The role of miRNAs 34a, 146a, 320a and 542 in the synergistic anticancer effects of methyl 2-(5-fluoro-2-hydroxyphenyl)-1H- benzo[d]imidazole-5-carboxylate (MBIC) with doxorubicin in breast cancer cells

Combination Index (CI) analysis suggested that MBIC and doxorubicin synergistically inhibited up to 97% of cell proliferation in ER+/PR+MCF-7 and triple negative MDA-MB-231 breast cancer cell lines. Moreover, treatment of the breast cancer cells with the combined drugs resulted in lower IC50 values in contrast to the individual drug treatment. Small noncoding microRNAs (miRNA) may function as non-mutational gene regulators at post-transcriptional level of protein synthesis. In the present study, the effect of the combined treatment of MBIC and doxorubicin on the expression level of several miRNAs including miR-34a, miR-146a, miR-320a and miR-542 were evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines. These miRNAs have the potential to alter the protein level of survivin, the anti-apoptotic protein and reduce the metastatic activity in human breast cancer cell lines by interfering with the nuclear accumulation of NF-κB. Our results demonstrated the several fold changes in expression of miRNAs, which is drug and cell line dependent. This finding demonstrated a functional synergistic network between miR-34a, miR-320a and miR-542 that are negatively involved in post-transcriptional regulation of survivin in MCF-7 cells. While in MDA-MB-231 cells, changes in expression level of miR-146a was correlated with inhibition of the nuclear translocation of NF-κB. The overall result suggested that alteration in protein level and location of survivin and NF-κB by miR-34a, miR-320a, miR-146a and miR-542, remarkably influenced the synergistic enhancement of combined MBIC and doxorubicin in treatment of aggressive and less aggressive human breast cancer cell lines

Boldine suppresses dextran sulfate sodium-induced mouse experimental colitis: NF-κB and IL-6/STAT3 as potential targets

Ulcerative colitis (UC) is a nonspecific inflammatory disorder characterized by oxidative and nitrosative stress, leucocyte infiltration, and upregulation of inflammatory mediators. Boldine is an alkaloid compound found in Boldo tree, with multiple pharmacological actions, mainly anti-inflammatory, antioxidant, antitumor, and immunomodulatory activities. Hence, the effect of boldine for its anti-inflammatory properties against dextran sulfate sodium (DSS)-induced UC in BALB/c mice was studied. Administration of boldine to DSS-induced mice protects colon damage by reduced disease activity index, spleen weight, and increased colon length. Also administration of boldine showed a reduction in the activity of myeloperoxidase (MPO) and CD 68+ expression. Boldine reduced the colon damage, with significant reductions in both the extent and the severity of the inflammation as well as in crypt damage and leukocyte infiltration in the mucosa. Analysis in vivo showed clear decrease in the production of tumor necrosis factor (TNF)-α, Interleukin (IL)-6, IL-17, and signal transducer and activator of transcription-(p-STAT3)(Y705) with nuclear factor (p65-NF-κB) production being reduced significantly. Moreover, p65-NF-κB activation was reduced in mouse macrophage RAW 264.7 cells in vitro. The data demonstrated that boldine may be beneficial in colitis through selective immunomodulatory effects, which may be mediated, at least in part, by inhibition of p65-NF-κB and STAT3 signaling pathways

Boldine suppresses dextran sulfate sodium-induced mouse experimental colitis: NF-κB and IL-6/STAT3 as potential targets

Ulcerative colitis (UC) is a nonspecific inflammatory disorder characterized by oxidative and nitrosative stress, leucocyte infiltration, and upregulation of inflammatory mediators. Boldine is an alkaloid compound found in Boldo tree, with multiple pharmacological actions, mainly anti-inflammatory, antioxidant, antitumor, and immunomodulatory activities. Hence, the effect of boldine for its anti-inflammatory properties against dextran sulfate sodium (DSS)-induced UC in BALB/c mice was studied. Administration of boldine to DSS-induced mice protects colon damage by reduced disease activity index, spleen weight, and increased colon length. Also administration of boldine showed a reduction in the activity of myeloperoxidase (MPO) and CD 68+ expression. Boldine reduced the colon damage, with significant reductions in both the extent and the severity of the inflammation as well as in crypt damage and leukocyte infiltration in the mucosa. Analysis in vivo showed clear decrease in the production of tumor necrosis factor (TNF)-α, Interleukin (IL)-6, IL-17, and signal transducer and activator of transcription-(p-STAT3)(Y705) with nuclear factor (p65-NF-κB) production being reduced significantly. Moreover, p65-NF-κB activation was reduced in mouse macrophage RAW 264.7 cells in vitro. The data demonstrated that boldine may be beneficial in colitis through selective immunomodulatory effects, which may be mediated, at least in part, by inhibition of p65-NF-κB and STAT3 signaling pathways

Association of DNA repair gene polymorphism (XRCC1) and oral cancer risk / Mohadeseh Hasanpourghadi

The main aim of the present study was to determine the distribution of XRCC1 Arg399Gln genotypes in oral cancer and non-oral cancer patients. This study was also to investigate the association between XRCC1 Arg399Gln genotypes and oral cancer risk and to compare the distribution of XRCC1 Arg399Gln genotypes among different ethnic groups in Malaysia. This case-control study involved a total of 209 cases of oral squamous cell carcinoma (OSCC) patients and 212 controls with neither any trace of cancers nor any family history of cancer. Mean age of the OSCC patients for cases was 61.34 ± 14.01 years, while for the control the mean age was 45.56 ± 12 years. About 62.07% (131) and 37.03% (78) were females and males respectively for cases and 54.02% (115) and 45.08% (97) females and males respectively for controls. Determination of XRCC1 Arg399Gln genotypes was done using genomic DNA from blood samples. The final genotypes were determined using PCR and PCR-RFLP where 3 genotypes were recognized; namely the normal/wild-type (Arg/Arg), the 2 polymorphic genotypes namely the heterozygote (Arg/Gln) and the homozygote (Gln/Gln). The results revealed that the distribution of XRCC1 Arg399Gln polymorphism (Arg/Gln; Gln/Gln) was 65.1% for cases and 58.5% for controls. When the polymorphisms were considered separately, the distribution of Arg/Gln among the cases was 48.8% and among controls was 41%. The distribution of Gln/Gln among cases and controls were almost similar which is 16.3% and 17.5% respectively. The Chi square test revealed either individually or in combination that there was no significant association between XRCC1 Arg399Gln genotypes and oral cancer risk. Similarly, there was no significant difference in the distribution of XRCC1 Arg399Gln genotypes when analyzed either individually (p=0.617) or in combination (p=0.641) between three different ethnic groups. In conclusion, there was a higher distribution of XRCC1 Arg399Gln polymorphism in cases as compared to control. There was no association between XRCC1 polymorphism and oral cancer risk and there was no significant difference observed in XRCC1 genotype distribution in the different ethnic groups

Activation of autophagy by stress-activated signals as a cellular self-defense mechanism against the cytotoxic effects of MBIC in human breast cancer cells in vitro

We recently reported that methyl 2-(-5-fluoro-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (MBIC) is a microtubule targeting agent (MTA) with multiple mechanisms of action including apoptosis in two human breast cancer cell-lines MCF-7 and MDA-MB-231. In the present study, investigation of early molecular events following MBIC treatment demonstrated the induction of autophagy. This early (<24 h) response to MBIC was characterized by accumulation of autophagy markers; LC3-II, Beclin1, autophagic proteins (ATGs) and collection of autophagosomes but with different variations in the two cell-lines. MBIC-induced autophagy was associated with generation of reactive oxygen species (ROS). In parallel, an increased activation of SAPK/JNK pathway was detected, as an intersection of ROS production and induction of autophagy. The cytotoxic effect of MBIC was enhanced by inhibition of autophagy through blockage of SAPK/JNK signaling, suggesting that MBIC-induced autophagy, is a possible cellular self-defense mechanism against toxicity of this agent in both breast cancer cell-lines. The present findings suggest that inhibition of autophagy eliminates the cytoprotective activity of MDA-MB-231 and MCF-7 cells, and sensitizes both the aggressive and non-aggressive human breast cancer cell-lines to the cytotoxic effects of MBIC

Caffeic acid phenethyl ester attenuates dextran sulfate sodium-induced ulcerative colitis through modulation of NF-κB and cell adhesion molecules

Ulcerative colitis (UC) is a serious health condition and defined as inflammation in the colon. Untreated, UC can develop into colitis-associated cancer (CAC), for which effective medicines are not available. Natural products are a better choice to treat UC by alleviating the inflammation. Caffeic acid phenethyl ester (CAPE) is a phenolic compound and known for its beneficial effects, including antibacterial, anti-inflammatory, anti-diabetic, and anticancer. We aimed to study the effect of CAPE on dextran sulfate sodium (DSS)-induced UC in mouse model. Administration of CAPE to DSS-induced mice protected against colon damage by improving body weight of mice, reducing the weight of spleen, and increased colon length. In addition, administration of CAPE resulted reduced the activity of myeloperoxidase (MPO) and CD68+ positive cells. Furthermore, a significant decrease in the production of key cytokines and the expression of nuclear factor (p65-NF)-κB. Moreover, p65-NF-κB activation was reduced in lipopolysaccharide (LPS)-treated RAW 264.7 macrophage cells from mouse origin. CAPE treatment leads to the reduced expressions of intercellular adhesion molecules (ICAM)-1 and vascular cell adhesion molecules (VCAM), both are key cell adhesion molecules. The results of this study clearly indicate that CAPE can potentially control inflammation in the colon and can be used as a therapy for UC

Treatment with the PPARα agonist fenofibrate improves the efficacy of CD8+ T cell therapy for melanoma

Adoptive transfer of tumor antigen-specific CD8+ T cells can limit tumor progression but is hampered by the T cells’ rapid functional impairment within the tumor microenvironment (TME). This is in part caused by metabolic stress due to lack of oxygen and glucose. Here, we report that fenofibrate treatment of human ex vivo expanded tumor-infiltrating lymphocytes (TILs) improves their ability to limit melanoma progression in a patient-derived xenograft (PDX) mouse model. TILs treated with fenofibrate, a peroxisome proliferator receptor alpha (PPARα) agonist, switch from glycolysis to fatty acid oxidation (FAO) and increase the ability to slow the progression of autologous melanomas in mice with freshly transplanted human tumor fragments or injected with tumor cell lines established from the patients’ melanomas and ex vivo expanded TILs

Additional file 3: Figure S3. of Forkhead Box Transcription Factor (FOXO3a) mediates the cytotoxic effect of vernodalin in vitro and inhibits the breast tumor growth in vivo

Vernodalin treatment induces FOXO3a nuclear translocation in MDA-MB-231 cells. MDA-MB231 cells were treated with DMSO (control) or indicated concentration of vernodalin for 24 h. Immunofluorescent staining was then performed using the FOXO3a antibody (green) and stained with Hoechst 33258 (blue). Images were acquired using Cellomic HCS array scan reader (objective 20X). Representative figures (control, 6.25, 9.5 μg/ml of vernodalin and Doxorubicin 3 μg/ml) were shown. Bar chart shows average fluorescence intensities of FOXO3a accumulation in the nucleus. Data were mean ± SD of fluorescence intensity readings representative of three independent experiments. (*P < 0.05). (JPG 573 kb