Quantitative Investigation of MicroRNA-32 in the Urine of Prostate Cancer Patients and Its Relationship With Clinicopathological Characteristics.

INTRODUCTION: Prostate cancer (PCa) is one of the most common cancers worldwide. PCa diagnosis is mostly based on solid biopsy and prostate-specific antigen (PSA), which have the disadvantages of being invasive and insensitive, respectively. Recently, the detection of microRNAs (miRNAs) in expressed prostatic secretions (EPS) has been a promising approach for PCa diagnosis. The aim of this study is to quantify transcriptional levels of miRNA-32 in the urine of prostate cancer patients. MATERIALS AND METHODS: In this study, we evaluated the expression of miRNA-32 in the urine of 27 PCa patients, 48 benign prostatic hyperplasia (BPH) and 20 healthy controls, using quantitative real-time PCR (qPCR). The expression levels were then compared with the clinicopathological characteristics of patients. RESULTS: The expression level of miRNA-32 in PCa patients was significantly higher than the control group (P < .01) and BPH cases (P < .01), and was associated with advanced tumor stage (P < .05). In addition, the expression of miRNA-32 had significant correlation with patients' age (r = 0.39, P = .043). Area under ROC curve (AUC) for the discrimination of PCa samples from control and BPH samples were 0.93 (P < .0001) and 0.78 (P < .0001), respectively. We also used logistic regression analysis to integrate the results of PSA, prostate volume and miRNA-32, and presented a predictive model for distinguishing PCa from BPH, highlighting the clinical utility of miRNA-32 in cancer diagnosis and risk assessment. CONCLUSIONS: Measurement of miRNA-32 expression in urine may have significance for the detection of PCa. Inclusion of miRNA-32 in logistic regression along with PSA and prostate volume increases the accuracy of cancer diagnosis.

Prognostic Significance of Circulating and Disseminated Tumor Cells in Breast Cancer Patients before and after Adjuvant Chemotherapy.

OBJECTIVE: Despite the advances in treatment, breast cancer (BC) remains a major cause of death in women. This study aims to evaluate the prognostic significance of detecting circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in paired peripheral blood (PB) and bone marrow (BM) samples obtained both before and after adjuvant chemotherapy from patients with operable BC. MATERIALS AND METHODS: In this experimental study, from 160 patients with primary BC, we collected 160 PB and BM samples before and we could be able to collect PB and BM samples from 100 of them after adjuvant chemotherapy. The expression level of cytokeratin 19 (CK19), carcinoembryonic antigen (CEA), mammaglobin 1 (MGB1), mucin 2 (MUC2) and trefoil factor 1 (TFF1) mRNAs in the PB/BM samples were analyzed by quantitative real-time polymerase chain reaction (PCR). RESULTS: Multivariate Cox regression analyses indicated that the detection of CK19 mRNA-positive CTCs/DTCs either before or after adjuvant chemotherapy was an independent factor for prognosis associated with decreased diseasefree survival (DFS). Patients with tumor cells detected in both PB and BM and patients with persistent detection of tumor cells before and after chemotherapy had worse outcomes compared to those with tumor cells detected in one or neither of the compartments. CONCLUSION: This study suggests that the detection of CK19 mRNA-positive CTCs/DTCs either before or after adjuvant chemotherapy could be an independent predictor of DFS in operable BC patients.

An update to experimental and clinical aspects of tumor-associated macrophages in cancer development: hopes and pitfalls.

Tumor-associated macrophages (TAMs) represent one of the most abundant tumor-infiltrating stromal cells, and their normal function in tumor microenvironment (TME) is to suppress tumor cells by producing cytokines which trigger both direct cell cytotoxicity and antibody-mediated immune response. However, upon prolonged exposure to TME, the classical function of these so-called M1-type TAMs can be converted to another type, "M2-type," which are recruited by tumor cells so that they promote tumor growth and metastasis. This is the reason why the accumulation of TAMs in TME is correlated with poor prognosis in cancer patients. Both M1- and M2-types have high degree of plasticity, and M2-type cells can be reprogrammed to M1-type for therapeutic purposes. This characteristic introduces TAMs as promising target for developing novel cancer treatments. In addition, inhibition of M2-type cells and blocking their recruitment in TME, as well as their depletion by inducing apoptosis, are other approaches for effective immunotherapy of cancer. In this review, we summarize the potential of TAMs to be targeted for cancer immunotherapy and provide an up-to-date about novel strategies for targeting TAMs.

MicroRNAs as biomarkers for early diagnosis, targeting and prognosis of prostate cancer.

Globally, prostate cancer (PC) is leading cause of cancer-related mortality in men worldwide. Despite significant advances in the treatment and management of this disease, the cure rates for PC remains low, largely due to late detection. PC detection is mostly reliant on prostate-specific antigen (PSA) and digital rectal examination (DRE); however, due to the low positive predictive value of current diagnostics, there is an urgent need to identify new accurate biomarkers. Recent studies support the biological role of microRNAs (miRNAs) in the initiation and progression of PC, as well as their potential as novel biomarkers for patients' diagnosis, prognosis, and disease relapse. In the advanced stages, cancer-cell-derived small extracellular vesicles (SEVs) may constitute a significant part of circulating vesicles and cause detectable changes in the plasma vesicular miRNA profile. Recent computational model for the identification of miRNA biomarkers discussed. In addition, accumulating evidence indicates that miRNAs can be utilized to target PC cells. In this article, the current understanding of the role of microRNAs and exosomes in the pathogenesis and their significance in PC prognosis, early diagnosis, chemoresistance, and treatment are reviewed.

Gynecologic Cancer, Cancer Stem Cells, and Possible Targeted Therapies.

Gynecologic cancer is one of the main causes of death in women. In this type of cancer, several molecules (oncogenes or tumor suppressor genes) contribute to the tumorigenic process, invasion, metastasis, and resistance to treatment. Based on recent evidence, the detection of molecular changes in these genes could have clinical importance for the early detection and evaluation of tumor grade, as well as the selection of targeted treatment. Researchers have recently focused on cancer stem cells (CSCs) in the treatment of gynecologic cancer because of their ability to induce progression and recurrence of malignancy. This has highlighted the importance of a better understanding of the molecular basis of CSCs. The purpose of this review is to focus on the molecular mechanism of gynecologic cancer and the role of CSCs to discover more specific therapeutic approaches to gynecologic cancer treatment.

MicroRNAs as Biomarkers for Early Diagnosis, Prognosis, and Therapeutic Targeting of Ovarian Cancer.

Ovarian cancer is the major cause of gynecologic cancer-related mortality. Regardless of outstanding advances, which have been made for improving the prognosis, diagnosis, and treatment of ovarian cancer, the majority of the patients will die of the disease. Late-stage diagnosis and the occurrence of recurrent cancer after treatment are the most important causes of the high mortality rate observed in ovarian cancer patients. Unraveling the molecular mechanisms involved in the pathogenesis of ovarian cancer may help find new biomarkers and therapeutic targets for ovarian cancer. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression, mostly at the posttranscriptional stage, through binding to mRNA targets and inducing translational repression or degradation of target via the RNA-induced silencing complex. Over the last two decades, the role of miRNAs in the pathogenesis of various human cancers, including ovarian cancer, has been documented in multiple studies. Consequently, these small RNAs could be considered as reliable markers for prognosis and early diagnosis. Furthermore, given the function of miRNAs in various cellular pathways, including cell survival and differentiation, targeting miRNAs could be an interesting approach for the treatment of human cancers. Here, we review our current understanding of the most updated role of the important dysregulation of miRNAs and their roles in the progression and metastasis of ovarian cancer. Furthermore, we meticulously discuss the significance of miRNAs as prognostic and diagnostic markers. Lastly, we mention the opportunities and the efforts made for targeting ovarian cancer through inhibition and/or stimulation of the miRNAs.

Clinical significance of circulating tumor cell related markers in patients with epithelial ovarian cancer before and after adjuvant chemotherapy.

Circulating tumor cells (CTCs) have recently been considered as new prognostic and diagnostic markers for various human cancers; however, their significance in epithelial ovarian cancer (EOC) remains to be elucidated. In this study, using quantitative real-time PCR, we evaluated the expression of EPCAM, MUC1, CEA, HE4 and CA125 mRNAs, as putative markers of CTCs, in the blood of 51 EOC patients before and/or after adjuvant chemotherapy. Our results demonstrated that, before chemotherapy, the expression of EPCAM, MUC1, CEA and HE4 mRNAs were correlated to each other. CEA expression was correlated with tumor stage (r = 0.594, p = 0.000) before chemotherapy, whereas its expression after chemotherapy was correlated with serum levels of CA125 antigen (r = 0.658, p = 0.000). HE4 mRNA showed the highest sensitivity both before and after chemotherapy (82.98% and 85.19%, respectively) and the persistence of this marker after chemotherapy was associated with advanced disease stage. The expression of CA125 mRNA had negative correlation with the other markers and with tumor stage and therapy response (evaluated by the measurement of serum CA125 antigen). Collectively, our results indicated a better clinical significance of tumor-specific markers (CEA and HE4 mRNAs) compared to epithelial-specific markers (EPCAM and MUC1 mRNAs).

Genomic Instability in Cancer: Molecular Mechanisms and Therapeutic Potentials.

DNA damage usually happens in all cell types, which may originate from endogenous sources (i.e., DNA replication errors) or be emanated from radiations or chemicals. These damages range from changes in few nucleotides to significant structural abnormalities on chromosomes and, if not repaired, could disturb the cellular homeostasis or cause cell death. As the most significant response to DNA damage, DNA repair provides biological pathways by which DNA damages are corrected and returned into their natural circumstance. However, an aberration in the DNA repair mechanisms may result in genomic and chromosomal instability and the accumulation of mutations. The activation of oncogenes and/or inactivation of tumor suppressor genes is a serious consequence of genomic and chromosomal instability and may bring the cells into a cancerous phenotype. Therefore, genomic and chromosomal instability is usually considered a crucial factor in carcinogenesis and an important hallmark of various human malignancies. In the present study, we review our current understanding of the most updated mechanisms underlying genomic instability in cancer and discuss the potential promises of these mechanisms in finding new targets for the treatment of cancer.

Current insights into the metastasis of epithelial ovarian cancer - hopes and hurdles.

BACKGROUND: Ovarian cancer is the most lethal gynecologic cancer and the fifth leading cause of cancer-related mortality in women worldwide. Despite various attempts to improve the diagnosis and therapy of ovarian cancer patients, the survival rate for these patients is still dismal, mainly because most of them are diagnosed at a late stage. Up to 90% of ovarian cancers arise from neoplastic transformation of ovarian surface epithelial cells, and are usually referred to as epithelial ovarian cancer (EOC). Unlike most human cancers, which are disseminated through blood-borne metastatic routes, EOC has traditionally been thought to be disseminated through direct migration of ovarian tumor cells to the peritoneal cavity and omentum via peritoneal fluid. It has recently been shown, however, that EOC can also be disseminated through blood-borne metastatic routes, challenging previous thoughts about ovarian cancer metastasis. CONCLUSIONS: Here, we review our current understanding of the most updated cellular and molecular mechanisms underlying EOC metastasis and discuss in more detail two main metastatic routes of EOC, i.e., transcoelomic metastasis and hematogenous metastasis. The emerging concept of blood-borne EOC metastasis has led to exploration of the significance of circulating tumor cells (CTCs) as novel and non-invasive prognostic markers in this daunting cancer. We also evaluate the role of tumor stroma, including cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs), endothelial cells, adipocytes, dendritic cells and extracellular matrix (ECM) components in EOC growth and metastasis. Lastly, we discuss therapeutic approaches for targeting EOC. Unraveling the mechanisms underlying EOC metastasis will open up avenues to the design of new therapeutic options. For instance, understanding the molecular mechanisms involved in the hematogenous metastasis of EOC, the biology of CTCs, and the detailed mechanisms through which EOC cells take advantage of stromal cells may help to find new opportunities for targeting EOC metastasis.

Prognostic and therapeutic significance of circulating tumor cells in patients with lung cancer.

BACKGROUND: Lung cancer is the second most common cancer and the main cause of cancer-related mortality worldwide. In spite of various efforts that have been made to facilitate the early diagnosis of lung cancer, most patients are diagnosed when the disease is already in stage IV, which is generally associated with the occurrence of distant metastases and a poor survival. Moreover, a large proportion of these patients will relapse after treatment, heralding the need for the stratification of lung cancer patients in addition to identifying those who are at a higher risk of relapse and, thus, require alternative and/or additional therapies. Recently, circulating tumor cells (CTCs) have been considered as valuable markers for the early diagnosis, prognosis and risk stratification of cancer patients, and they have been found to be able to predict the survival of patients with various types of cancer, including lung cancer. Additionally, the characterization of CTCs has recently provided fascinating insights into the heterogeneity of tumors, which may be instrumental for the development of novel targeted therapies. CONCLUSIONS: Here we review our current understanding of the significance of CTCs in lung cancer metastasis. We also discuss prominent studies reporting the utility of enumeration and characterization of CTCs in lung cancer patients as prognostic and pharmacodynamic biomarkers for those who are at a higher risk of metastasis and drug resistance.

Aptasensors as a new sensing technology developed for the detection of MUC1 mucin: A review.

Mucin 1 protein (MUC1) is a membrane-associated glycoprotein overexpressed in the majority of human malignancies and considered as a predominant protein biomarker in cancers. Owing to the crucial role of MUC1 in cancer dissemination and metastasis, detection and quantification of this biomarker is of great importance in clinical diagnostics. Today, there exist a wide variety of strategies for the determination of various types of disease biomarkers, especially MUC1. In this regard, aptamers, as artificial single-stranded DNA or RNA oligonucleotides with catalytic and receptor properties, have drawn lots of attention for the development of biosensing platforms. So far, various sensitivity-enhancement techniques in combination with a broad range of smart nanomaterials have integrated into the design of novel aptamer-based biosensors (aptasensors) to improve detection limit and sensitivity of analyte determination. This review article provides a brief classification and description of the research progresses of aptamer-based biosensors and nanobiosensors for the detection and quantitative determination of MUC1 based on optical and electrochemical platforms.

Aptamer-based biosensors and nanosensors for the detection of vascular endothelial growth factor (VEGF): A review.

Vascular endothelial growth factor (VEGF) is a key regulator of vascular formation and a predominant protein biomarker in cancer angiogenesis. Owing to its crucial roles in the cancer metastasis, VEGF detection and quantification is of great importance in clinical diagnostics. Today, there exist a wide variety of detection strategies for identifying many types of disease biomarkers, especially for VEGF. As artificial single-stranded DNA or RNA oligonucleotides with catalytic and receptor properties, aptamers have drawn lots of attention to be applied in biosensing platforms due to their target-induced conformational changes as well as high stability and target versatility. So far, various sensitivity-enhancement techniques in combination with a broad range of smart nanomaterials have integrated into the design of novel aptasensors to improve detection limit and sensitivity of analyte detection. This review article provides a brief classification and description of the research progresses of aptamer-based biosensors and nanobiosensors for the detection and quantitative determination of VEGF based on optical and electrochemical platforms.

Organ-specific metastasis of breast cancer: molecular and cellular mechanisms underlying lung metastasis.

BACKGROUND: Breast cancer (BC) is the most common type of cancer in women and the second cause of cancer-related mortality world-wide. The majority of BC-related deaths is due to metastasis. Bone, lung, brain and liver are the primary target sites of BC metastasis. The clinical implications and mechanisms underlying bone metastasis have been reviewed before. Given the fact that BC lung metastasis (BCLM) usually produces symptoms only after the lungs have been vastly occupied with metastatic tumor masses, it is of paramount importance for diagnostic and prognostic, as well as therapeutic purposes to comprehend the molecular and cellular mechanisms underlying BCLM. Here, we review current insights into the organ-specificity of BC metastasis, including the role of cancer stem cells in triggering BC spread, the traveling of tumor cells in the blood stream and their migration across endothelial barriers, their adaptation to the lung microenvironment and the initiation of metastatic colonization within the lung. CONCLUSIONS: Detailed understanding of the mechanisms underlying BCLM will shed a new light on the identification of novel molecular targets to impede daunting pulmonary metastases in patients with breast cancer.

Colorectal Cancer Screening: A Comprehensive Review to Recent Non-Invasive Methods.

Colorectal cancer (CRC) is one of the most common cancers worldwide and considered to be one of the hassles in medical communities. CRC develops from precancerous polyps in the colon or rectum and is preventable and curable by an early diagnosis and with the removal of premalignant polyps. In recent years, scientists have looked for inexpensive and safe ways to detect CRC in its earliest stages. Strong evidence shows that screening for CRC is a crucial way to reduce the incidence and mortality of this devastating disease. The main purpose for screening is to detect cancer or pre-cancer signs in all asymptomatic patients. In this review, we holistically introduce major pathways involved in the initiation and progression of colorectal tumorgenesis, which mainly includes chromosome instability (CIN), microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), and we then will discuss different screening tests and especially the latest non-invasive fecal screening test kits for the detection of CRC.

Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options.

BACKGROUND: Lung cancer is the most common cause of cancer-related mortality in humans. There are several reasons for this high rate of mortality, including metastasis to several organs, especially the brain. In fact, lung cancer is responsible for approximately 50% of all brain metastases, which are very difficult to manage. Understanding the cellular and molecular mechanisms underlying lung cancer-associated brain metastasis brings up novel therapeutic promises with the hope to ameliorate the severity of the disease. Here, we provide an overview of the molecular mechanisms underlying the pathogenesis of lung cancer dissemination and metastasis to the brain, as well as promising horizons for impeding lung cancer brain metastasis, including the role of cancer stem cells, the blood-brain barrier, interactions of lung cancer cells with the brain microenvironment and lung cancer-driven systemic processes, as well as the role of growth factor/receptor tyrosine kinases, cell adhesion molecules and non-coding RNAs. In addition, we provide an overview of current and novel therapeutic approaches, including radiotherapy, surgery and stereotactic radiosurgery, chemotherapy, as also targeted cancer stem cell and epithelial-mesenchymal transition (EMT)-based therapies, micro-RNA-based therapies and other small molecule or antibody-based therapies. We will also discuss the daunting potential of some combined therapies. CONCLUSIONS: The identification of molecular mechanisms underlying lung cancer metastasis has opened up new avenues towards their eradication and provides interesting opportunities for future research aimed at the development of novel targeted therapies.

Genetics and immunodysfunction underlying Behçet's disease and immunomodulant treatment approaches.

Behçet's disease (BD) is a chronic autoimmune condition primarily prevalent in populations along the Mediterranean Sea. The exact etiology of BD has not been fully explained yet, but the disease occurrence is associated with a genetic factor, human leukocyte antigen (HLA)-B51 antigen. Among the various immunodysfunctions that are found in BD, patients are increased neutrophil motility and superoxide production, as well as elevated production of tumor necrosis factor (TNF)-α and decreased production of interleukin (IL)-10. Elevated levels of inflammatory cytokines like IL-1 and IL-17 in BD have been found associated with aberrant expression of microRNA. Gene polymorphisms in BD patients have been observed in molecules involved in responses to pathogens that can ultimately modulate the host antimicrobial response. Moreover, several single nucleotide polymorphisms (SNPs) have been reported in genes encoding chemokines and adhesion molecules; many of these changes manifest as increases in vascular inflammation and vascular damage. Lastly, genetic and epigenetic changes have been suggested as involved in the pathogenesis of BD. Modifications in DNA methylation have been found in BD patient monocytes and lymphocytes, leading to adverse function of these cells. This review presents a comprehensive compilation of the literature with regard to the immunodysfunction underlying BD, as well as of the genetics, newly described clinical specifications and novel treatment strategies using immunomodulants based on the current understanding of BD.

Significance of AZD1152 as a potential treatment against Aurora B overexpression in acute promyelocytic leukemia.

Aurora B kinase as a chromosomal passenger protein plays multiple roles in regulating mitosis and cytokinesis. The function of Aurora B in leukemic cells has made it an important treatment target. In this study, we explored the expressions of Aurora (A, B, and C) kinases in newly diagnosed acute promyelocytic leukemia (APL) patients. In addition, we investigated the effects of AZD1152 as a specific inhibitor of Aurora B on cell survival, DNA synthesis, nuclear morphology, apoptosis induction, cell cycle distribution, and gene expression in an APL-derived NB4 cell line. Our results showed that Aurora B was overexpressed in 88 % of APL patients. AZD1152 treatment of NB4 cells led to viability reduction and G2/M arrest followed by an increase in cell size and polyploidy induction. These giant cells showed morphological evidence of mitotic catastrophe. AZD1152 treatment induced activation of G2/M checkpoint which in turn led to transient G2/M arrest in a p21-independent manner. Lack of functional p53 in NB4 cells might provide an opportunity to escape from G2/M block and to endure repeated rounds of replication and polyploidy. Treated cells were probably eliminated via p73-mediated overexpression of BAX, PUMA, and APAF1 and downregulation of survivin and MCL-1. In summary, AZD1152 treatment led to endomitosis and polyploidy in TP53-mutated NB4 cells. These giant polyploid cells might undergo mitotic catastrophe and p73-mediated apoptosis. It seems that induction of polyploidy via AZD1152 could be a novel form of anti-cancer therapy for APL that may be clinically accessible in the near future.

Arsenic Trioxide Induces Apoptosis and Incapacitates Proliferation and Invasive Properties of U87MG Glioblastoma Cells through a Possible NF-κB-Mediated Mechanism.

Identification of novel therapeutics in glioblastoma remains crucial due to the devastating and infiltrative capacity of this malignancy. The current study was aimed to appraise effect of arsenic trioxide (ATO) in U87MG cells. The results demonstrated that ATO induced apoptosis and impeded proliferation of U87MG cells in a dosedependent manner and also inhibited classical NF-κB signaling pathway. ATO further upregulated expression of Bax as an important proapoptotic target of NF-κB and also inhibited mRNA expression of survivin, c-Myc and hTERT and suppressed telomerase activity. Moreover, ATO significantly increased adhesion of U87MG cells and also diminished transcription of NF-κB down-stream targets involved in cell migration and invasion, including cathepsin B, uPA, MMP-2, MMP-9 and MMP-14 and suppressed proteolytic activity of cathepsin B, MMP-2 and MMP-9, demonstrating a possible mechanism of ATO effect on a well-known signaling in glioblastoma dissemination. Taken together, here we suggest that ATO inhibits survival and invasion of U87MG cells possibly through NF-κB-mediated inhibition of survivin and telomerase activity and NF-κB-dependent suppression of cathepsin B, MMP-2 and MMP-9.

Silibinin induces apoptosis and inhibits proliferation of estrogen receptor (ER)-negative breast carcinoma cells through suppression of nuclear factor kappa B activation.

BACKGROUND: Silibinin is a traditionally well-known drug for its hepatoprotective efficacy against various types of liver afflictions. In addition, it has recently been considered broadly as a potential chemopreventive agent against many types of cancers. The current study was designed to evaluate the restrictive effects of pharmacological doses of silibinin on SKBR3, an ErbB2-overexpressed and ER-negative human breast carcinoma cell line. METHODS: Effect of silibinin on metabolic activity and proliferation of human breast carcinoma (SKBR3) cell line were evaluated by MTT and BrdU assays respectively. Furthermore, the proapoptotic effect of silibinin was investigated using flow cytometry. The NF-κB phosphorylation assay was also used to assess the effect of silibinin on NF-κB activation. The alkalizing effect of silibinin on SKBR3 cell line was evaluated by measuring pH of media of the silibinin-treated cells compared to control. RESULTS: Our results indicate that silibinin inhibited metabolic activity and cell proliferation of SKBR3 cells in a dose-dependent manner. Moreover, silibinin significantly induced apoptosis in SKBR3 cells. On the other hand, silibinin significantly inhibited activation of NF-κB which is known to be highly active in this cell line. Alkalizing effect of silibinin was also observed. CONCLUSION: The results obtained here indicate that silibinin may be an efficacious therapeutic agent against ER-negative breast carcinomas with high inhibitory effect on NF-κB.

Differential sensitivity of p44/p42-MAPK- and PI3K/Akt-targeted neuroblastoma subtypes to arsenic trioxide.

PI3K/Akt and MAPK/ERK pathways are differentially activated in neuroblastoma (NB) cell types. In an effort to enhance the effectiveness of the NB treatment, we designed experiments to evaluate the effects of ATO in combination with PI3K and MEK1/2 specific inhibitors, LY29004 and U0126, respectively, in SK-N-MC and SK-N-BE(2) cell lines. The results indicated that specific inhibition of PI3K and MEK1/2 significantly enhanced antiproliferative and proapoptotic effects of ATO in SK-N-BE(2), but not in SK-N-MC. Furthermore, in SK-N-BE(2), NF-κB activation was significantly suppressed by LY29004+ATO treatments as compared with ATO alone, indicating that inhibition of PI3K may enhance anti-neoplastic properties of ATO in I-type NB cells through suppression of NF-κB. Moreover, expressions of c-Myc, Bad, Bax and ATM in SK-N-BE(2) cell line were significantly increased by U0126+ATO treatment as compared to treatment with ATO alone. Expression of telomerase hTERT was almost depleted by U0126+ATO treatment. Regarding the fact that activation of PI3K and MAPK in SK-N-BE(2) is higher than in other NB subtypes, we hypothesize that growth of SK-N-BE(2) cell line is highly dependent on these pathways and inhibition of these pathways may has promise for the treatment of multi-drug resistant I-type NB cells by ATO. However, for successful strategies for the treatment of this heterogeneous tumor, other combinations approaches need to be considered to simultaneously target other NB cells.