Benzophenone-3 exposure alters composition of tumor infiltrating immune cells and increases lung seeding of 4T1 breast cancer cells.

Environmental chemicals are a persistent and pervasive part of everyday life. A subset of environmental chemicals are xenoestrogens, compounds that bind to the estrogen receptor (ER) and drive estrogen-related processes. One such chemical, benzophenone-3 (BP3), is a common chemical in sunscreen. It is a potent UV protectant but also is quickly absorbed through the skin. While it has been approved by the FDA, there is a renewed interest in the safety of BP3, particularly in relation to breast cancer. The focus of this study was to examine the impact that BP3 has on triple negative breast cancer (TNBC) through alterations to cells in the immune microenvironment. In this study, we exposed female mice to one of two doses of BP3 before injecting them with a TNBC cell line. Several immune endpoints were examined both in the primary tissues and from in vitro studies of T cell behavior. Our studies revealed that in the lung tumor microenvironment, exposure to BP3 not only increased the number of metastases, but also the total area of tumor coverage. We also found that BP3 caused alterations in immune populations in a tissue-dependent manner, particularly in T cells. Taken together, our data suggest that while BP3 may not directly affect the proliferation of TNBC, growth and metastasis of TNBC-derived tumors can be altered by BP3 exposures via the alterations in the immune populations of the tumor microenvironment.

Gene editing therapeutics based on mRNA delivery.

The field of gene editing has received much attention in recent years due to its immense therapeutic potential. In particular, gene editing therapeutics, such as the CRISPR-Cas systems, base editors, and other emerging gene editors, offer the opportunity to address previously untreatable disorders. This review aims to summarize the therapeutic applications of gene editing based on mRNA delivery. We introduce gene editing therapeutics using mRNA and focus on engineering and improvement of gene editing technology. We subsequently examine ex vivo and in vivo gene editing techniques and conclude with an exploration of the next generation of CRISPR and base editing systems.

The anti-dyslipidemia property of saffron petal hydroalcoholicextract in cardiovascular patients: A double-blinded randomized clinical trial.

BACKGROUND AND AIMS: Dyslipidemia is one of the most important risk factors of cardiovascular diseases (CVDs). Despite developments in pharmacological treatments for dyslipidemia there are several challenges. Recently some herbs highly considered to control dyslipidemia due to their low toxicity and high potency. In this study we investigated the effects of saffron petals on the lipid profile of dyslipidemia patients as well as several other biochemical blood factors. METHODS: In this double blind, placebo controlled, clinical trial, we used systematic random sampling to divide 40 patients with at least two abnormalities in the following factors: (high-density lipoproteins (HDL) ≤40, low-density lipoproteins (LDL) ≥130, triglycerides (TG) ≥200, total cholesterol (Cho) ≥200), into 2 groups of 21 ones. At the end of the intervention period, serum lipid factors, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), urea, creatinin (CR) and fasting blood sugar (FBS) were measured and statistically compared with their values just before the intervention. RESULTS: We found that the saffron petal pills markedly (P < 0.001) decreased the serum lipid levels of patients (TG, Cho and LDL) in the intervention group (113.81 ± 12.93, 56.52 ± 4.68 and 48.28 ± 3.70) as compared to the placebo group (18.42 ± 15.79, 4.57 ± 4.40 and 7.38 ± 3.54). Also, comparing the mean value of differences in two groups before and after the intervention showed significant reduction in TG (113.81 ± 26), Cho (56.53 ± 0.30) and LDL (48.28 ± 4.30) levels (P < 0.001). CONCLUSIONS: The saffron petal pills considerably reduced blood serum lipid profile and as well as urea and CR of dyslipidemia patients. So, this plant may be used as a potent phytomedicine for treatment and prevention of dyslipidemia and cardiovascular disorders. However, the results indicated that no statistical change was observed in the level of other biochemical blood factors such as ALT, AST, ALP and FBS.

Sources of Cancer Neoantigens beyond Single-Nucleotide Variants.

The success of checkpoint blockade therapy against cancer has unequivocally shown that cancer cells can be effectively recognized by the immune system and eliminated. However, the identity of the cancer antigens that elicit protective immunity remains to be fully explored. Over the last decade, most of the focus has been on somatic mutations derived from non-synonymous single-nucleotide variants (SNVs) and small insertion/deletion mutations (indels) that accumulate during cancer progression. Mutated peptides can be presented on MHC molecules and give rise to novel antigens or neoantigens, which have been shown to induce potent anti-tumor immune responses. A limitation with SNV-neoantigens is that they are patient-specific and their accurate prediction is critical for the development of effective immunotherapies. In addition, cancer types with low mutation burden may not display sufficient high-quality [SNV/small indels] neoantigens to alone stimulate effective T cell responses. Accumulating evidence suggests the existence of alternative sources of cancer neoantigens, such as gene fusions, alternative splicing variants, post-translational modifications, and transposable elements, which may be attractive novel targets for immunotherapy. In this review, we describe the recent technological advances in the identification of these novel sources of neoantigens, the experimental evidence for their presentation on MHC molecules and their immunogenicity, as well as the current clinical development stage of immunotherapy targeting these neoantigens.

Countering Triple Negative Breast Cancer via Impeding Wnt/ß-Catenin Signaling, a Phytotherapeutic Approach.

Triple negative breast cancer (TNBC) is characterized as a heterogeneous disease with severe malignancy and high mortality. Aberrant Wnt/ß-catenin signaling is responsible for self-renewal and mammosphere generation, metastasis and resistance to apoptosis and chemotherapy in TNBC. Nonetheless, in the absence of a targeted therapy, chemotherapy is regarded as the exclusive treatment strategy for the treatment of TNBC. This review aims to provide an unprecedented overview of the plants and herbal derivatives which repress the progression of TNBC through prohibiting the Wnt/ß-catenin pathway. Herbal medicine extracts and bioactive compounds (alkaloids, retinoids. flavonoids, terpenes, carotenoids and lignans) alone, in combination with each other and/or with chemotherapy agents could interrupt the various steps of Wnt/ß-catenin signaling, i.e., WNT, FZD, LRP, GSK3ß, Dsh, APC, ß-catenin and TCF/LEF. These phytotherapy agents diminish proliferation, metastasis, breast cancer stem cell self-renewal and induce apoptosis in cell and animal models of TNBC through the down-expression of the downstream target genes of Wnt signaling. Some of the herbal derivatives simultaneously impede Wnt/ß-catenin signaling and other overactive pathways in triple negative breast cancer, including: mTORC1; ER stress and SATB1 signaling. The herbal remedies and their bioactive ingredients perform essential roles in the treatment of the very fatal TNBC via repression of Wnt/ß-catenin signaling.

Prediction and validation of GUCA2B as the hub-gene in colorectal cancer based on co-expression network analysis: In-silico and in-vivo study.

BACKGROUND: Several serious attempts to treat colorectal cancer have been made in recent decades. However, no effective treatment has yet been discovered due to the complexities of its etiology. METHODS: we used Weighted Gene Co-expression Network Analysis (WGCNA) to identify key modules, hub-genes, and mRNA-miRNA regulatory networks associated with CRC. Next, enrichment analysis of modules has been performed using Cluepedia. Next, quantitative real-time PCR (RT-qPCR) was used to validate the expression of selected hub-genes in CRC tissues. RESULTS: Based on the WGCNA results, the brown module had a significant positive correlation (r = 0.98, p-value=9e-07) with CRC. Using the survival and DEGs analyses, 22 genes were identified as hub-genes. Next, three candidate hub-genes were selected for RT-qPCR validation, and 22 pairs of cancerous and non-cancerous tissues were collected from CRC patients referred to the Gastroenterology and Liver Clinic. The RT-qPCR results revealed that the expression of GUCA2B was significantly reduced in CRC tissues, which is consistent with the results of differential expression analysis. Finally, top miRNAs correlated with GUCA2B were identified, and ROC analyses revealed that GUCA2B has a high diagnostic performance for CRC. CONCLUSIONS: The current study discovered key modules and GUCA2B as a hub-gene associated with CRC, providing references to understand the pathogenesis and be considered a novel candidate to CRC target therapy.

Saffron anti-metastatic properties, ancient spice novel application.

Crocus sativus L. (saffron), was applied as a spice, food colorant and medicine since four millennia ago and has been used as a remedy for various maladies. In the last three decades, the anti-primary tumor properties of saffron and its main carotenoids, crocin and crocetin, have been well explored. Despite the fact that metastasis is the leading cause of death in cancer patients, the anti-metastatic potential of saffron and its carotenoids has been surveyed only this decade. This review aims to provide an unprecedented overview of the anti-metastatic effects of saffron, crocin and crocetin, and the mechanisms underlying these effects. Investigations on various cancers demonstrated the anti-migratory, anti-invasion, anti-angiogenic potentials of saffron and its carotenoids, as well as their effects suppressing cell-ECM adhesion and enhancing cell-cell attachment. Saffron and its carotenoids exert their impact through different mechanisms such as reduction of CD34 and suppression of Wnt/ß-catenin, Ras/ERK, P38, DCLK1, EMT, matrix metalloproteinases and urokinases. Crocin displayed more effective anti-metastatic potency, in comparison with saffron extract and crocetin. The bioaccessibility/bioavailability, nontoxicity on normal cells, confirmed anti-tumor efficiency and the recent evidence on the anti-metastatic potential of saffron and its carotenoids, recommends them as a propitious multipotent dietary agent and herbal medicine.

Crocin and Metformin suppress metastatic breast cancer progression via VEGF and MMP9 downregulations: in vitro and in vivo studies.

Metastatic breast cancer remains a serious health concern and numerous investigations recommended medicinal plants as a complementary therapy. Crocin is one of the known anticancer bio-component. Recently, the inhibitory effect of metformin has been studied on the various aspects of cancer. However, no study reported their combination effects on metastatic breast cancer. In the present study, we have assessed their anti-metastatic effects on in vitro and in vivo breast cancer models. Using MTT assay, scratch, and adhesion tests, we have evaluated the cytotoxic, anti-invasive and anti-adhesion effects of crocin and metformin on 4T1 cell line, respectively. Their protective effects and MMP9 as well as VEGF protein expression levels (Western blotting) investigated in the 4T1 murine breast cancer model. Our results showed that both crocin and metformin reduced cell viability, delayed scratch healing and inhibited the cell adhesion, in vitro. While crocin alone restored the mice's weight reduction, crocin, metformin, and their combination significantly reduced the tumor volume size and enhanced animal survival rate in murine breast cancer model, responses that were associated with VEGF and MMP9 down-regulation. These findings suggest that a combination of crocin and metformin could serve as a novel therapeutic approach to enhance the effectiveness of metastatic breast cancer therapy.

Anticancer and apoptotic activities of parthenolide in combination with epirubicin in mda-mb-468 breast cancer cells.

Breast cancer is the most common malignancy in women worldwide. Unfortunately, current therapeutic methods are not completely efficient. Hence, combination therapy with medicinal plants has attracted several kinds of research. In the current study, we aimed to investigate the apoptotic and anti-cancer effect of Parthenolide in combination with Epirubicin in the MDA-MB-468 breast cancer cell line. In this study,  the anti-proliferative and pro-apoptotic effect of Parthenolide in combination with Epirubicin and without it, in the MDA-MB-468 cell line have been assessed by MTT test, Hoescht staining and flow cytometry methods. Our outcomes showed that Parthenolide treatment in the present of Epirubicin led to a decrease in the minimum toxic concentration of Parthenolide and Epirubicin in comparison with individual treatments. Then, to achieve a likely molecular mechanism of mentioned drugs Bax and Bcl2 expression level evaluated by Real-time PCR and subsequently, Western blotting has been estimated the protein level of Caspase 3. Our data indicated that the treatment of cells with Parthenolide led to up-regulation of Bax and downregulation of Bcl2 at mRNA level. Moreover, Parthenolide treatment led to the obvious alternation of Caspase3 protein level. These results indicated that Parthenolide in combination with Epirubicin have significant cytotoxicity due to targeting the main regulators of apoptosis. Hence, according to lack of cytotoxicity of Parthenolide on normal cells that lead to reduction of drug side effects, it could be suggested as an adjuvant therapy with Epirubicin after complementary research on animal model and clinical trial.

Anti-metastatic properties of a potent herbal combination in cell and mice models of triple negative breast cancer.

AIM: To determine the anti-metastatic potential of combinations of two bioactive carotenoids of saffron, crocin and crocetin, on 4T1 breast cancer and on a mice model of TNBC, and assess the effect of the most potent combination on the Wnt/ß-catenin pathway. MAIN METHODS: The effects of the carotenoid combinations on the viability of 4T1 cells were determined by MTT assay. The effects of the nontoxic doses on migration, mobility, invasion and adhesion to ECM were examined by scratch assay, Transwell/Matrigel-coated Transwell chamber and adhesion assay respectively. Tumors were inoculated by injecting mice with 4T1 cells. The weights and survival rates of the mice and tumor sizes were monitored. Histological analysis of the tissues was conducted. The expression levels of Wnt/ß-catenin pathway genes were measured by Real-time PCR and western blotting. KEY FINDINGS: Treatment of 4T1 cells with combination doses inhibited viability in a dose-dependent manner. The nontoxic combinations significantly inhibited migration, cell mobility and invasion, also attenuating adhesion to ECM. The combination therapy mice possessed more weight, higher survival rates and smaller tumors. Histological examination detected remarkably fewer metastatic foci in their livers and lungs. It was also demonstrated that the combinations exerted anti-metastatic effects by disturbing the Wnt/ß-catenin target genes in the liver and tumors. SIGNIFICANCE: Our findings propose a carotenoid combination as an alternative potent herbal treatment for TNBC, which lacks the adverse effects associated with either chemotherapeutic agents or herb-chemotherapeutic drugs.

High-Intensity Training and Saffron: Effects on Breast Cancer-related Gene Expression.

PURPOSE: Exercise training and some herbal components have an anticancer function and can suppress tumor growth. However, the role of these protective factors in altering breast cancer-related gene expression is still unknown. Thus, this study aimed to assess the effect of 4 wk of high-intensity interval training (HIIT) and saffron (Crocus sativus L.) aqueous extract (SAE) on Sirtuin-1 (SIRT1), human telomerase reverse transcriptase (hTERT), and p53 gene expression in female mice breast tumor tissue induced by 4T1 cell line. METHODS: This study was performed on female BALB/c mice. The 4T1 breast cancer cells were subcutaneously implanted, and mice were randomly sorted into the following groups: control, HIIT, SAE, HIIT + SAE (n = 10 mice per group), and sham (n = 4 mice per group). Mice were sacrificed at the end of the intervention period, and the expression of SIRT-1, hTERT, and p53 was determined by real-time polymerase chain reaction. RESULTS: The mRNA level of SIRT1 was increased in the HIIT + SAE group compared with the HIIT and control groups (P = 0.007 and P = 0.03, respectively). Moreover, the amount of mRNA of p53 was increased after a 4-wk HIIT compared with the control and HIIT + SAE groups in tumor tissue (P = 0.03 and P = 0.02, respectively). No change was found in the mRNA expression of hTERT between groups (P = 0.92). CONCLUSIONS: These findings suggest that HIIT may reduce tumor burden through the upregulation of p53 associated with tumor suppression pathway. In contrast, the combination of HIIT and SAE did not alter p53 and SIRT1 expression levels and may suppress tumor growth by other mechanisms.

Benzophenone-3 promotion of mammary tumorigenesis is diet-dependent.

Benzophenone-3 is a putative endocrine disrupting chemical and common ingredient in sunscreens. The potential of endocrine disrupting chemicals to act as agonists or antagonists in critical hormonally regulated processes, such as mammary gland development and mammary tumorigenesis, demands evaluation of its potential in promoting breast cancer. This study identifies the effects of BP-3 on mammary tumorigenesis with high-fat diet during puberty versus adulthood in Trp53-null transplant BALB/c mice. Benzophenone-3 exposure yielded levels in urine similar to humans subjected to heavy topical sunscreen exposure. Benzophenone-3 was protective for epithelial tumorigenesis in mice fed lifelong low-fat diet, while promotional for epithelial tumorigenesis in mice fed adult high-fat diet. Benzophenone-3 increased tumor cell proliferation, decreased tumor cell apoptosis, and increased tumor vascularity dependent on specific dietary regimen and tumor histopathology. Even in instances of an ostensibly protective effect, other parameters suggest greater risk. Although benzophenone-3 seemed protective on low-fat diet, spindle cell tumors arising in these mice showed increased proliferation and decreased apoptosis. This points to a need for further studies of benzophenone-3 in both animal models and humans as a potential breast cancer risk factor, as well as a more general need to evaluate endocrine disrupting chemicals in varying dietary contexts.

The impact of Crocus sativus stigma against methotrexate-induced liver toxicity in rats.

Background The adverse effects of methotrexate (MTX) mainly hepatotoxicity restrict its clinical use. This study was designed to investigate the protective effects of saffron (Crocus sativus) (CS) extract on MTX-induced hepatotoxicity. Methods Twenty-eight male Wistar rats randomly divided into four equal groups. Except for control, all groups received a single intraperitoneal (i.p.) injection of MTX on the 3rd day of study. The CS extract was given (80 mg/kg i.p.) to rats 3 days before MTX and continued for the next 7 days (Pre&Post-CS group) or administrated after MTX injection and lasted for 7 days (Post-CS group). On the 11th day, all rats were sacrificed and their plasma levels of liver enzymes including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were determined. Also, liver histopathology and hepatic levels of malondialdehyde (MDA), nitric oxide (NO) and super oxidase dismutase (SOD) were evaluated. Results The results showed that MTX significantly incremented plasma levels of AST, ALT, ALP and LDH (all p<0.001) and hepatic MDA and NO levels; whereas, decreased SOD activity. Histological alterations such as early fatty changes were evident in the MTX group. Administration of CS extract at both methods could ameliorate liver enzyme elevation, oxidative/nitrosative stresses and morphological alterations of the liver. Pre-and-post treatment with CS extract showed better protective effects than only post-treatment. Conclusion The present findings provide showing CS could effectively alleviate MTX-induced hepatotoxicity in rats. Further investigations are recommended to determine the exact mechanisms underlying the hepatoprotective potential of saffron.

Biomonitorization of metal ions in the serum of Iranian patients treated with fixed orthodontic appliances in comparison with controls in eastern Iran.

The present study aimed to assess the level of metal ions [chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), and zinc (Zn)] in the serum of patients with fixed orthodontic appliances. One hundred samples (32 males, 68 females) were collected from patients undergoing fixed orthodontic treatment for different periods. A reference (control) group (24 males, 16 females) who had no appliances was used to properly evaluate the changes in the level of these elements in orthodontic appliance users. The element concentrations were measured using inductively coupled plasma mass spectrometry (ICP-MS). Higher concentrations of metal ions (except for Cr) were found in the serum of the orthodontic group. Bivariate scatter plot showed a highly significant (p < 0.001) correlation between Ni and other elements. The duration of orthodontic treatment increased significantly the Ni levels whereas the bracket type was found to have no significant impact on altering the concentration level of metal ions. The results of the SEM-EDS showed a high variation in the level of metal ions in the brackets and wires. In conclusion, fixed orthodontic appliances increased serum levels of Ni, Zn, Mn, Fe, and Cu but did not change Cr levels.

A mini review of bisphenol A (BPA) effects on cancer-related cellular signaling pathways.

Bisphenol A (BPA) is a plasticizer used widely in many industrial products and is now well established as an endocrine-disrupting chemical (EDC). BPA readily leaches out from these products into the environment and into foodstuffs (from packaging materials) and human exposure can be considerable. Many studies have shown that BPA exposure is associated with a range of chronic human health conditions, including diabetes, cardiovascular disorders, polycystic ovarian disease, hepatotoxicity, and various types of cancer. BPA exerts its effects through deregulating cell signaling pathways associated with cell growth, proliferation, migration, invasion, and apoptosis. Previous studies on the molecular mechanisms of BPA have illustrated a variety of pathways impaired at very low exposure concentrations and that stimulate cellular responses relating to tumorigenesis both in cancer onset and progression. In this mini review, the recent advancements made through in vitro analyses are reported on for the effect of BPA on various cellular signaling pathways focusing on the signaling pathways that play a major role in carcinogenesis.

Inhibitory Effect of Crocin on Metastasis of Triple-Negative Breast Cancer by Interfering with Wnt/ß-Catenin Pathway in Murine Model.

Triple-negative breast cancer (TNBC) is the most metastatic subtype of breast cancer and cannot be controlled with any standard-of-care therapy. However, various studies have recommended medicinal plants as complementary treatments for cancer. In particular, crocin, the main bioactive carotenoid of saffron, has exhibited anticancer effects on primary tumors. This research, for the first time, investigated the antimetastatic potency of crocin on murine model of metastatic TNBC and its effect on the Wnt/ß-catenin pathway. To induce tumors, 4T1 cells were injected to female BALB/c mice. Measurement of biochemical markers showed nontoxicity of crocin. The crocin-treated mice possessed more weight, higher survival rates, and smaller tumors. Histological examination detected no metastatic deposits in their livers and lungs. Also, downregulation of the expression of Wnt/ß-catenin target genes in tumors and lungs was observed compared to the untreated group. Our findings suggest crocin as a promising complementary antimetastatic herbal medicine for treatment of TNBC.

The role of expression and activity of 15-Lipoxygenase isoforms and related cytokines in patients with Multiple Sclerosis and healthy controls.

BACKGROUND: Multiple Sclerosis (MS) as an inflammatory multifactorial auto immune nervous system disease imposes devastating burden of morbidity worldwide. Among environmental and genetic factors, the relevance of inflammatory mediators in MS pathogenesis is well documented. 15-Lipoxygense enzyme and its derived products have received attention as possible mediators of inflammatory responses. The involvement of 15-Lipoxygense pathway in the pathogenesis of inflammatory diseases such as MS has yet to be illustrated which is perused in the current study. METHODS: The expression level of 15-Lipoxygense isoforms was assessed via Real-Time PCR in the peripheral blood mononuclear cells separated from patients with MS and healthy subjects. The level of 15-Lipoxygense products (15(S) HETE, 13(S) HODE) and related cytokines (IL4 and IL13) were evaluated using enzyme immunoassay kits in serum samples. RESULTS: Our results demonstrated that 15-Lipoxygense-1 and 15-Lipoxygense-2 expression levels were increased in patients suffering from MS comparing to healthy subjects which were more obvious in Relapsing-Remitting MS. The elevated levels of 15-Lipoxygense isoforms were accompanied with 15(S) HETE and 13(S) HODE enhancement in serum of patients and the IL 13 elevation but not IL4 was consistent with higher expression of 15-Lipoxygense. The diagnostic value of 15-Lipoxygense isoforms and products were considerable between patients and healthy groups. CONCLUSION: The possible effect of 15-Lipoxygense pathway in the regulation of inflammatory events may light up new therapeutic possibilities regarding MS pathogenesis.

Comparison of atherogenic index and lipid profiles in candidates for coronary artery bypass graft surgery versus normal people.

Information on incidence and risk factors of cardiovascular disease (CVD) is rare in the Middle East. This study aims to compare Iranian candidates for coronary artery bypass graft (CABG) surgery and healthy controls in terms of lipid profile, atherogenic index of plasma (AIP), and atherosclerosis index (ASTI). The individuals recruited in this study were 135 CVD patients before CABG surgery and 135 healthy subjects matching in age with the cases. Lipid profiles of the two groups were analyzed with a commercial kit. The AIP and ASTI indexes were calculated with related formula. The TC, TG, LDL-C and HDL-c parameters were dramatically changed (p<0.01) between study groups. AIP and ASTI indexes were significantly higher in patients than in healthy people (p=0.001). In individuals with CVD, it is suggested to measure these indexes in order for effective diagnosis before CABG surgery.

A Comparative Study on Anti-Invasion, Antimigration, and Antiadhesion Effects of the Bioactive Carotenoids of Saffron on 4T1 Breast Cancer Cells Through Their Effects on Wnt/ß-Catenin Pathway Genes.

Crocus sativus L. (saffron) has been used as a spice and as a medicine for the past four thousand years. Recently, saffron has been well documented to possess anticancer effects on primary tumors. However studies of its antimetastatic potential are lacking. The present study is a comparative investigation of the antimetastatic effects of saffron carotenoids, crocin and crocetin, on triple negative metastatic breast cancer cells (4T1) and their effects on the Wnt/ß-catenin pathway. It was found that treatment of 4T1 cells with crocin and crocetin resulted in the inhibition of viability in a dose-dependent manner. Scratch and Transwell chamber assays showed that the nontoxic doses of crocin and crocetin significantly inhibited migration, cell mobility, and invasion, also attenuating adhesion to extracellular matrix. Crocin downregulated mRNA expression of FZD7, NEDD9, VIM, and VEGF-α genes and upregulated E-CAD. Crocin and crocetin exhibited comparable anti-invasion properties on 4T1 cells. However, crocin and crocetin exerted more pronounced antimigration and antiadhesion potency, respectively. Furthermore, we showed that the antimetastatic effects of crocin can occur through interfering with the Wnt/ß-catenin pathway.

Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response.

Despite advances in neurosurgical techniques and radio-/chemotherapy, the treatment of brain tumors remains a challenge. This is particularly true for the most frequent and fatal adult brain tumor, glioblastoma (GB). Upon diagnosis, the average survival time of GB patients remains only approximately 15months. The alkylating drug temozolomide (TMZ) is routinely used in brain tumor patients and induces apoptosis, autophagy and unfolded protein response (UPR). Here, we review these cellular mechanisms and their contributions to TMZ chemoresistance in brain tumors, with a particular emphasis on TMZ chemoresistance in glioma stem cells and GB.