recurrence of PTC with metastasis to the lung.

Keywords: papillary thyroid cancer, lung metastasis, autopsy, histopathological findings

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Authors: Ziyun Li, Jiudi Zhong, June Zhang

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Background: The diagnosis and treatment of lung cancer lead to varying degrees of psychological and social maladjustment among patients with lung cancer. Understanding psychosocial adjustment (PA) and its influencing factors in young and middle-aged lung cancer patients is essential to help them return to society and lead a normal life. Objectives: This study aims to examine the mediating role of resilience in the association between stigma and psychosocial adjustment among young and middle-aged patients with lung cancer. Methods: A total of 235 patients with lung cancer were recruited from a tertiary grade A cancer center in southern China and investigated using a self-designed general information questionnaire, Psychosocial Adjustment to Illness Scale Self-Report, Social Impact Scale, and Conner-Davidson Resilience Scale. Results: The mean score of PA was (32.61±14.75), and its influencing factors included treatment modalities, stigma, and resilience. The total effect of stigma on PA was significant (total effect=0.418, SE=0.045, 95%CI [0.310-0.497]), and a positive indirect effect was identified for stigma on PA via resilience (indirect effect=0.143, SE=0.041, 95% CI [0.075-0.236]). Conclusion: Stigma and resilience are significantly associated with PA, and resilience is also a mediating variable between stigma and PA. This study suggests that individualized interventions can be made to improve the PA by alleviating their stigma, or by enhancing their resilience in young and middle-aged lung cancer patients.

Keywords: psychosocial adjustment, lung cancer, cancer caring, nursing, young and middle-aged

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Authors: Rahaba Marima, Clement Penny

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The Health-related quality of life (HRQoL) for HIV positive patients has improved since the introduction of the highly active antiretroviral treatment (HAART). However, in the present HAART era, HIV co-morbidities such as lung cancer, a non-AIDS (NAIDS) defining cancer have been documented to be on the rise. Under normal physiological conditions, cells grow, repair and proliferate through the cell-cycle as cellular homeostasis is important in the maintenance and proper regulation of tissues and organs. Contrarily, the deregulation of the cell-cycle is a hallmark of cancer, including lung cancer. The association between lung cancer and the use of HAART components such as Efavirenz (EFV) is poorly understood. This study aimed at elucidating the effects of EFV on the cell-cycle genes’ expression in lung cancer. For this purpose, the human cell-cycle gene array composed of 84 genes was evaluated on both normal lung fibroblasts (MRC-5) cells and adenocarcinoma (A549) lung cells, in response to 13µM EFV or 0.01% vehicle. The ±2 up or down fold change was used as a basis of target selection, with p < 0.05. Additionally, RT-qPCR was done to validate the gene array results. Next, In-silico bio-informatics tools, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Reactome, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Ingenuity Pathway Analysis (IPA) were used for gene/gene interaction studies as well as to map the molecular and biological pathways influenced by the identified targets. Interestingly, the DNA damage response (DDR) pathway genes such as p53, Ataxia telangiectasia mutated and Rad3 related (ATR), Growth arrest and DNA damage inducible alpha (GADD45A), HUS1 checkpoint homolog (HUS1) and Role of radiation (RAD) genes were shown to be upregulated following EFV treatment, as revealed by STRING analysis. Additionally, functional enrichment analysis by the KEGG pathway revealed that most of the differentially expressed gene targets function at the cell-cycle checkpoint such as p21, Aurora kinase B (AURKB) and Mitotic Arrest Deficient-Like 2 (MAD2L2). Core analysis by IPA revealed that p53 downstream targets such as survivin, Bcl2, and cyclin/cyclin dependent kinases (CDKs) complexes are down-regulated, following exposure to EFV. Furthermore, Reactome analysis showed a significant increase in cellular response to stress genes, DNA repair genes, and apoptosis genes, as observed in both normal and cancerous cells. These findings implicate the genotoxic effects of EFV on lung cells, provoking the DDR pathway. Notably, the constitutive expression of this pathway (DDR) often leads to uncontrolled cell proliferation and eventually tumourigenesis, which could be the attribute of HAART components’ (such as EFV) effect on human cancers. Targeting the cell-cycle and its regulation holds a promising therapeutic intervention to the potential HAART associated carcinogenesis, particularly lung cancer.

Keywords: cell-cycle, DNA damage response, Efavirenz, lung cancer

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Authors: Ammar Asma, Bouafia Nabiha, Dhahri Meriem, Ben Cheikh Asma, Ezzi Olfa, Chafai Rim, Njah Mansour

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Despite recent advances in treatment of the lung cancer patients, the prognosis remains poor. Information is limited regarding health related quality of life (QOL) status of advanced lung cancer patients. The purposes of this study were: to assess patient reported symptom burden, to measure their QOL, and to identify determinant factors associated with QOL. Materials/Methods: A cross sectional study of 60 patients was carried out from over the period of 03 months from February 1st to 30 April 2016. Patients were recruited in two department of health care: Pneumology department in a university hospital in Sousse and an oncology unit in a University Hospital in Kairouan. Patients with advanced stage (III and IV) of lung cancer who were hospitalized or admitted in the day hospital were recruited by convenience sampling. We used a questionnaire administrated and completed by a trained interviewer. This questionnaire is composed of three parts: demographic, clinical and therapeutic information’s, QOL measurements: based on the SF-36 questionnaire, Symptom’s burden measurement using the Lung Cancer Symptom Scale (LCSS). To assess Correlation between symptoms burden and QOL, we compared the scores of two scales two by two using the Pearson correlation. To identify factors influencing QOL in Lung cancer, a univariate statistical analysis then, a stepwise backward approach, wherein the variables with p< 0.2, were carried out to determine the association between SF-36 scores and different variables. Results: During the study period, 60 patients consented to complete symptom and quality of life questionnaires at a single point time (72% were recruited from day hospital). The majority of patients were male (88%), age ranged from 21 to 79 years with a mean of 60.5 years. Among patients, 48 (80%) were diagnosed as having non-small cell lung carcinoma (NSCLC). Approximately, 60 % (n=36) of patients were in stage IV, 25 % in stage IIIa and 15 % in stage IIIb. For symptom burden, the symptom burden index was 43.07 (Standard Deviation, 21.45). Loss of appetite and fatigue were rated as the most severe symptoms with mean scores (SD): 49.6 (25.7) and 58.2 (15.5). The average overall score of SF36 was 39.3 (SD, 15.4). The physical and emotional limitations had the lowest scores. Univariate analysis showed that factors which influence negatively QOL were: married status (p<0.03), smoking cessation after diagnosis (p<0.024), LCSS total score (p<0.001), LCSS symptom burden index (p<0.001), fatigue (p<0.001), loss of appetite (p<0.001), dyspnea (p<0.001), pain (p<0.002), and metastatic stage (p<0.01). In multivariate analysis, unemployment (p<0.014), smoking cessation after diagnosis (p<0.013), consumption of analgesic (p<0.002) and the indication of an analgesic radiotherapy (p<0.001) are revealed as independent determinants of QOL. The result of the correlation analyses between total LCSS scores and the total and individual domain SF36 scores was significant (p<0.001); the higher total LCSS score is, the poorer QOL is. Conclusion: A built in support of lung cancer patients would better control the symptoms and promote the QOL of these patients.

Keywords: quality of life, lung cancer, metastasis, symptoms burden

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Authors: Min-Chien Su, Tzu-Hsuan Hsu, Guan-Xuan Wu, Shyh-Ming Kuo

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Lung cancer is one of the clinically challenging malignant diseases worldwide. For efficient therapeutics in cancer, combination therapy has developed to acquire a better outcome. PLK-1 was one of the major factors affecting cell mitosis in cancer cells, its inhibitor Bi6727 was proven effective in treating several different cancers namely oral cancer, colon cancer and lung cancer. Despite its low toxicity toward normal cells compared to traditional chemotherapy, it is still yet to be evaluated in detail. Livistona Chinensis (LC) is a Chinese herb that used as a traditional prescription to treat lung cancer. Due to the uncertainty of the efficacy of LC, we utilized a water extraction method to extract the Livistona Chinensis and then lyophilized into powder for further study. In this study we investigated the antiproliferation activities of Bi6727 and LC extracts (LCE) on A549 non-small lung cancer cells. The IC50 of Bi6727 and LCE on A549 are 60 nM and 0.8 mg/mL, respectively. The fluorescent staining images shown nucleolus damage in cells treated with Bi6727 and mitochondrial damage after treated with LCE. A549 cells treated with Bi6727 and LCE showed increased expression of Bax, Caspase-3 and Caspase-9 proteins from Western blot assay. LCE also inhibited A549 cells growth keeping cells at G2-M phase from cell cycle assay. Apoptosis assay results showed that LCE induced late apoptosis of A549 cells. JC-1 assay showed that the mitochondria damaged at the LCE concentration of 0.4 mg/mL. In our preliminary anti-proliferation test of combined LCE and Bi-6727 on A549 cells, we found a dramatically decrease in proliferation after treated with LCE first for 24-h and then Bi-6727 for extra 24-h. This was an important finding regarding synergistic anti-proliferation effect of these drugs, However, the usage, the application sequence of LCE and Bi-6727 on A549 cells and their related mechanisms still need to be evaluated. In summary, the drugs exerted anti-proliferation effect on A549 cells independently. We hopefully combine the usage of these two drugs will bring a different and potential outcome in treating lung cancer.

Keywords: anti-proliferation, A549, Livistona Chinensis fruit extracts, PLK-1 inhibitor

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Authors: Adebisi Adunola Demehin, Wanlaya Thamnarak, Jaruwan Chatwichien, Chatchakorn Eurtivong, Kiattawee Choowongkomon, Somsak Ruchirawat, Nopporn Thasana

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The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein involved in cellular signalling processes and, its aberrant activity is crucial in the development of many cancers such as lung cancer. Selaginellaceae are fern allies that have long been used in Chinese traditional medicine to treat various cancer types, especially lung cancer. Biflavonoids, the major secondary metabolites in Selaginellaceae, have numerous pharmacological activities, including anti-cancer and anti-inflammatory. For instance, amentoflavone induces a cytotoxic effect in the human NSCLC cell line via the inhibition of PARP-1. However, to the best of our knowledge, there are no studies on biflavonoids as EGFR inhibitors. Thus, this study aims to investigate the EGFR inhibitory activities of biflavonoids isolated from Selaginella siamensis and Selaginella bryopteris. Amentoflavone, tetrahydroamentoflavone, sciadopitysin, robustaflavone, robustaflavone-4-methylether, delicaflavone, and chrysocauloflavone were isolated from the ethyl-acetate extract of the whole plants. The structures were determined using NMR spectroscopy and mass spectrometry. In vitro study was conducted to evaluate their cytotoxicity against A549, HEPG2, and T47D human cancer cell lines using the MTT assay. In addition, a target-based assay was performed to investigate their EGFR inhibitory activity using the kinase inhibition assay. Finally, a molecular docking study was conducted to predict the binding modes of the compounds. Robustaflavone-4-methylether and delicaflavone showed the best cytotoxic activity on all the cell lines with IC50 (µM) values of 18.9 ± 2.1 and 22.7 ± 3.3 on A549, respectively. Of these biflavonoids, delicaflavone showed the most potent EGFR inhibitory activity with an 84% relative inhibition at 0.02 nM using erlotinib as a positive control. Robustaflavone-4-methylether showed a 78% inhibition at 0.15 nM. The docking scores obtained from the molecular docking study correlated with the kinase inhibition assay. Robustaflavone-4-methylether and delicaflavone had a docking score of 72.0 and 86.5, respectively. The inhibitory activity of delicaflavone seemed to be linked with the C2”=C3” and 3-O-4”’ linkage pattern. Thus, this study suggests that the structural features of these compounds could serve as a basis for developing new EGFR-TK inhibitors.

Keywords: anticancer, biflavonoids, EGFR, molecular docking, Selaginellaceae

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Authors: Soheil Zorofchian Moghadamtousi, Habsah Abdul Kadir, Mohammadjavad Paydar, Elham Rouhollahi, Hamed Karimian

Abstract:

The present study was designed to evaluate the molecular mechanisms of Annona muricata leaves ethyl acetate extract (AMEAE) against lung cancer A549 cells. Cell viability analysis revealed the selective cytotoxic effect of AMEAE towards A549 cells. Treatment of A549 cells with AMEAE significantly elevated the reactive oxygen species formation, followed by attenuation of mitochondrial membrane potential via upregulation of Bax and downregulation of Bcl-2, accompanied by cytochrome c release to the cytosol. The released cytochrome c triggered the activation of caspase-9 followed by caspase-3. In addition, AMEAE-induced apoptosis was accompanied by cell cycle arrest at G1 phase. Our data showed for the first time that AMEAE inhibited the proliferation of A549 cells, leading to cell cycle arrest and programmed cell death through activation of the mitochondrial-mediated signaling pathway.

Keywords: Annona muricata, lung cancer, apoptosis, mitochondria

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Authors: Hirowati Ali, Aisyah Ellyanti, Dewi Rusnita, Septelia Inawati Wanandi

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Stem cell has been known for its potency to be differentiated in many cells. Recently stem cell has been used for many treatment of degenerative medicine. It is still controversy whether stem cell can be used for therapy or these cells can activate cancer stem cell. SCUBE2 is a novel secreted and membrane-anchored protein which has been reported to its role in better prognosis and inhibition of cancer cell proliferation. Our study aims to observe whether stem cell can up-regulate SCUBE2 gene in MCF7 breast cancer cell line. We used in vitro study using MCF-7 cell treated with stem cell derived from placenta Wharton's jelly which has been known for its stemness and widely used. Our results showed that MCF-7 cell line grows up rapidly in 6-well culture dish. Stem cell was cultured in 6-well dish. After 50%-60% MCF-7 confluence, we co-cultured these cells with stem cells for 24 hours and 48 hours. We hypothesize SCUBE2 gene which is previously known for its higher expression in better prognosis of breast cancer, is up-regulated after stem cells addition in MCF7 culture dishes.

Keywords: breast cancer cells, inhibition of cancer cells, mesenchymal stem cells, SCUBE2

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Authors: Kirti Hira, A. Sajeli Begum, S. Mahibalan, Poorna Chandra Rao

Abstract:

Introduction: Cancer is one of the leading causes of death worldwide. Although existing therapy effectively kills cancer cells, they do affect normal growing cells leading to many undesirable side effects. Hence there is need to develop effective as well as safe drug molecules to combat cancer, which is possible through phyto-research. The currently available plant-derived blockbuster drugs are the example for this. In view of this, an investigation was done to identify cytotoxic lead molecules from Hedyotis umbellata (Family Rubiaceae), a widely distributed weed in India. Materials and Methods: The methanolic extract of the whole plant of H. umbellata (MHU), prepared through Soxhlet extraction method was further fractionated with diethyl ether and n-butanol, successively. MHU, ether fraction (EMHU) and butanol fraction (BMHU) were lyophilized and were tested for the cytotoxic effect using 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay against non-small cell lung cancer (NSCLC) A549 cell lines. The potentially active EMHU was subjected to chromatographic purification using normal-phase silica columns, in order to isolate the responsible bioactive compounds. The isolated pure compounds were tested for their cytotoxic effect by MTT assay against A549 cells. Compound-3, which was found to be most active, was characterized using IR, 1H- and 13C-NMR and MS analysis. The study was further extended to decipher the mechanism of action of cytotoxicity of compound-3 against A549 cells through various in vitro cellular models. Cell cycle analysis was done using flow cytometry following PI (Propidium Iodide) staining. Protein analysis was done using Western blot technique. Results: Among MHU, EMHU, and BMHU, the non-polar fraction EMHU demonstrated a significant dose-dependent cytotoxic effect with IC50 of 67.7μg/ml. Chromatography of EMHU yielded seven compounds. MTT assay of isolated compounds explored compound-3 as potentially active one, which inhibited the growth of A549 cells with IC50value of 14.2μM. Further, compound-3 was identified as cedrelopsin, a coumarin derivative having molecular weight of 260. Results of in vitro mechanistic studies explained that cedrelopsin induced cell cycle arrest at G2/M phase and down-regulated the expression of G2/M regulatory proteins such as cyclin B1, cdc2, and cdc25C, dose dependently. This is the first report that explores the cytotoxic mechanism of cedrelopsin. Conclusion: Thus a potential small lead molecule, cedrelopsin isolated from H. umbellata, showing antiproliferative effect mediated by G2/M arrest in A549 cells was discovered. The effect of cedrelopsin against other cancer cell lines followed by in vivo studies can be performed in future to develop a new drug candidate.

Keywords: A549, cedrelopsin, G2/M phase, Hedyotis umbellata

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Authors: Eunhwa Jun

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This case report describes the misdiagnosis of a patient who presented with right arm pain as cervical disc herniation. The patient had several underlying conditions, including hypertension, diabetes mellitus, liver cirrhosis, a history of lung cancer with left lower lobe lobectomy, and adjuvant chemoradiotherapy. An external cervical spine MRI revealed central protruding discs at the C4-5-6-7 levels. Despite treatment with medication and epidural blocks, the patient's pain persisted. A C-RACZ procedure was planned, but the patient's pain had worsened before admission. Using ultrasound, a brachial plexus block was attempted, but the brachial plexus eluded clear visualization, hinting at underlying neurological complexities. Chest CT revealed a new, large soft tissue mass in the right supraclavicular region with adjacent right axillary lymphadenopathy, leading to the diagnosis of metastatic squamous cell carcinoma. Palliative radiation therapy and chemotherapy were initiated as part of the treatment plan, and the patient's pain score decreased to 3 out of 10 on the Numeric Rating Scale (NRS), revealing the pain was due to metastatic lung cancer.

Keywords: supraclavicula brachial plexus metastasis, cervical disc herniation, brachial plexus block, metastatic lung cancer

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Authors: Mehrnaz Mostafavi

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Lung cancer is one of the most harmful forms of cancer. The long-term survival rate of lung cancer patients treated by conventional modalities such as surgical resection, radiation, and chemotherapy remains far from satisfactory. Systemic drug delivery is rarely successful because only a limited amount of the chemotherapeutic drug targets lung tumor sites, even when administered at a high dose. Targeted delivery of drug molecules to organs or special sites is one of the most challenging research areas in pharmaceutical sciences. By developing colloidal delivery systems such as liposomes, micelles and nanoparticles a new frontier was opened for improving drug delivery. Nanoparticles with their special characteristics such as small particle size, large surface area and the capability of changing their surface properties have numerous advantages compared with other delivery systems. Targeted nanoparticle delivery to the lungs is an emerging area of interest.Multimodal or combination therapy represents a promising new method to fight disease. Therefore, a combination of different therapeutic strategies may be the best alternative to improve treatment outcomes for lung cancer. Photothermal therapy was proposed as a novel approach to treatment. In this work, photothermal therapy with gold nanoparticles and near infrared laser (NIR) irradiation was investigated.Four types of small (<100nm), NIR absorbing gold nanoparticles (nanospheres, nanorods) were synthesized using wet chemical methods and characterized by transmission electron microscopy, dynamic light scattering and UV-vis spectroscopy. Their synthesis and properties were evaluated, to determine their feasibility as a photothermal agent for clinical applications. In vitro cellular uptake studies of the nanoparticles into lung cancer cell lines was measured using light scattering microscopy.Small gold nanorods had good photothermal properties and the greatest cellular uptake, and were used in photothermal studies. Under 4W laser irradiation, an increase in temperature of 10°C and decrease in cell viability of up to 80% were obtained.

Keywords: photothermal, therapy, cancer, gold nanorods

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Authors: Yousif Mohamed Y. Abdallah

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This is an experimental study deals with detection, measurement and analysis of the periodic physiological organ motion during external beam radiotherapy; to improve the accuracy of the radiation field placement, and to reduce the exposure of healthy tissue during radiation treatments. The importance of this study is to detect the maximum path of the mobile structures during radiotherapy delivery, to define the planning target volume (PTV) and irradiated volume during both inspiration and expiration period and to verify the target volume. In addition to its role to highlight the importance of the application of Intense Guided Radiotherapy (IGRT) methods in the field of radiotherapy. The results showed (body contour was equally (3.17 + 0.23 mm), for left lung displacement reading (2.56 + 0.99 mm) and right lung is (2.42 + 0.77 mm) which the radiation oncologist to take suitable countermeasures in case of significant errors. In addition, the use of the image registration technique for automatic position control is predicted potential motion. The motion ranged between 2.13 mm and 12.2 mm (low and high). In conclusion, individualized assessment of tumor mobility can improve the accuracy of target areas definition in patients undergo Sterostatic RT for stage I, II and III lung cancer (NSCLC). Definition of the target volume based on a single CT scan with a margin of 10 mm is clearly inappropriate.

Keywords: respiratory motion, external beam radiotherapy, image processing, lung

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Authors: Omar Youssef, Aija Knuuttila, Paivi Piirilä, Virinder Sarhadi, Sakari Knuutila

Abstract:

Exhaled breath condensate (EBC) is a unique sample that allows studying different genetic changes in lung carcinoma through a non-invasive way. With the aid of next generation sequencing (NGS) technology, analysis of genetic mutations has been more efficient with increased sensitivity for detection of genetic variants. In order to investigate the possibility of applying this method for cancer diagnostics, mutations in EBC DNA from lung cancer patients and healthy individuals were studied by using NGS. The key aim is to assess the feasibility of using this approach to detect clinically important mutations in EBC. EBC was collected from 20 healthy individuals and 9 lung cancer patients (four lung adenocarcinomas, four 8 squamous cell carcinoma, and one case of mesothelioma). Mutations in hotpot regions of 22 genes were studied by using Ampliseq Colon and Lung cancer panel and sequenced on Ion PGM. Results demonstrated that all nine patients showed a total of 19 cosmic mutations in APC, BRAF, EGFR, ERBB4, FBXW7, FGFR1, KRAS, MAP2K1, NRAS, PIK3CA, PTEN, RET, SMAD4, and TP53. In controls, 15 individuals showed 35 cosmic mutations in BRAF, CTNNB1, DDR2, EGFR, ERBB2, FBXW7, FGFR3, KRAS, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, and TP53. Additionally, 45 novel mutations not reported previously were also seen in patients’ samples, and 106 novel mutations were seen in controls’ specimens. KRAS exon 2 mutations G12D was identified in one control specimen with mutant allele fraction of 6.8%, while KRAS G13D mutation seen in one patient sample showed mutant allele fraction of 17%. These findings illustrate that hotspot mutations are present in DNA from EBC of both cancer patients and healthy controls. As some of the cosmic mutations were seen in controls too, no firm conclusion can be drawn on the clinical importance of cosmic mutations in patients. Mutations reported in controls could represent early neoplastic changes or normal homeostatic process of apoptosis occurring in lung tissue to get rid of mutant cells. At the same time, mutations detected in patients might represent a non-invasive easily accessible way for early cancer detection. Follow up of individuals with important cancer mutations is necessary to clarify the significance of these mutations in both healthy individuals and cancer patients.

Keywords: exhaled breath condensate, lung cancer, mutations, next generation sequencing

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Authors: Salma Baig, Bakrudeen Ali Ahmad, Ainnul Hamidah Syahadah Azizan, Hapipah Mohd Ali, Elham Rouhollahi, Mahmood Ameen Abdulla

Abstract:

Free radical damage induced by reactive oxygen species (ROS) contributes to etiology of many chronic diseases, cancer being one of them. Recent studies have been successful in ROS targeted therapies via antioxidants using mouse models in cancer therapeutics. The present study was designed to scrutinize anticancer activity, antioxidant activity of 5 different extracts of Thymus serpyllum in MDA-MB-231, MCF-7, HepG2, HCT-116, PC3, and A549. Identification of the phytochemicals present in the most active extract of Thymus serpyllum was conducted using gas chromatography coupled with mass spectrophotometry and antioxidant activity was measured by using DPPH radical scavenging and FRAP assay. Anticancer impact of the extract in terms of IC50 was evaluated using MTT cell viability assay. Results revealed that the hexane extract showed the best anticancer activity in HepG2 (Liver Carcinoma Cell Line) with an IC50 value of 23 ± 0.14 µg/ml followed by 25 µg/ml in HCT-116 (Colon Cancer Cell Line), 30 µm/ml in MCF-7 (Breast Cancer Cell Line), 35 µg/ml in MDA-MB-231 (Breast Cancer Cell Line), 57 µg/ml in PC3 (Prostate Cancer Cell Line) and 60 µg/ml in A549 (Lung Carcinoma Cell Line). GC-MS profile of the hexane extract showed the presence of 31 compounds with carvacrol, thymol and thymoquione being the major compounds. Phenolics such as Vitamin E, terpinen-4-ol, borneol and phytol were also identified. Hence, here we present the first report on cytotoxicity of hexane extract of Thymus serpyllum extract in HepG2 cell line with a robust anticancer activity with an IC50 of 23 ± 0.14 µg/ml.

Keywords: Thymus serpyllum L., hexane extract, GC-MS profile, antioxidant activity, anticancer activity, HepG2 cell line

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Authors: Asghar Arif

Abstract:

Lung cancer has been recognized as one of the greatest common cancers, causing the annual mortality rate of about 1.2 million people in the world. Lung cancer is the most prevalent cancer in men and the third-most common cancer among women (after breast and digestive cancers).Recent evidences have shown the inflammatory process as one of the potential factors of cancer. Tuberculosis (TB), pneumonia, and chronic bronchitis are among the most important inflammation-inducing factors in the lungs, among which TB has a more profound role in the emergence of cancer.TB is one of the important mortality factors throughout the world, and 205,000 death cases are reported annually due to this disease. Chronic inflammation and fibrosis due to TB can induce genetic mutation and alternations. Parenchyma tissue of lung is involved in both diseases of TB and lung cancer, and continuous cough in lung cancer, morphological vascular variations, lymphocytosis processes, and generation of immune system mediators such as interleukins, are all among the factors leading to the hypothesis regarding the role of TB in lung cancer Some reports have shown that the induction of necrosis and apoptosis or TB reactivation, especially in patients with immune-deficiency, may result in increasing IL-17 and TNF_α, which will either decrease P53 activity or increase the expression of Bcl-2, decrease Bax-T, and cause the inhibition of caspase-3 expression due to decreasing the expression of mitochondria cytochrome oxidase. It has been also indicated that following the injection of BCG vaccine, the host immune system will be reinforced, and in particular, the rates of gamma interferon, nitric oxide, and interleukin-2 are increased. Therefore, CD4 + lymphocyte function will be improved, and the person will be immune against cancer.Numerous prospective studies have so far been conducted on the role of TB in lung cancer, and it seems that this disease is effective in that particular cancer.One of the main challenges of lung cancer is its correct and timely diagnosis. Unfortunately, clinical symptoms (such as continuous cough, hemoptysis, weight loss, fever, chest pain, dyspnea, and loss of appetite) and radiological images are similar in TB and lung cancer. Therefore, anti-TB drugs are routinely prescribed for the patients in the countries with high prevalence of TB, like Pakistan. Regarding the similarity in clinical symptoms and radiological findings of lung cancer, proper diagnosis is necessary for TB and respiratory infections due to nontuberculousmycobacteria (NTM). Some of the drug resistive TB cases are, in fact, lung cancer or NTM lung infections. Acid-fast staining and histological study of phlegm and bronchial washing, culturing and polymerase chain reaction TB are among the most important solutions for differential diagnosis of these diseases. Briefly, it is assumed that TB is one of the risk factors for cancer. Numerous studies have been conducted in this regard throughout the world, and it has been observed that there is a significant relationship between previous TB infection and lung cancer. However, to prove this hypothesis, further and more extensive studies are required. In addition, as the clinical symptoms and radiological findings of TB, lung cancer, and non-TB mycobacteria lung infections are similar, they can be misdiagnosed as TB.

Keywords: TB and lung cancer, TB people, TB servivers, TB and HIV aids

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Authors: Ismail Celik, Gulgun Ayhan Kilcigil, Berna Guven, Zumra Kara, Arzu Onay-Besikci

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Epidermal Growth Factor Receptor is the cell-surface receptor of the ErbB (erythroblastic leukemia viral oncogene homologue receptors) family of tyrosine kinases. It plays a vital role in regulating the proliferation and differentiation of cells. However, a variety of mechanisms, such as EGFR expression, mutation, and ligand-dependent receptor dimerization, are associated with the development of various activated EGFR tumors. EGFR is highly expressed in most solid tumors, including breast, head and neck cancer, non-small cell lung cancer (NSCLC), renal, ovarian, and colon cancers. Thus, specific EGFR inhibition plays one of the key roles in cancer treatment. The compounds used in the treatment as tyrosine kinase inhibitors are known to contain the benzimidazole isosterium indole, pazopanib, and axitinibin indazole rings. In addition, benzimidazoles have been shown to exhibit protein kinase inhibitory activity in addition to their different biological activities.Based on these data, it was planned and synthesized of some oxadiazole bearing benzimidazole derivatives [N-cyclohexyl-5-((2-phenyl/substitutedphenyl-1H-benzo[d]imidazole-1-yl) methyl)-1,3,4-oxadiazole-2-amine]. EGFR kinase inhibitory efficiency of the synthesized compounds was determined by comparing them with a known kinase inhibitor erlotinib in vitro, and two of the compounds bearing phenyl (19a) and 3,4-dibenzyloxyphenyl (21a) ring exhibited significant activities.

Keywords: benzimidazole, EGFR kinase inhibitory, oxadiazole, synthesis

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Authors: Elsie M. Nolte, Annie M. Joubert, Roy Lakier, Maryke Etsebeth, Jolene M. Helena, Marcel Verwey, Laurence Lafanechere, Anne E. Theron

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Treatment regimens for breast- and lung cancers may include both radiation- and chemotherapy. Ideally, a pharmaceutical agent which selectively sensitizes cancer cells to gamma (γ)-radiation would allow administration of lower doses of each modality, yielding synergistic anti-cancer benefits and lower metastasis occurrence, in addition to decreasing the side-effect profiles. A range of 2-methoxyestradiol (2-ME) analogues, namely 2-ethyl-3-O-sulphamoyl-estra-1,3,5 (10) 15-tetraene-3-ol-17one (ESE-15-one), 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol) and 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16) were in silico-designed by our laboratory, with the aim of improving the parent compound’s bioavailability in vivo. The main effect of these compounds is the disruption of microtubule dynamics with a resultant mitotic accumulation and induction of programmed cell death in various cancer cell lines. This in vitro study aimed to determine the cellular responses involved in the radiation sensitization effects of these analogues at low doses in breast- and lung cancer cell lines. The oestrogen receptor positive MCF-7-, oestrogen receptor negative MDA-MB-231- and triple negative BT-20 breast cancer cell lines as well as the A549 lung cancer cell line were used. The minimal compound- and radiation doses able to induce apoptosis were determined using annexin-V and cell cycle progression markers. These doses (cell line dependent) were used to pre-sensitize the cancer cells 24 hours prior to 6 gray (Gy) radiation. Experiments were conducted on samples exposed to the individual- as well as the combination treatment conditions in order to determine whether the combination treatment yielded an additive cell death response. Morphological studies included light-, fluorescence- and transmission electron microscopy. Apoptosis induction was determined by flow cytometry employing annexin V, cell cycle analysis, B-cell lymphoma 2 (Bcl-2) signalling, as well as reactive oxygen species (ROS) production. Clonogenic studies were performed by allowing colony formation for 10 days post radiation. Deoxyribonucleic acid (DNA) damage was quantified via γ-H2AX foci and micronuclei quantification. Amplification of the p53 signalling pathway was determined by western blot. Results indicated that exposing breast- and lung cancer cells to nanomolar concentrations of these analogues 24 hours prior to γ-radiation induced more cell death than the compound- and radiation treatments alone. Hypercondensed chromatin, decreased cell density, a damaged cytoskeleton and an increase in apoptotic body formation were observed in cells exposed to the combination treatment condition. An increased number of cells present in the sub-G1 phase as well as increased annexin-V staining, elevation of ROS formation and decreased Bcl-2 signalling confirmed the additive effect of the combination treatment. In addition, colony formation decreased significantly. p53 signalling pathways were significantly amplified in cells exposed to the analogues 24 hours prior to radiation, as was the amount of DNA damage. In conclusion, our results indicated that pre-treatment of breast- and lung cancer cells with low doses of 2-ME analogues sensitized breast- and lung cancer cells to γ-radiation and induced apoptosis more so than the individual treatments alone. Future studies will focus on the effect of the combination treatment on non-malignant cellular counterparts.

Keywords: cancer, microtubule dynamics, radiation therapy, radiosensitization

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