Potential role of genetic polymorphisms in neoadjuvant chemotherapy response in breast cancer.

Chemoresistance leads to treatment failure, which can arise through different mechanisms including patients' characteristics. Searching for genetic profiles as a predictor for drug response and toxicity has been extensively studied in pharmacogenomics, thus contributing to personalized medicine and providing alternative treatments. Numerous studies have demonstrated significant evidence of association between genetic polymorphisms and response to neoadjuvant chemotherapy (NAC) in breast cancer. In this review, we explored the potential impact of genetic polymorphisms in NAC primary resistance through selecting a specific clinical profile. The genetic variability within pharmacokinetics, pharmacodynamics, DNA synthesis and repair, and oncogenic signaling pathways genes could be predictive or prognostic markers for NAC resistance. The clinical implication of these results can help provide individualized treatment plans in the early stages of breast cancer treatment. Further studies are needed to determine the genetic hosts of primary chemoresistance mechanisms in order to further emphasize the implementation of genotypic approaches in personalized medicine.

Association between the ELAVL1 gene single nucleotide polymorphisms and the Genetic Susceptibility to cervical cancer by high resolution melting in a Tunisian population.

BACKGROUND: Human papillomavirus is the major cause of cervical cancer, but only few cases develop into cancer. Nevertheless, HuR (ELAVL1) gene has been implicated in the oncogenesis of certain cancers. The correlation between ELAVL1 gene and the risk of cervical cancer remains unclear. Therefore, this study investigated the effect of ELAVL1 gene polymorphisms (SNPs) in cervical cancer development in Tunisian women. METHOD: ELAVL1 gene SNPs: ELAVL1 rs12983784 T > C, ELAVL1 rs14394 T > C, ELAVL1 rs74369359 G > T, ELAVL1 rs35986520 G > A, ELAVL1 rs10402477 C > T, ELAVL1 rs12985234 A > G and ELAVL1 rs2042920 T > G, were genotyped by High resolution melting (HRM). SNPStats software was used to perform linkage disequilibrium (LD) and haplotype analysis. RESULTS: Comparing the cervical cancer patients with healthy control participants, the SNPs rs12983784 (P = 0.032), rs74369359 (p = < 10- 3) and rs10402477 (P = 0.001) were associated with an increased cervical cancer risk. Contrary to the SNPs rs14394, rs7469359, rs35986520, rs12985234 and rs2042920 (p˃0.05). The haplotype analysis of the seven SNPs of ELAVL1 gene showed that there is no association between the different haplotypes and a possible risk of cervical cancer disease. Moreover, there was a significant Linkage disequilibrium between rs35986520 and rs2042920 (D'=0.9972) and between rs2042920 and rs10402477 (D'=0.9977). CONCLUSION: Our results indicated that genetic variants in the ELAVL1 gene might be associated with susceptibility to cervical cancer in the Tunisian population.

Association of xenobiotic-metabolizing genes polymorphisms with cervical cancer risk in the Tunisian population.

BACKGROUND: Host genetic characteristics and environmental factors interactions may play a crucial role in cervical carcinogenesis. We investigated the impact of functional genetic variants of four xenobiotic-metabolizing genes (AhR, CYP1A1, GSTM1, and GSTT1) on cervical cancer development in Tunisian women. METHODS: The AhR gene polymorphism was analyzed using the tetra-primer ARMS-PCR, whereas the CYP1A1 polymorphism genotypes were identified by PCR-RFLP. A multiplex ligation-dependent polymerase chain reaction approach was applied for the analysis of GSTM1 and GSTT1 polymorphisms. RESULTS: The homozygous A/A genotype of the AhR gene (rs2066853) and the heterozygous T/C genotype of the CYP1A1 SNP (CYP1A1-MspI) appeared to be associated with an increased risk of cervical tumorigenesis (ORa = 2.81; ORa = 5.52, respectively). Furthermore, a significantly increased risk of cervical cancer was associated with the GSTT1 null genotype (ORa = 2.65). However, the null GSTM1 genotype showed any significant association with the risk of cervical cancer compared to the wild genotype (ORa = 1.18; p = 0.784). Considering the combined effect, we noted a significantly higher association with cancer risk for individuals with at least two high-risk genotypes of CYP1A1/GSTT1 (ORa = 4.2), individuals with at least two high-risk genotypes of CYP1A1/GSTT1/AhR (ORa = 11.3) and individuals with at least two high-risk genotypes of CYP1A1/GSTM1/GSTT1/AhR exploitation low-risk genotype as a reference. CONCLUSION: This study indicated that the single-gene contribution and the combined effect of xenobiotic-metabolizing gene polymorphisms (AhR, CYP1A1-MspI, GSTM1, and GSTT1) may have a considerable association with increased cervical cancer risk.

Natural dietary compound naringin inhibits glioblastoma cancer neoangiogenesis.

BACKGROUND: Flavonoids, which existed nearly in all fruits and vegetables, are considered as a class of plant-secondary metabolites with a polyphenolic structure and have properties with health-improving potential. Yet, not so many experimental focus on the benefits of flavonoid in vivo after external application. Here we assessed the impacts of naringin in vitro and in vivo in the human glioma U-87 cells implanted into athymic mice. METHODS: Tumor size and animal survival time were followed in naringin-treated mice bearing subcutaneous gliomas. To define the effects of naringin on angiogenesis, in vitro, tube formation and migration were assayed using endothelial HUVEC cell line. RESULTS: Low concentration of naringin remarkably inhibited tubulogenesis and reduced cell invasion. Moreover, naringin has been shown to have a toxicity effect on U-87 cells in a dose-dependent way. Furthermore, naringin administration (120 mg/kg/day) applies serious anti-cancer belongings on glioblastoma, as demonstrated by a slow cancer progression. CONCLUSIONS: Our study has provided the first evidence on the antitumor effect of naringin, which is somehow due to the inhibition of invasion and angiogenesis.

IGF1 polymorphisms and colon cancer risk in Tunisian population.

BACKGROUND: Insuline-like growth factor I (IGF1) is a peptide growth factor that promotes cell proliferation and inhibits apoptosis. AIM: To examine the association of genetic variants in IGF1 (rs12423791, rs1019731, rs5742632, rs2033178 and rs2373722) with risk of colon cancer in Tunisia. METHODS: The study included 76 formalin-fixed paraffin embedded primary colorectal carcinomas and paired normal colon. The five IGF1 polymorphisms were determined by polymerase chain-restriction fragment length polymorphism (PCR-RFLP). RESULT: A significant differences in genotypes and alleles frequency of the five examined IGF1 polymorphisms was determined between tumor and healthy tissues of colon cancer patients (P<0,01). While, no significant association was found between genetic variation in IGF1 variants and clinic-pathological parameters in tumors tissues. Expect for rs2373722, a statistically significant correlation was detected between tumor localization and the presence of the (A) mutated allele (OR=0,49; 95% CI 0,25-0,99; P=0,03). CONCLUSION: This analysis shows that IGF1gene polymorphisms rs12423791, rs1019731, rs5742632, rs2033178 and rs2373722 are associated with the risk of colon cancer in Tunisian population.

Association between HER2 and IL-6 genes polymorphisms and clinicopathological characteristics of breast cancer: significant role of genetic variability in specific breast cancer subtype.

Clinical implications of single nucleotide polymorphisms (SNPs) in breast cancer have been explored to determine the impact of SNP in modulating the pathogenesis of breast cancer. This study aimed to evaluate the association between HER2 (rs2517956) and (IL-6) (rs1800795 and rs2069837) and clinicopathological characteristics in HER2-positive and HER2-negative breast cancer in Tunisian women. A retrospective cohort study included 273 patients. Genomic DNA was extracted from peripheral blood samples, and genotyping of selected SNP was performed by PCR-RFLP assays. Statistical analysis was then carried out to assess genotypic frequencies and genetic association in relation to breast cancer subtypes. SHEsis software was applied to IL-6 haplotypic structure analysis. The distribution of genotype frequencies of rs2517956, rs1800795 and rs2069837 showed no statistically difference between HER2-positive and HER2-negative breast cancer. HER2 (rs2517956) was associated with tumor size (p = 0.01) and age at diagnosis (p = 0.02) in HER2-negative breast cancers, but no significant association was observed in HER2-positive breast cancer. For IL-6 gene, none of the clinicopathological parameters were associated with rs1800795 and rs2069837 in both breast cancer subtypes (p > 0.05). SHEsis analysis revealed a high linkage disequilibrium between rs1800795 and rs2069837; differences in the distribution of IL-6 two loci haplotypes were statistically negative between HER2-positive and HER2-negative breast cancer (p = 0.20) which confirmed no association with HER2 overexpression. This study demonstrates that rs2517956 is associated with clinicopathological characteristics in HER2-negative breast cancer, which could have a differential prognostic role compared to HER2-positive breast cancer.

IGF1 polymorphisms and colon cancer risk in Tunisian population.

BACKGROUND: Insuline-like growth factor I (IGF1) is a peptide growth factor that promotes cell proliferation and inhibits apoptosis. AIM: To examine the association of genetic variants in IGF1 (rs12423791, rs1019731, rs5742632, rs2033178 and rs2373722) with risk of colon cancer in Tunisia. METHODS: The study included 76 formalin-fixed paraffin embedded primary colorectal carcinomas and paired normal colon. The five IGF1 polymorphisms were determined by polymerase chain-restriction fragment length polymorphism (PCR-RFLP). RESULT: A significant differences in genotypes and alleles frequency of the five examined IGF1 polymorphisms was determined between tumor and healthy tissues of colon cancer patients (P<0,01). While, no significant association was found between genetic variation in IGF1 variants and clinic-pathological parameters in tumors tissues. Expect for rs2373722, a statistically significant correlation was detected between tumor localization and the presence of the (A) mutated allele (OR=0,49; 95% CI 0,25-0,99; P=0,03). CONCLUSION: This analysis shows that IGF1gene polymorphisms rs12423791, rs1019731, rs5742632, rs2033178 and rs2373722 are associated with the risk of colon cancer in Tunisian population.

miR-10b, miR-26a, miR-146a And miR-153 Expression in Triple Negative Vs Non Triple Negative Breast Cancer: Potential Biomarkers.

MicroRNAs (miRNAs) are small non-coding RNAs composed of 18-25 nucleotides that can post-transcriptionally regulate gene expression and have key regulatory roles in cancer, acting as both oncogenes and tumor suppressors. About 1000 genes in humans encode miRNAs, which account for approximately 3% of the human genome, and up to 30% of human protein coding genes may be regulated by miRNAs. The objective of this article is to evaluate the expression profile of four miRNAs previously implicated in triple negative breast cancer: miR-10b, miR-26a, miR-146a and miR-153, and to determine their possible interaction in triple negative and non triple negative breast cancer based on clinical outcome and the expression of BRCA1. 24 triple-negative and 13 non triple negative breast cancer cases, were studied by q-RT-PCR and immunohistochemistry to determine the expression of the four studied miRNAs and the BRCA1 protein, respectively. We observed that the BRCA1 protein was absent in 62.5% of the triple negative cases. Besides, the miR-146a and miR-26a were over expressed in triple negative breast cancer. These two miRNAs, miR-10b and miR-153 were significantly associated to lymph node metastases occurrence in triple negative breast carcinoma. All the analyzed microRNAs were not associated with the expression of BRCA1 in our conditions. Our work provides evidence that miR-146a, miR-26a, miR-10b and miR-153 could be defined as biomarkers in triple negative breast cancer to predict lymph node metastases (LNM).

A bioactivity guided study on the antibacterial activity of Hertia cheirifolia L. extracts.

This study was carried out with the objective to investigate the antibacterial activity of Hertia cheirifolia L. extracts against Gram-positive and Gram-negative strains including Staphylococcus aureus (ATCC 6538), Bacillus subtilis (ATCC 6633), Bacillus licheniformis, Esherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027), Salmonella enterica (CIP 8039) and Salmonella typhimirium. The results of this antibacterial screening showed that the ethyl acetate (EtOAc) extracts had the best activity against the tested microorganisms. A bioassay-oriented fractionation approach for the more active extract (roots ethyl acetate extract) led to the obtaining five sub-fractions. Furthermore, these sub-fractions were also tested for antimicrobial activity and the best results were obtained for the roots EtOAc sub-fraction (C) with MICs values between 0.039 and 0.156 mg/mL. Reversed-phase high performance liquid chromatography (RP-HPLC) analysis indicated that the major phenolic components of active (EtOAc) extracts and sub-fraction (C) are fisetin hydrate (82.06%), trans cinnamic acid (63.66%), gallic acid (38.97%) and myricetin (20.92%). These results may help to improve these natural antibacterial substances that could serve as selective agents for bacterial diseases.

Biological properties of Hertia cheirifolia L. flower extracts and effect of the nopol on α-glucosidase.

In screening for antioxidant and α-glucosidase inhibitors from the extracts of Hertia cheirifolia L. flowers, the petroleum ether extract showed interesting antioxidant activity and inhibitory effect on the activity of α-glucosidase. The fractionation of this extract resulted in the isolation of a compound which is characterized by NMR and ESI-MS as a nopol. The nopol exhibited potent α-glucosidase inhibitory potential with IC50 value of 220µM. The kinetic evaluation indicated that it acts as a non-competitive inhibitor. A molecular docking study proved that the nopol presented a strong affinity with amino acid residues of α-glucosidase.

Effect of SP600125 on the mitotic spindle in HeLa Cells, leading to mitotic arrest, endoreduplication and apoptosis.

BACKGROUND: The JNK inhibitor SP600125 strongly inhibits cell proliferation in many human cancer cells by blocking mitosis progression and inducing cell death. Despite, all this study, the mechanism by which SP600125 inhibits mitosis-related effects in human cervical cells (HeLa cells) remains unclear. In this study, we investigated the effects of SP600125 on the cell viability, cell cycle, and on the spindle assembly during mitosis in HeLa cells. METHODS: To explore this approach, we used a viability test, an immunofluorescence microscopy to detect Histone phosphorylation and mitotic spindle aberrations. Apoptosis was characterised using Western Blotting. RESULTS: Treatment of HeLa cells with varying concentrations of SP600125 induces significant G2/M cell cycle arrest with elevated phosphorylation of histone H3 within 48 h, and endoreduplication after 48 h. SP600125 also induces significant abnormal mitotic spindle. High concentrations of SP600125 (20 µM) induce disturbing microtubule assembly in vitro. Additionally, SP600125- induced delayed apoptosis and cell death was accompanied by significant poly ADP-ribose polymerase (PARP) cleavage and caspase-3 activation in the late phase (at 72 h). CONCLUSION: Our results confirmed that SP600125 induce mitosis arrest in G2/M, endoreduplication, mitotic spindle aberrations and apoptosis.

PTEN-regulated AKT/FoxO3a/Bim signaling contributes to Human cell glioblastoma apoptosis by platinum-maurocalcin conjugate.

A previous report has shown that a chimera between a platinum complexing agent (1) and the cell penetrating peptide maurocalcin, synthesized with D-amino acids, (DMCa), termed Pt-1-DMCa, is a highly successful anticancer compound that works by targeting the intracellular redox system in glioblastoma (GBM) cells. However, the detailed cellular mechanism whereby the conjugate specifically kills tumor cells remains unclear. Herein, we show that Pt-1-DMCa induces apoptosis in Human U87 GBM cells through reactive oxygen species (ROS)-dependent modulation of the PI3K/AKT/FoxO3a signalling pathway. First, we found that Pt-1-DMCa treatment of these cells induces inhibition of AKT and nuclear accumulation of FoxO3a thereby facilitating transcription of the target genes Bim and PTEN. Modulation of the AKT/FoxO3a/Bim signaling pathway by RNA interference confirms that these signaling events are critical for Pt-1-DMCa-induced apoptosis of U87 GBM cells. Furthermore, we reveal that FoxO3a-mediated up-regulation of PTEN exerts an additional inhibitory effect on the AKT survival pathway. Thus, our results demonstrate that the conjugate can induce ROS-dependent FoxO3a-mediated apoptosis in U87 cells through PTEN-mediated inhibition of the PI3K/AKT survival axis. Our results help elucidate the molecular mechanisms underlying Pt-1-DMCa-induced cell death in U87 GBM cells and support a theoretical basis for future applications of the MCa peptide.

ANGPTL4 variants E40K and T266M are associated with lower fasting triglyceride levels and predicts cardiovascular disease risk in Type 2 diabetic Tunisian population.

BACKGROUND: Angiopoietin-like protein 4 (ANGPTL4) is a metabolic factor that increases plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). The objective of this study was to investigate the association of ANGPTL4 variants (E40K and T266M) with triglyceride levels and with cardiovascular risk factors, such as metabolic syndrome (MetS) and obesity in type 2 diabetic Tunisian population. METHODS: We investigated the effect of the tagging single nucleotide polymorphisms (SNPs) rs1044250 (T266M) and rs116843064 (E40K) with triglyceride (TG) levels and CAD risk factors in a cohort of 220 patients undergoing coronary angiography for the evaluation of stable CAD, all of whom had (type 2 diabetes) T2D and were at least overweight. Multivariate logistic regressions were performed on association studies. RESULTS: TT genotype of rs1044250 (T266M variant) showed a protective effect on CVD risk in CAD group patients (OR 1.92, 95% CI 0.601.42, p =0.05) compared with control Group patients (OR 1.17, 95% CI 0.70-1.66, p = 0.72). Likewise, GA genotype of rs116843064 (E40K variant): (OR 0.74, 95% CI 0.54-1.65, p =0.01) for the CAD group compared with control Group patients (OR 1.12, 95% CI 0.68-1.74, p = 0.074). CONCLUSIONS: ANGPTL4 variants are associated with, not only lower fasting triglyceride levels, but also a decreased cardiovascular risk in T2D Tunisian patients. So, T266M and E40K polymorphism predicts cardiovascular disease risk in Type 2 diabetic Tunisian population.

Deglycosylated bleomycin has the antitumor activity of bleomycin without pulmonary toxicity.

Bleomycin (BLM) is a potent anticancer drug used to treat different malignancies, mainly lymphomas, germ cell tumors, and melanomas. Unfortunately, BLM has major, dose-dependent, pulmonary toxicity that affects 20% of treated individuals. The most severe form of BLM-induced pulmonary toxicity is lung fibrosis. Deglyco-BLM is a molecule derived from BLM in which the sugar residue d-mannosyl-l-glucose disaccharide has been deleted. The objective of this study was to assess the anticancer activity and lung toxicity of deglyco-BLM. We compared the antitumor activity and pulmonary toxicity of intraperitoneally administrated deglyco-BLM and BLM in three rodent models. Pulmonary toxicity was examined in depth after intratracheal administration of both chemotherapeutic agents. The effect of both drugs was further studied in epithelial alveolar cells in vitro. We demonstrated in rodent cancer models, including a human Hodgkin's lymphoma xenograft and a syngeneic melanoma model, that intraperitoneal deglyco-BLM is as effective as BLM in inducing tumor regression. Whereas the antitumor effect of BLM was accompanied by a loss of body weight and the development of pulmonary toxicity, deglyco-BLM did not affect body weight and did not engender lung injury. Both molecules induced lung epithelial cell apoptosis after intratracheal administration, but deglyco-BLM lost the ability to induce caspase-1 activation and the production of ROS (reactive oxygen species), transforming growth factor-ß1, and other profibrotic and inflammatory cytokines in the lungs of mice and in vitro. Deglyco-BLM should be considered for clinical testing as a less toxic alternative to BLM in cancer therapy.

Naringin suppresses cell metastasis and the expression of matrix metalloproteinases (MMP-2 and MMP-9) via the inhibition of ERK-P38-JNK signaling pathway in human glioblastoma.

Naringin (4',5,7-trihydroxyflavanone 7-rhamnoglucoside), a natural flavonoid, has pharmacological properties. In the present study, we investigated the anti-metastatic activity of naringin and its molecular mechanism(s) of action in human glioblastoma cells. Naringin exhibits inhibitory effects on the invasion and adhesion of U87 cells in a concentration-dependent manner by Matrigel Transwell and cell adhesion assays. Naringin also inhibited the migration of U87 cells in a concentration-dependent manner by wound-healing assay. Additional experiments showed that naringin treatment reduced the enzymatic activities and protein levels of matrix metalloproteinase (MMP)-2 and MMP-9 using a gelatin zymography assay and western blot analyses. Furthermore, naringin was able to reduce the protein phosphorylation of extracellular signal-regulated kinase ERK, p38 mitogen-activated protein kinase and c-Jun N-terminal kinase by western blotting. Collectively, our data showed that naringin attenuated the MAPK signaling pathways including ERK, JNK and p38 and resulted in the downregulation of the expression and enzymatic activities of MMP-2, MMP-9, contributing to the inhibition of metastasis in U87 cells. These findings proved that naringin may offer further application as an antimetastatic agent.

Toxic effects of methamidophos on paraoxonase 1 activity and on rat kidney and liver and ameliorating effects of alpha-tocopherol.

The role of alpha-tocopherol on nephrotoxicity and hepatotoxicity induced by methamidophos (MT) was investigated in wistar rats. Animals were given via gavage, for four weeks, a low dose of MT (MT1), a high dose of MT (MT2), vitamin E (200 mg/kg of bw) or both MT2 plus vitamin E (Vit E) and control group was given distillate water. MT treatment resulted in a significant decrease in the body weight of MT2-treated group. Moreover, MT-treated groups had significantly lower butyrylcholinesterase (p < 0.01) and paraoxonase 1 (PON1) activities compared with the control group (p < 0.05). However, MT2-treated group had significantly higher alkaline phosphatase activity compared with untreated rats (p < 0.05). Both MT-treated groups had significantly higher urea (p < 0.01) and uric acid levels (p < 0.05) compared with the control group. However, significant low uric acid level (p < 0.05) was noted in MT2 plus vit E-treated rats compared with MT2-treated group. Histopathological changes in organ tissues were observed in both MT-treated groups and MT2 plus vit E-treated rats. However, the damage was reduced in MT2 plus vit E-treated rats. Therefore, this study deduces that alpha-tocopherol administration may ameliorate the adverse effects of subacute exposure to MT on rat liver and kidney and this antioxidant can protect PON1 from oxidative stress induced by this organophosphorus pesticide. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 842-854, 2016.

Naringin inhibits the invasion and migration of human glioblastoma cell via downregulation of MMP-2 and MMP-9 expression and inactivation of p38 signaling pathway.

Gliomas are the most common and malignant primary brain tumors. They are associated with a poor prognosis despite the availability of multiple therapeutic options. Naringin, a common dietary flavonoid abundantly present in fruits and vegetables, is believed to possess strong anti-proliferative and anti-cancer properties. However, there are no reports describing its effects on the invasion and migration of glioblastoma cell lines. Our results showed that the treatment of U251 glioma cell lines with different concentrations of naringin inhibited the invasion and migration of these cells. In addition, we revealed a decrease in the levels of matrix metalloproteinases (MMP-2) and (MMP-9) expression as well as proteinase activity in U251 glioma cells. In contrast, the expression of tissue inhibitor of metalloproteinases (TIMP-1) and (TIMP-2) was increased. Furthermore, naringin treatment decreased significantly the phosphorylated level of p38. Combined treatment with a p38 inhibitor (SB203580) resulted in the synergistic reduction of MMP-2 and MMP-9 expressions correlated with an increase of TIMP-1 and TIMP-2 expressions and the anti-invasive properties. However, p38 chemical activator (anisomycin) could block these effects produced by naringin, suggesting a direct downregulation of the p38 signaling pathway. These data suggest that naringin may have therapeutic potential for controlling invasiveness of malignant gliomas by inhibiting of p38 signal transduction pathways.

A Novel Platinum-Maurocalcine Conjugate Induces Apoptosis of Human Glioblastoma Cells by Acting through the ROS-ERK/AKT-p53 Pathway.

Glioblastoma multiforme (GBM) is a highly malignant and aggressive primary brain tumor. In spite of an arsenal of therapeutic interventions, the prognosis of glioblastoma remains very poor. Cisplatin-based therapy is one of the most important chemotherapy treatments for GBM, although its efficacy is limited by drug resistance and undesirable side effects. In the present study, we designed a chimera molecule containing the platinum binding moiety MBL-III-7 (1) attached N-terminal to the sequence of d-maurocalcine (D-MCa), a protease-resistant and highly efficient cell-penetrating peptide (CPP) derived from the Tunisian chactid scorpion toxin, L-MCa. The concept behind this design is that MCa, through its cell retention properties, should reduce cell expulsion of the platinum complex and increase its efficiency. The anti-cancer properties of the synthesized platinum analogue Pt-MBL-III_7-D_MCa (Pt-1-DMCa) were assessed in human glioblastoma cells (U87) by assaying cell viability and apoptosis. The new molecule exhibited enhanced anti-cancer efficacy compared to cisplatin, especially at low doses. By inducing intracellular oxidative stress, Pt-1-DMCa potentiated platinum-induced DNA damage and led to enhanced p53 phosphorylation, followed by increased activation of both mitochondrial and death receptor pathways. Decreased phosphorylated AKT and ERK levels were associated with the apoptosis induced by the novel synthesized cisplatin analogue. Our results suggested that a chimera between platinum and a maurocalcine-derived CPP is a highly successful anti-cancer compound that works by targeting the intracellular redox system. Pt-1-DMCa is an interesting candidate for a preclinical assessment of platinum-based therapy in GBM treatments and possibly other cancer types.

Identification of miR-10b, miR-26a, miR-146a and miR-153 as potential triple-negative breast cancer biomarkers.

BACKGROUND: Familial triple-negative breast cancers are often linked to mutations in the BRCA1 tumor suppressor gene. In sporadic triple-negative breast cancers BRCA1 is frequently inactivated at the transcriptional level, and it has been reported that this inactivation may be brought about by promoter methylation. More recently, it was found that BRCA1 may also be regulated at the post-transcriptional level by miRNAs. Here, we explored the expression of putative BRCA1-regulating miRNAs in sporadic human triple-negative breast cancer cells. METHODS: Nine sporadic human breast cancer-derived cell lines and one benign breast epithelium-derived cell line were assessed for their hormone receptor, growth factor receptor and cytokeratin status by immunocytochemistry. The expression of 5 selected miRNAs predicted to target BRCA1 was assessed using qRT-PCR in the 10 cell lines. In addition, expression profiles of 84 known breast cancer-associated miRNAs were established in these 10 cell lines using PCR Array and qRT-PCR, respectively. The putative role of pre-selected candidate miRNAs in breast cancer development was assessed through exogenous expression of these miRNAs and their anti-miRNAs ('antagomirs') in MDA-MB-231 and MCF7 breast cancer-derived cells. RESULTS: Based on our expression profiling results, four candidate miRNAs (miR-10b, miR-26a, miR-146a and miR-153) were selected as being potentially involved in triple-negative breast cancer development. Exogenous expression assays revealed that miR-10b and miR-26a, but not miR-146a, can down-regulate the expression of BRCA1 in both triple-negative MDA-MB-231 and luminal epithelial MCF7 breast cancer-derived cells, whereas miR-153 could down-regulate BRCA1 expression only in MCF7 cells. In silico analysis of The Cancer Genome Atlas (TCGA) data confirmed that miR-146a is significantly higher expressed in triple-negative breast tumors compared to other (non triple-negative) breast tumors. CONCLUSION: Our work provides evidence for the involvement of specific miRNAs in triple-negative breast cancer development through regulating BRCA1 expression.

Localization and role of RAP55/LSM14 in HeLa cells: a new finding on the mitotic spindle assembly.

The MAP family includes large proteins like MAP-1A, MAP-1B, MAP-1C, MAP-2, and MAP-4 and smaller components like tau and MAP-2C. This article focuses on the relevant aspects of RAP55/LSM14 position with emphasis on its role in mitotic spindle formation and stability. In this context, the localization of RNA associated Protein 55kDa (RAP55/LSM14) during mitosis was identified as a Mitotic Spindle Protein (MSP). We found a new location obtained by expressing GFP-tagged proteins in HeLa Cells during mitosis that has never been previously reported. We demonstrated also, for the first time, that the depletion of RAP55/LSM14 destabilizes spindle assembly, stops cells in mitosis and induces many other cell cytoskeletal disorders. Finally, by using an "in vitro" assay investigation, we found that RAP55/LSM14 binds directly the tubulin and that is implicated in the process of the mitotic spindle stabilization, which is a novel discovery in this field of research.