SKA3 Expression as a Prognostic Factor for Patients with Pancreatic Adenocarcinoma.

The spindle and kinetochore-associated complex subunit 3 (SKA3) is a protein essential for proper chromosome segregation during mitosis and thus responsible for maintaining genome stability. Although its involvement in the pathogenesis of various cancer types has been reported, the potential clinicopathological significance of SKA3 in pancreatic ductal adenocarcinoma (PDAC) has not been fully elucidated. Therefore, this study aimed to assess clinicopathological associations and prognostic value of SKA3 in PDAC. For this purpose, in-house immunohistochemical analysis on tissue macroarrays (TMAs), as well as a bioinformatic examination using publicly available RNA-Seq dataset, were performed. It was demonstrated that SKA3 expression at both mRNA and protein levels was significantly elevated in PDAC compared to control tissues. Upregulated mRNA expression constituted an independent unfavorable prognostic factor for the overall survival of PDAC patients, whereas altered SKA3 protein levels were associated with significantly better clinical outcomes. The last observation was particularly clear in the early-stage tumors. These findings render SKA3 a promising prognostic biomarker for patients with pancreatic ductal adenocarcinoma. However, further studies are needed to confirm this conclusion.

Prognostic significance of SDF-1 chemokine and its receptors CXCR4 and CXCR7 involved in EMT of prostate cancer.

Tendency to conversion from state of chronic inflammation to malignancy is a tumor characteristic trait, which encourages progression to its metastatic stage.. The inflammatory cells maintaining in the tumor inaugurate a communication with cancer cells and become tumor-fostering cells. Epithelial-mesenchymal transition (EMT) is a program supporting malignant cells during switch phenotype into metastatic form, providing looseness of cell-cell adherence and strengthens migratory or invasive features. EMT-undergone tumor cells become more aggressive and resistant to apoptosis. Additionally, malignant cells can be stimulated to manufacture proinflammatory factors throughout EMT program. Chronic inflammation is responsible for EMT induction in malignancies. Developed tumors induce inflammatory response through excretion of cytokines, chemokines and growth factors, which recruit populations of infiltrating immune cells straight to the tumor microenvironment. The inflammatory reaction potentially exerts tumor control, but instead it can be intercepted by the tumor to stimulate its own development in direction to metastatic form. Our study confirmed that SDF-1 chemokine and its receptors, CXCR4 and CXCR7 may participate in initiation of metastases formation and EMT process.

Overexpression of kif11 is a poor prognostic factor in clear cell renal cell carcinoma.

INTRODUCTION: Unresectable renal cell carcinoma continues to be a great challenge due to our limited understanding of its underlying pathophysiology. We explored the relationship between KIF11 protein expression and the clinical courses of clear cell renal cell carcinoma (ccRCC) using a tissue microarray. MATERIAL AND METHODS: The tissue microarray contained specimens derived from 90 patients, cancer and matched adjacent non-cancerous tissue (2 cores per case), followed up for 7 years. Tumour samples were evaluated for KIF11 expression using the H-score, and their correlations with clinicopathological data and survival data were analysed. RESULTS: 72.7% of ccRCC tissues presented KIF11 cytoplasmic expression with a median value of 20 (interquartile range 0-200). The nuclear staining was positive in 36.36% of ccRCC tissues. Among controls, nuclear KIF11 expression was absent, but cytoplasmic expression was identified in all cases, with a median value of 230 (interquartile range 45-290). Cytoplasmic KIF11 expression in ccRCC tissues was lower than in the control tissues and was positively correlated with tumour grade and mortality (p < 0.05). KIF11 nuclear expression did not correlate with overall survival. CONCLUSIONS: Elevated expression of KIF11 predicts poor clinical outcome in ccRCC patients. Downregulation of KIF11 may provide a new therapeutic strategy for ccRCC.

Usefulness of Molecular Methods for Helicobacter pylori Detection in Pediatric Patients and Their Correlation with Histopathological Sydney Classification.

Helicobacter pylori infections, as one of the most prevalent among humans, are generally acquired during childhood, and are one of the main causes of chronic gastritis and peptic ulcer disease. A bacterial culture from a gastric biopsy is the gold standard and is the only method that has 100% specificity. However, its sensitivity varies, depending on experience of the laboratory staff, applied culture media, specimen transport conditions, biopsy site, and quality of the sample. The same factors compromise all invasive methods and a culture-based H. pylori infection diagnostic, as well as a recent intake of antibiotics, bismuth-containing compounds, and proton pump inhibitors. Molecular methods have been used for clinical microbiology investigation since the beginning of the 21st century. However, their usefulness for H. pylori infections diagnosis remains unclear, especially in pediatric patients. The aim of the study was to assess the incidence of H. pylori infections in a group of 104 pediatric patients and to compare the results of the PCR test with the corresponding histopathological investigation effects. Among the biopsy samples collected from 104 children, 44 (42.3%) were positive in PCR, while 43 (41.3%) and 39 (37.5%) presented histologically-confirmed signs of inflammation and H. pylori colonization, respectively. Moreover, the mean grades of the parameters of the histopathological examination were higher in the group of PCR-positive samples. The compatibility of both research methods was confirmed, emphasizing the usefulness of molecular methods for detecting H. pylori infections in pediatric patients. Considering that the PCR-based method gives reliable results and is less time-consuming and costly, it is worth discussing this method as a new standard in the diagnosis of H. pylori infections, at least among pediatric patients, for which culture-based diagnostics is not sufficient or histopathological examination is negative, while inflammation signs are observed macroscopically.

SPDL1 Is an Independent Predictor of Patient Outcome in Colorectal Cancer.

Spindle Apparatus Coiled-Coil Protein 1 (SPDL1) is a relatively recently identified coiled-coil domain containing protein and an important determinant of DNA fidelity by ensuring faithful mitosis. Hence, SPDL1 is suspected to underlie genomic (in-)stability in human cancers, yet its exact roles in these diseases remain largely underexplored. Given that genomic instability (GIN) is a crucial feature in colorectal cancer (CRC), we primarily asked whether the expression of this protein may account for differences in clinicopathological features and survival rates of CRC patients. Protein expression was evaluated by immunohistochemistry in the institutional tissue microarray (TMA), and gene expression by the analysis of publicly available datasets. To place the prognostic relevance in a predicted biological context, gene co-expression set around SPDL1 identified by public data mining was annotated and assessed for enrichment in gene ontology (GO) categories, BRITE hierarchies, and Reactome pathways. The comparison with adjacent normal tissue revealed a high expression of SPDL1 protein in a subset of tumor cases (48.84%), and these had better prognosis than the SPDL1-low expression counterpart even after adjustment for multiple confounders. SPDL1-high expression within tumors was associated with a median 56-month survival advantage, but not with any clinicopathological characteristics of our cohort. In the TCGA cohort, SPDL1 was overexpressed in tumor tissue and positively associated with improved survival, chromosome instability phenotype, and various GIN markers. In addition to the genes critically involved in the cell cycle and mitosis, a gene set co-expressed with SPDL1 contained checkpoint members of both chromosome segregation and DNA replication, as well as those associated with defective DNA repair, and retrograde vesicle-mediated transport. In conclusion, SPDL1 is an independent predictor of CRC patient survival in a possible connection with chromosomal instability.

TOLLIP Protein Expression Predicts Unfavorable Outcome in Renal Cell Carcinoma.

Resistance to systemic therapy is one of the hallmarks of renal cell carcinoma (RCC). Recently, TOLLIP has emerged as a possible driver of autophagy and chemoresistance. We explored the relationship between primary and metastatic RCC tumor characteristics, patient survival, and TOLLIP expression. The tissue microarrays cohort contained 95 cores of the primary tumor, matched metastases, and matched adjacent tissues derived from 32 RCC patients. TOLLIP expression in tumor samples was evaluated using the H-score. All examined samples showed cytoplasmic TOLLIP expression, with a median value of 100 in primary tumors, 107.5 in metastases, and 220 in the control group. The expression was significantly higher in the normal adjacent tissues compared to primary or metastatic RCC (p < 0.05). We found a positive correlation between expressions of TOLLIP in the primary tumor and its metastases (p < 0.05; k = 0.48). TOLLIP expression significantly correlates with a lower overall survival rate (p = 0.047). TOLLIP functions as a ubiquitin-LC3 adaptor in the intracellular pathway associated with autophagy. Relative TOLLIP overexpression may augment autophagy-related signaling, limiting susceptibility to therapy. The blockade of TOLLIP physiological function seems to be a promising approach to overcoming resistance to systemic therapy.

Systematic review and meta-analysis of the prognostic significance of microRNAs related to metastatic and EMT process among prostate cancer patients.

The ability of tumor cells to spread from their origin place and form secondary tumor foci is determined by the epithelial-mesenchymal transition process. In epithelial tumors such as prostate cancer (PCa), the loss of intercellular interactions can be observed as a change in expression of polarity proteins. Epithelial cells acquire ability to migrate, what leads to the formation of distal metastases. In recent years, the interest in miRNA molecules as potential future treatment options has increased. In tumor microenvironment, miRNAs have the ability to regulate signal transduction pathways, where they can act as suppressors or oncogenes. MiRNAs are secreted by cancer cells, and the changes in their expression levels are closely related to a cancer progression, including epithelial-mesenchymal transition. These molecules offer new diagnostic and therapeutic possibilities. Therapeutics which make use of synthesized RNA fragments and mimic or block miRNAs affected in PCa, may lead to inhibition of tumor progression and even disease re-emission. Based on appropriate qualification criteria, we conducted a selection process to identify scientific articles describing miRNAs and their relation to epithelial-mesenchymal transition in PCa patients. The studies were published in English on Pubmed, Scopus and the Web of Science before August 08, 2019. Hazard ratios (HRs) and 95% confidence intervals (CI) as well as total Gleason score were used to assess the concordance between miRNAs and presence of metastases. A total of 13 studies were included in our meta-analysis, representing 1608 PCa patients and 15 miRNA molecules. Our study clarifies a relationship between the clinicopathological features of PCa and the aberrant expression of several miRNA as well as the complex mechanism of miRNA molecules involvement in the induction and promotion of the metastatic mechanism in PCa.

Prognostic Significance of TLR2, SMAD3 and Localization-dependent SATB1 in Stage I and II Non-Small-Cell Lung Cancer Patients.

This study aimed to explore the prognostic value of SATB1, SMAD3, and TLR2 expression in non-small-cell lung carcinoma patients with clinical stages I-II. To investigate, we evaluated immunohistochemical staining to each of these markers using tissue sections from 69 patients from our cohort and gene expression data for The Cancer Genome Atlas (TCGA) cohort. We found that, in our cohort, high expression levels of nuclear SATB1n and SMAD3 were independent prognostic markers for better overall survival (OS) in NSCLC patients. Interestingly, expression of cytoplasmic SATB1c exhibited a significant but inverse association with survival rate, and it was an independent predictor of unfavorable prognosis. Likewise, TLR2 was a negative outcome biomarker for NSCLC even when adjusting for covariates. Importantly, stratification of NSCLCs with respect to combined expression of the three biomarkers allowed us to identify subgroups of patients with the greatest difference in duration of survival. Specifically, expression profile of SATB1n-high/SMAD3high/TLR2low was associated with the best OS, and it was superior to each single protein alone in predicting patient prognosis. Furthermore, based on the TCGA dataset, we found that overexpression of SATB1 mRNA was significantly associated with better OS, whereas high mRNA levels of SMAD3 and TLR2 with poor OS. In conclusion, the present study identified a set of proteins that may play a significant role in predicting prognosis of NSCLC patients with clinical stages I-II.

Prognostic Impact and Functional Annotations of KIF11 and KIF14 Expression in Patients with Colorectal Cancer.

Genomic instability (GIN) has an important contribution to the pathology of colorectal cancer (CRC). Therefore, we selected mitosis and cytokinesis kinesins, KIF11 and KIF14, as factors of potential clinical and functional value in CRC, as their aberrant expression has been suspected to underlie GIN. We examined the expression and the prognostic and biological significance of KIF11 and KIF14 in CRC via in-house immunohistochemistry on tissue microarrays, public mRNA expression datasets, as well as bioinformatics tools. We found that KIF11 and KIF14 expression, at both the protein and mRNA level, was markedly altered in cancer tissues compared to respective controls, which was reflected in the clinical outcome of CRC patients. Specifically, we provide the first evidence that KIF11 protein and mRNA, KIF14 mRNA, as well as both proteins together, can significantly discriminate between CRC patients with better and worse overall survival independently of other relevant clinical risk factors. The negative prognostic factors for OS were high KIF11 protein, high KIF11 protein + low KIF14 protein, low KIF11 mRNA and low KIF14 mRNA. Functional enrichment analysis revealed that the gene sets related to the cell cycle, DNA replication, DNA repair and recombination, among others, were positively associated with KIF11 or KIF14 expression in CRC tissues. In TCGA cohort, the positive correlations between several measures related to GIN and the expression of KIFs were also demonstrated. In conclusion, our results suggest that CRC patients can be stratified into distinct risk categories by biological and molecular determinants, such as KIF11 and KIF14 expression and, mechanistically, this is likely attributable to their role in maintaining genome integrity.

Porphyrin Based 2D-MOF Structures as Dual-Kinetic Sorafenib Nanocarriers for Hepatoma Treatment.

The existing clinical protocols of hepatoma treatment require improvement of drug efficacy that can be achieved by harnessing nanomedicine. Porphyrin-based, paddle-wheel framework (PPF) structures were obtained and tested as dual-kinetic Sorafenib (SOR) nanocarriers against hepatoma. We experimentally proved that sloughing of PPF structures combined with gradual dissolving are effective mechanisms for releasing the drug from the nanocarrier. By controlling the PPF degradation and size of adsorbed SOR deposits, we were able to augment SOR anticancer effects, both in vitro and in vivo, due to the dual kinetic behavior of SOR@PPF. Obtained drug delivery systems with slow and fast release of SOR influenced effectively, although in a different way, the cancer cells proliferation (reflected with EC50 and ERK 1/2 phosphorylation level). The in vivo studies proved that fast-released SOR@PPF reduces the tumor size considerably, while the slow-released SOR@PPF much better prevents from lymph nodes involvement and distant metastases.

The Bonar Score in the Histopathological Assessment of Tendinopathy and Its Clinical Relevance-A Systematic Review.

This study aimed to perform a comprehensive systematic review, which reports the role of the Bonar score in the histopathological assessment of tendinopathy and its clinical relevance. To identify all of the studies that reported relevant information on the Bonar scoring system and tendinopathy, an extensive search of the major and the most significant electronic databases (PubMed, Cochrane Central, ScienceDirect, SciELO, Web of Science) was performed. A systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The extracted data included-year of study, geographical location, type of the study, radiological modifications, gender, number of patients, region of tendinopathy, mean age, control group, characteristics of the Bonar score and alterations in the scale, mean Bonar score, number of investigators, area of tendon investigation, clinical and radiological implications. An extensive search of the databases and other sources yielded a total of 807 articles. Eighteen papers were finally included in this systematic review, and of these, 13 original papers included the clinical and radiological implications of tendinopathy. Radiological evaluation was present in eight studies (both magnetic resonance imaging (MRI) and ultrasound (US)). The clinical implications were more frequent and present in 10 studies. Using the Bonar score, it is easy to quantify the pathological changes in tendinous tissue. However, its connection with clinical and radiological evaluation is much more complicated. Based on the current state of knowledge, we concluded that the neovascularization variable in the Bonar system should be reconsidered. Ideally, the microscopic assessment score should follow the established classification scale with the radiological and clinical agreement and should have a prognostic value.

Does HSP90 play an important role in psoriasis?

Introduction: Psoriasis is a chronic, inflammatory skin disease. Environmental, genetic, autoinflammatory and autoimmune factors play a role in the pathogenesis of disease. It is believed that heat shock protein 90 (HSP90) is an interleukin-17 (IL-17) receptor, which plays an essential role in the psoriasis pathogenesis. Aim: To evaluate the expression of the gene encoding HSP90 protein in keratinocytes of patients with psoriasis depending on its duration, recurrences, exacerbating factors, therapy form, and the coexistence of metabolic disorders and cardiovascular diseases. Material and methods: Skin samples from 40 psoriatic patients were investigated in this study. Control skin biopsies were collected from 20 healthy volunteers. HSP90 expression level was measured by qRT-PCR reaction. Results: This study has shown an increased mRNA expression of HSP90 in psoriatic patients as compared to healthy volunteers. A positive correlation of HSP90 expression and the frequency of exacerbations was found. A negative correlation between the HSP90 activity and the age of patients was demonstrated in the coexistence of psoriasis with hyperlipidaemia or diabetes. Among the factors exacerbating psoriasis, acute infections induced HSP90 expression most significantly. Conclusions: HSP90 plays a role in the pathogenesis of psoriasis. The expression of HSP90 increases with the frequency of exacerbations of psoriasis throughout the year. Hyperlipidaemia or diabetes associated with psoriasis in young adults, and acute infections and emotional stress increase the expression of HSP90. The expression of HSP90 in psoriatic patients is not dependent on the type of psoriasis, comorbidity of cardiovascular diseases, smoking and alcohol addiction.

Markers of pancreatic cancer stem cells and their clinical and therapeutic implications.

Pancreatic cancer (PC) is the fourth most common cause of death among all cancers. Poor prognosis of PC may be caused by a prevalence of cancer stem cells (CSCs). CSCs are a population of cancer cells showing stem cell-like characteristics. CSCs have the ability to self-renew and may initiate tumorigenesis. PC CSCs express markers such as CD133, CD24, CD44, DCLK1, CXCR4, ESA, Oct4 and ABCB1. There is a wide complexity of interaction and relationships between CSC markers in PC. These markers are negative prognostic factors and are connected with tumor recurrence and clinical progression. Additionally, PC CSCs are resistant to treatment with gemcitabine. Thus, most current therapies for PC are ineffective. Numerous studies have shown, that targeting of these proteins may increase both disease-free and overall survival in PC.

Cigarette smoking intensifies tendinopathy of the LHBT. A microscopic study after arthroscopic treatment.

Smoking has a damaging effect on the musculoskeletal system, which was presented by authors in the rotator cuff and Achilles tendons studies; however, there are a lack of data about the effect of smoking on disorders of the long head of the biceps tendon (LHBT), particularly at the microscopic level. The purpose of this study was to investigate the effect of the tobacco smoking on the histopathologic alterations of the LHBT. Thirty-six patients with preoperatively diagnosed tendinopathy of the LHBT were referred to the Orthopaedics Department. All patients underwent arthroscopic treatment with further macroscopic and microscopic evaluation of biceps tendon samples. The active and former smokers were characterised by more advanced degenerative process of the tendinous tissue; moreover, it was intensified in the group of former smokers. Subjects who smoke more than 20 cigarettes per day also had more advanced microscopic alterations. The most severe microscopic alterations occurred in the former smokers who used tobacco for more than 20 years. However, the non-smokers group revealed moderate degeneration in all LHBT samples. Tobacco smoking is an important risk factor of the LHBT disease, which essentially intensifies the degeneration of the tendinous tissue.

Evaluation of Anti-Metastatic Potential of the Combination of Fisetin with Paclitaxel on A549 Non-Small Cell Lung Cancer Cells.

The identification and development of new agents with a therapeutic potential as well as novel drug combinations are gaining the attention of scientists and clinicians as a plausible approach to improve therapeutic regimens for chemoresistant tumors. We have recently reported that the flavonoid fisetin (FIS), at physiologically attainable concentrations, acts synergistically with clinically achievable doses of paclitaxel (PTX) to produce growth inhibitory and pro-death effects on A549 human non-small cell lung cancer (NSCLC) cells. To further investigate a potential therapeutic efficacy of the combination of fisetin with paclitaxel, we decided to assess its impact on metastatic capability of A549 cells as well as its toxicity toward normal human lung fibroblast. Cell viability, cell migration, and invasion were measured by thiazolyl blue tetrazolium bromide (MTT) assay, wound healing assay, and Transwell chamber assay, respectively. The expression of metastasis-related genes was assessed with quantitative reverse transcriptase real-time polymerase chain reaction (qRT-PCR). Actin and vimentin filaments were examined under the fluorescence microscope. The combination of FIS and PTX significantly reduced cancer cell migration and invasion, at least partially, through a marked rearrangement of actin and vimentin cytoskeleton and the modulation of metastasis-related genes. Most of these effects of the combination treatment were significantly greater than those of individual agents. Paclitaxel alone was even more toxic to normal cells than the combination of this drug with the flavonoid, suggesting that FIS may provide some protection against PTX-mediated cytotoxicity. The combination of FIS and PTX is expected to have a synergistic anticancer efficacy and a significant potential for the treatment of NSCLC, however, further in vitro and in vivo studies are required to confirm this preliminary evidence.

KRAS mutation testing in borderline ovarian tumors and low-grade ovarian carcinomas with a rapid, fully integrated molecular diagnostic system.

Epithelial ovarian neoplasms are a heterogeneous group of tumors, including various malignancies with distinct clinicopathologic and molecular features. Mutations in BRAF and KRAS genes are the most frequent genetic aberrations found in low-grade serous ovarian carcinomas and serous and mucinous borderline tumors. Implementation of targeted therapeutic strategies requires access to highly specific and highly sensitive diagnostic tests for rapid determination of mutation status. One candidate for such test is fully integrated, real-time polymerase chain reaction-based Idylla™ system for quick and simple detection of KRAS mutations in formaldehyde fixed-paraffin embedded tumor samples. The primary aim of this study was to verify whether fully integrated real-time polymerase chain reaction-based Idylla system may be useful in determination of KRAS mutation status in patients with borderline ovarian tumors and low-grade ovarian carcinomas. The study included tissue specimens from 37 patients with histopathologically verified ovarian masses, operated on at the Department of Obstetrics and Gynecology, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz (Poland) between January 2009 and June 2012. Based on histopathological examination of surgical specimens, 30 lesions were classified as low-grade ovarian carcinomas and 7 as borderline ovarian tumors. Seven patients examined with Idylla KRAS Mutation Test tested positive for KRAS mutation. No statistically significant association was found between the incidence of KRAS mutations and histopathological type of ovarian tumors. Mean survival of the study subjects was 48.51 months (range 3-60 months). Presence of KRAS mutation did not exert a significant effect on the duration of survival in our series. Our findings suggest that Idylla KRAS Mutation Test may be a useful tool for rapid detection of KRAS mutations in ovarian tumor tissue.

Is the inflammation process absolutely absent in tendinopathy of the long head of the biceps tendon? Histopathologic study of the long head of the biceps tendon after arthroscopic treatment.

Tendinopathy of the long head of the biceps tendon is a difficult medical issue. Its pathogenesis and etiology is multifactorial and unclear. Tendinopathy is thought to be primarily degenerative in nature, as tendons are characterized by impaired regeneration and healing. Thirty-five patients with preoperatively diagnosed tendinopathy of long head of the biceps tendon were referred to the Orthopedics Department. All patients underwent an arthroscopic-assisted biceps tenodesis or tenotomy. The intra-articular portion of the long head of the biceps tendon was obtained from each of the patients who underwent arthroscopy. A macroscopic and microscopic evaluation of biceps tendon samples revealed degeneration among all specimens. This study demonstrates the prevalence of the degeneration process and the presence of marginal inflammation process in tendinopathy of the long head of biceps tendon. The role, that inflammation process plays in tendinopathy is important in the early phase and gradually becomes secondary to the developing degeneration. The inflammatory cells, occasionally seen in pathological tendons, could be an evidence of re-injury and recent healing response.

Paclitaxel and the dietary flavonoid fisetin: a synergistic combination that induces mitotic catastrophe and autophagic cell death in A549 non-small cell lung cancer cells.

BACKGROUND: The use of the dietary polyphenols as chemosensitizing agents to enhance the efficacy of conventional cytostatic drugs has recently gained the attention of scientists and clinicians as a plausible approach for overcoming the limitations of chemotherapy (e.g. drug resistance and cytotoxicity). The aim of this study was to investigate whether a naturally occurring diet-based flavonoid, fisetin, at physiologically attainable concentrations, could act synergistically with clinically achievable doses of paclitaxel to produce growth inhibitory and/or pro-death effects on A549 non-small cell lung cancer cells, and if it does, what mechanisms might be involved. METHODS: The drug-drug interactions were analyzed based on the combination index method of Chou and Talalay and the data from MTT assays. To provide some insights into the mechanism underlying the synergistic action of fisetin and paclitaxel, selected morphological, biochemical and molecular parameters were examined, including the morphology of cell nuclei and mitotic spindles, the pattern of LC3-II immunostaining, the formation of autophagic vacuoles at the electron and fluorescence microscopic level, the disruption of cell membrane asymmetry/integrity, cell cycle progression and the expression level of LC3-II, Bax, Bcl-2 and caspase-3 mRNA. RESULTS: Here, we reported the first experimental evidence for the existence of synergism between fisetin and paclitaxel in the in vitro model of non-small cell lung cancer. This synergism was, at least partially, ascribed to the induction of mitotic catastrophe. The switch from the cytoprotective autophagy to the autophagic cell death was also implicated in the mechanism of the synergistic action of fisetin and paclitaxel in the A549 cells. In addition, we revealed that the synergism between fisetin and paclitaxel was cell line-specific as well as that fisetin synergizes with arsenic trioxide, but not with mitoxantrone and methotrexate in the A549 cells. CONCLUSIONS: Our results provide rationale for further testing of fisetin in the combination with paclitaxel or arsenic trioxide to obtain detailed insights into the mechanism of their synergistic action as well as to evaluate their toxicity towards normal cells in an animal model in vivo. We conclude that this study is potentially interesting for the development of novel chemotherapeutic approach to non-small cell lung cancer.