Increasing the radiation-induced cytotoxicity by silver nanoparticles and docetaxel in prostate cancer cells.

BACKGROUND: Radiation therapy is utilized for treatment of localized prostate cancer. Nevertheless, cancerous cells frequently develop radiation resistance. While higher radiation doses have not always been effective, radiosensitizers have been extensively studied for their ability to enhance the cytotoxic effects of radiation. So, this study aims to evaluate the possible radiosensitization effects of docetaxel (DTX) and silver nanoparticles (SNP) in LNCaP cells. METHODS: The cytotoxic effects of DTX, SNP and 2 Gy of X-Ray radiation treatments were assessed in human LNCaP cell line using the MTT test after 24 h. Moreover, the effects of DTX, SNP and radiation on Epidermal growth factor (EGF), Caspase 3, inducible nitric oxide synthase and E-cadherin gene expression were analyzed using the Real-time PCR method. The level of Hydrogen peroxide (H2O2), an oxidative stress marker, was also detected 24 h after various single and combined treatments. RESULTS: The combinations of SNP (in low toxic concentration) and/or DTX (0.25× IC50 and 0.5 × IC50 concentrations for triple and double combinations respectively) with radiation induced significant cytotoxicity in LNCaP cells in comparison to monotherapies. These cytotoxic effects were associated with the downregulation of EGF mRNA. Additionally, H2O2 levels increased after Radiation + SNP + DTX triple combination and double combinations including Radiation + SNP and Radiation + DTX versus single treatments. The triple combination treatment also increased Caspase 3 and and E-cadherin mRNA levels in compared to single treatments in LNCaP cells. CONCLUSION: Our results indicate that the combination of SNP and DTX with radiation induces significant anti-cancer effects. Upregulation of Caspase 3 and E-cadherin gene expression, and decreased mRNA expression level of EGF may be exerted specifically by use of this combination versus single treatments.

Evaluation the -174G>C Genetic Polymorphism of Interleukin-6 in Iranian Patients with Chronic Lymphocytic Leukemia.

Background & Objective: Interleukin-6 (IL-6) is involved in inflammation and has a significant role in chronic lymphocytic leukemia (CLL) progression. Accordingly, IL-6 level may increase in CLL-affected patients compared to healthy individuals. The -174G>C single nucleotide polymorphism (SNP) in IL-6 promoter region has been related to differences in IL-6 transcription. Therefore, we investigated the possible association of IL-6 polymorphism with CLL. Methods: We examined the -174G>C SNP in IL-6 gene and studied its possible relationship with CLL in affected patients and in healthy controls using Amplification Refractory Mutation System- polymerase chain reaction genotyping method. IL-6 plasma level was measured in both studied groups. Results: According to the results, IL-6 mean plasma concentration was increased significantly in the CLL patients compared to the controls. However, 174G>C genotype of the IL-6 gene was not associated with CLL. Furthermore, there were no significant differences in the distribution of allele and genotype frequencies between the CLL-affected patients and the controls (P>0.05). Conclusion: Our study showed that -174G>C SNP in promotor of IL-6 gene could not be considered a risk factor for CLL. Larger prospective studies should be performed to confirm our results.

Cytotoxic and Radiosensitizing Effects of Folic Acid-Conjugated Gold Nanoparticles and Doxorubicin on Colorectal Cancer Cells.

Purpose: Radiotherapy is one of the most important therapeutic options used to treat cancers. Radiation effects can be improved using nanoparticles and chemotherapeutic drugs as radiosensitizing agents. The aim of the present study was to evaluate the effects of folic acid-conjugated gold nanoparticles (GNP-F) in combination with doxorubicin (DOX) and x-Ray irradiation in colorectal cancer (CRC) cell line (HT-29). Methods: The cell viability assay (WST-1) was performed to study the cytotoxic effects of different concentrations of DOX and GNP-F after 24 and 48 hours treatments. Then, the effects of the GNP-F, X-Ray irradiation, and DOX drug in single and combined treatments were examined after 24 and 48 hours treatment with effective doses. Likewise, the caspase 3 gene expression ratio and the caspase 3 activity were assessed after 48 h treatment. Moreover, the malondialdehyde (MDA) level was determined in treated and untreated cells. Results: When GNP-F (at a concentration of 70 µM) was combined with X-ray irradiation (2 Gy) and DOX drug, induced more cytotoxic effects compared to the control group. The results of cell viability assay showed that GNP-F + X-Ray in combination with a low concentration of DOX (0.25 × IC50) enhanced the cytotoxic effects of cells compared to related single treatments. Caspase 3 gene expression ratio and caspase 3 activity increased in double and triple combination treatments in comparison with the single groups. Moreover, the MDA level increased in triple combination compared to the single treatments. Conclusion: Our findings confirmed the potential anti-cancer effects of the GNP-F and DOX in combination with X-Ray irradiation in CRC cells.

Effects of Radiotherapy in Combination With Irinotecan and 17-AAG on Bcl-2 and Caspase 3 Gene Expression in Colorectal Cancer Cells.

Introduction: In this study, the cytotoxic and anti-cancer effects of Irinotecan as a conventional chemotherapeutic agent compared to 17-(allyl amino)-17-demethoxygeldanamycin (17-AAG) as possible radiosensitizers in the HCT-116 cell line were investigated. Methods: HCT-116 cells were treated with various concentrations of irinotecan and 17-AAG and also irradiated with a 2-Gy of X-ray radiation. Then, the cell viability was examined by a water-soluble tetrazolium-1 assay after 24 hours. For single therapies and double and triple combination cases, IC50, 0.5×IC50 and 0.25×IC50 concentrations of each drug were selected respectively for a terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay and other tests. In treated and untreated cells, the caspase 3 and Bcl-2 gene expression ratios were evaluated by the real-time PCR method. Likewise, caspase 3 activity was detected with a colorimetric assay. Results: In all combined treatments, including 17-AAG- radiation, irinotecan - radiation, irinotecan -17-AAG, and irinotecan-17-AAG-radiation, decreased cellular viability and increased TUNEL positive cells were presented versus the control group (P < 0.05). There were increased TUNEL positive cells in the triple combination, in concentrations of 0.25×IC50 of each drug, in comparison with single and double agent treatments. Moreover, in triple combination, the caspase 3 mRNA level and caspase 3 activity increased versus related single treatments. Likewise, in the irinotecan-17-AAG-radiation combined treatment and the 17-AAG-radiation double treatment, the Bcl-2 gene expression level decreased in comparison with single therapies. Conclusion: It can be indicated that the combination of chemo-radiotherapy versus single treatments has significant anti-cancer effects.

Regulatory Effects of Apatinib in Combination with Piperine on MDM-2 Gene Expression, Glutathione Peroxidase Activity and Nitric Oxide level as Mechanisms of Cytotoxicity in Colorectal Cancer Cells.

Purpose: Apatinib has been utilized in colon cancer therapies but its efficiency and molecularmechanism are not fully understood. Chemotherapy in combination with non-toxic compoundscan be an effective treatment strategy for cancer. Consequently, this study was carried out toevaluate the effects of apatinib and piperine on colorectal cancer (CRC) cell line and theirpotential anti-cancerous mechanisms in vitro. Methods: The effects of apatinib and piperine on HCT-116 CRC cells were detected byassessing cell viability using MTT assay. The potential cytotoxic mechanisms of apatinib andpiperine were investigated by evaluating MDM-2 gene expression ratio using real-time PCRassay. Moreover, the glutathione peroxidase (GPX) activity and nitric oxide (NO) levels wereassessed by colorimetric assays. Results: The proliferation rate of CRC cells decreased by increasing the concentrations ofpiperine or apatinib. When HCT-116 cells were treated with different concentrations of apatinibin combination with piperine, the synergistic effects were observed (combination index < 1).In HCT-116 cells treated with apatinib and piperine at the concentrations of 0.5×IC50 and0.2×IC50, the MDM-2 gene expression was downregulated and NO levels increased comparedto the untreated control cells and related single treatments. In addition, GPX activity significantlydecreased in combination treatment at 0.5×IC50 concentration of both agents versus singletreatments. Conclusion: Apatinib in combination with piperine could significantly inhibit the growth ofCRC cells. These cytotoxic effects were induced by regulation of MDM-2 gene expression andinhibition of antioxidant marker.

Overall survival and prognostic factors prostate cancer in Kurdistan Province-Iran: a population-based study (2011-2018).

BACKGROUND: The population-based survival rate is affected by the quality and effectiveness of health care systems. Overall, the survival of prostate cancer (PC) patients has improved over the past two decades worldwide. This study aimed to determine the overall survival rate and correlate it with the prognostic factors in patients with PC diagnosed in Kurdistan province. METHODS: In a retrospective cohort study, 410 PC patients registered in Kurdistan province population-based cancer registry from March 2011 to 2018 were recruited. Kaplan-Meier method and log-rank test were used to analyze the overall survival rates of PC patients. A Multivariate Cox regression model was used to determine adjusted hazard ratios for different variables. RESULTS: Of 410 patients with PC, 263 (64.1%) died within seven years due to the disease. The 1, 3, and 5 years survival rates were 93, 64.1, and 40.7%, respectively. According to the results of multiple Cox regression, the following factors were significantly related to PC survival: age at diagnosis (≥81-years old) (HR=2.23, 95% CI: 1.23-4.42) and 71-80 years old was (HR=1.26, 95% CI: 1.12-2.31), occupation (employee) (HR=0.42, 95% CI: 0.20-0.87), educational level: academic (HR=0.78, 95% CI: 0.64-0.91), AJCC stage of disease (HR=2.18, 95% CI: 1.9-3.68), Gleason score ≥ 9 (HR=7.12, 95% CI: 5.35-10.28), and Gleason score= 8 (HR=4.16, 95% CI: 2.50-6.93). There was less mortality rate among the patients who had received active care, radical prostatectomy, radiotherapy, combined treatment, and orchiectomy had a lower mortality rate than those who received no treatment (P<0.05). CONCLUSIONS: This study demonstrated that factors such as age at diagnosis, level of education, occupation, AJCC stage of disease, Gleason score, and type of treatments were influential factors in the survival of PC patients in Kurdistan province and needed more attention.

Combined treatment with silver graphene quantum dot, radiation, and 17-AAG induces anticancer effects in breast cancer cells.

We aimed to investigate the possible anticancer effects of radiation in combination with 17-allylamino-17-demethoxy geldanamycin (17-AAG) and silver graphene quantum dot (SQD) in breast cancer (BC) cells. MCF-7 BC cells treated with, or without, different concentrations of 17-AAG and synthesized SQD and cellular viability detected. The growth inhibitory effects of low concentrations of 17-AAG with minimally toxic concentration of SQD in combination with 2 Gy of X-ray radiation were examined. The apoptosis induction assessed by acridine orange/ethedium bromide staining. Likewise, the levels of lactate, hydrogen peroxide (H2 O2 ), nitric oxide (NO) were evaluated. The relative gene expression levels of Bax and Bcl-2 were detected by real-time polymerase chain reaction and the Bax/Bcl-2 expression ratio was determined. Moreover, the protein expression of epidermal growth factor receptor (EGFR) was assessed by western blot analysis. Treatment with low concentrations of 17-AAG and SQD at a minimally toxic concentration promoted inhibition of BC cell growth and induced apoptosis. In addition, significant reduction in cell viability was seen in triple combination versus all double and single treatments. Indeed 17-AAG and SQD in combined with radiation significantly increased the H2 O2 and NO versus single and double treated cases. In addition, triple combination treatment showed decreased lactate level in compared tomonotherapies. EGFR protein expression levels were found to decreased in all double and triple combined cases versus single treatments. Additionally, in double and triple treatments, Bax/Bcl2 ratio were higher in compared to single treatments. Treatment with low concentrations of 17-AAG and SQD at a minimally toxic concentration tends to induce anticancer effects and increase the radiation effects when applied with 2 Gy of radiation versus radiation monotherapy.

Dysregulation of body antioxidant content is related to initiation and progression of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative illness. It has been believed that oxidative stress (OS) is an important factor in the advancement of PD. This investigation attempts to evaluate the relations between blood trace elements, ferritin, and transferrin concentrations as well as the levels of protein and gene expression of ceruloplasmin (CP), Nrf-2, and HO-1 in patients suffering PD. METHODS: The serum concentrations of variables were assessed in 110 PD patients group and 110 normal subjects. Furthermore, we applied qRT-PCR as well as western blot (WB) analysis to measure the levels of gene and protein, respectively. RESULTS: Considerable differences were detected in the serum concentrations of copper (Cu), iron (Fe), and zinc (Zn), when healthy and patient groups were compared. Nevertheless, the levels of Se, ferritin, and transferrin were not significantly different between the two groups. qRT-PCR and WB data analysis revealed significant differences of CP, Nrf-2, and HO-1at genes expression and protein levels when comparing the two PD patients and control groups. CONCLUSION: The results of the current work revealed that blood levels of Cu, Fe, and Zn were significantly higher in subjects who had PD. In addition, it was found that the levels of protein and gene expression CP, Nrf-2, and HO-1 were markedly higher in PD group than in non-PD subjects. Indeed, in this study, the results showed that the antioxidant content of the body can be linked to PD.

Effects of co-administration of rapamycin and evening primrose/hemp seed oil supplement on immunologic factors and cell membrane fatty acids in experimental autoimmune encephalomyelitis.

BACKGROUND: The immune response is influenced by the administration of omega-3 polyunsaturated fatty acids (PUFA). Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE) are affected by PUFA. The combination of evening primrose/hemp seed oil (EPO/HSO) has essential fatty acids (EFAs) for human optimal health due to the favorable ratio of omega-6/omega-3 and antioxidantal properties. The study was conducted to evaluate the effects of EPO/HSO on improving the membrane fatty acids composition of spleen and blood cells and immunologic factors in compared to rapamycin (RAPA) in the EAE model. METHODS AND MATERIALS: Chronic-EAE was induced by induction of MOG in C57BL/6J mice (female, age: 6-8 weeks, weight 18-21). Mice were assigned to 5 groups (6/group) to evaluate the therapeutic effects of EPO/HSO supplement in comparison with rapamycin: A group; EPO/HSO + RAPA, B group; RAPA, C group; EPO/HSO. Results were compared to two control groups (EAE and naive). The fatty acid profile of the spleen and blood cell membrane was evaluated. Real-time-polymerase chain reaction was used for the evaluate the genes expression levels of interleukin (IL) -4, IL-5, and IL-13 in lymphocytes. Also, IL-4 of serum was evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our findings indicated that EPO/HSO therapy significantly increased the percentage of essential fatty acids in cell membrane of the spleen and blood. The relative expression of IL-4, IL-5, and IL-13 genes in lymphocytes and serum level of IL-4 was significantly increased in the HSO/EPO treated group versus other groups. CONCLUSION: These results point to potential therapeutic effects on the repair of the structure of cell membranes and suppression of inflammation by EPO/HSO in EAE.

Hsp90 Inhibitor; NVP-AUY922 in Combination with Doxorubicin Induces Apoptosis and Downregulates VEGF in MCF-7 Breast Cancer Cell Line.

OBJECTIVE: Breast cancer is one of the most prevalent malignancies and leading causes of females' mortality worldwide. Because of resistance to various treatment options, new treatments based on molecular targeting has introduced as noticeable strategies in cancer treatment. In this regard, heat shock protein 90 (Hsp90) inhibitors are proposed as effective anticancer drugs. The goal of the study was to utilize a combination of the doxorubicin (DOX) and NVP-AUY 922 on the MCF-7 breast cancer model to investigate the possible cytotoxic mechanisms. METHODS: MCF-7 breast cancer cell line was prepared and treated with various concentrations of DOX and NVP-AUY922 in single-drug treatments. We investigated the growth-inhibitory pattern by MTT assay after continuous exposure to NVP-AUY922 and DOX in order to determine dose-response. Then the combinatorial effects were evaluated in concentrations of 0.5 × IC50, 0.2 × IC50, 1 × IC50 and, 2 × IC50 of each drugs. Based on MTT results of double combinations, low effective doses were selected for Real-time PCR [caspase3 and vascular endothelial growth factor(VEGF)] and caspase 3 enzyme activity. RESULTS: A dose-dependent inhibitory effects were presented with increasing the doses of both drugs in single treatments. The upregulation of caspase 3 and downregulation of VEGF mRNA were observed in double combinations of NVP-AUY922 and DOX versus single treatments. Also, in these combinations in low doses of examined drugs (0.5 × IC50, 0.2 × IC50), higher caspase 3 activity were presented in comparison to single treatments (p<0.05). CONCLUSIONS: Our findings indicate an effective action of NVP-AUY922 in combined with DOX in this cell line. These results can predict the treatment outcome in this model.

The Effects of Evening Primrose/Hemp Seed Oil Compared to Rapamycin on the Gene Expression of Immunological Parameters in Experimental Autoimmune Encephalomyelitis Splenocytes.

Mouse model of multiple sclerosis (MS) is used for the inflammatory demyelinating disease. Rapamycin (RAPA) may contribute to the reduction of inflammatory responses to experimental autoimmune encephalomyelitis (EAE). Due to its adverse side effects, identifying new therapeutic agents is important. We investigated the transcriptional effects of evening primrose/hemp seed oil (EP/HS oil) compared to RAPA on the expression of immunological factors genes in spleen cells of EAE mouse models. We firstly induced EAE mice by injection of myelin oligodendrocyte glycoprotein (MOG). Then, the EAE mice treated and untreated with EP/HS oil were evaluated and compared with naïve mice. The spinal cords were examined histologically. The immunological factors including genes expression of the regulatory-associated protein of mammalian target of rapamycin (RAPTOR), regulatory-associated companion of mammalian target of rapamycin (RICTOR), interferon (IFN)-γ, interleukin (IL)-10, signal transducer and activator of transcription factors (STAT3), forkhead box P3 (FOXP3), and IL-17 of splenocytes were evaluated by real time-polymerase chain reaction (RT-PCR). The data showed that EP/HS oil was able to reduce the severity of EAE and inhibited the development of the disease. EP/HS oil treatment significantly inhibited the expression of RAPTOR, IFN-γ, IL-17, and STAT3 genes and promoted the expression of RICTOR, IL-10, and FOXP3 genes. In conclusion, the EP/HS oil is likely to be involved in transcription of factors in favor of EAE improvement as well as participating in remyelination in the EAE spinal cord and that it suggests to be effective in therapeutic approaches for MS.

The apatinib inhibits breast cancer cell line MDA-MB-231 in vitro by inducing apoptosis, cell cycle arrest, and regulating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways.

BACKGROUND AND PURPOSE: Breast cancer is one of the most common cancers and leading causes of death in the women worldwide. The evidence shows efficacy of apatinib against breast cancer. Accordingly, the present study was conducted to investigate the effect of apatinib on apoptosis, cell cycle, and Mitogen­Activated Protein Kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways in the breast cancer MDA-MB-231 cell line. METHODS: The effects of apatinib on viability, morphology, tumor spheroid, cell cycle, migration, invasion, and apoptosis of MDA-MB-231 breast cancer cells were evaluated in vitro. In addition, expression of proteins involved in NF-κB and MAPK signaling pathways was evaluated using the western blotting analysis. RESULTS: Apatinib decreased viability, tumor spheroid, migration, and invasion of MDA-MB-231 cells. Furthermore, apatinib altered morphology and regulated cell cycle which followed by apoptosis induction in MDA-MB-231 cells. Apatinib decreased expression of p-p65 and p65 proteins in NF-κB signaling pathways and increased expression of p38, p-p38, JNK, and p-JNK in MAPK signaling pathways. CONCLUSION: The results suggested that apatinib can inhibit proliferation, migration and invasion of breast cancer cell line MDA-MB-231 through inducing apoptosis, cell cycle arrest, and regulating NF-κB and MAPK signaling pathways.

Herpes Simplex Virus Type 2 Seroprevalence in Pregnant Women in Urmia, Northwest of Iran, during 2014-2015

Background: Herpes simplex virus type 2 (HSV-2) seroprevalence has been shown to be a potential sign of infection in pregnant women, and it could be applied to check HSV-2 transmission. This study evaluated the anti-HSV-2 IgG prevalence in pregnant women who were referred to health centers in Urmia, Northwest of Iran, during 2014-2015. Methods: Serum samples were collected from 86 pregnant women and tested for Anti-HSV-2-specific IgG using a commercial enzyme-linked immunosorbent assays kit. Results: Five (5.8%) pregnant women showed the presence of Anti-HSV-2-specific IgG antibodies. Previous abortion was reported in 16 (19.7%) and 2 subjects in the seronegative and seropositive groups, respectively. Conclusion: Data from the present study indicate a lower number of HSV-2 seropositives among the pregnant women in Urmia. This reduction would be a result of low number of studied subjects used in the present study; hence, assessing a large sample is recommended.

Dihydropyrimidine Dehydrogenase Levels in Colorectal Cancer Cells Treated with a Combination of Heat Shock Protein 90 Inhibitor and Oxaliplatin or Capecitabine.

Purpose: Dihydropyrimidine dehydrogenase (DPD) is the principal enzyme in the catabolism of fluoropyrimidine drugs including capecitabine. A recent report has suggested that oxaliplatin chemotherapy is associated with elevated DPD levels and chemoresistance pattern. As a newly developed chemotherapeutic agent, 17-allyloamino-17-demethoxy-geldanamycin (17-AAG) can be effective in combination therapy with oxaliplatin and capecitabine in colorectal cancer (CRC). DPD expression level can be a predictive factor in oxaliplatin and capecitabine-based chemotherapy. We evaluated DPD in mRNA and protein levels with new treatments: 17-AAG in combination with oxaliplatin and capecitabine in HT-29 and HCT-116 cell lines. Methods: Drug sensitivity was determined by the water-soluble tetrazolium-1 assay in a previous survey. Then, we evaluated the expression levels of DPD and its relationship with the chemotherapy response in capecitabine, oxaliplatin, and 17-AAG treated cases in single and combination cases in two panels of CRC cell lines. DPD gene and protein expression levels were determined by real-time polymerase chain reaction and western blotting assay, respectively. Results: DPD gene expression levels insignificantly increased in single-treated cases versus untreated controls in both cell lines versus controls. Then, the capecitabine and oxaliplatin were added in double combinations, where DPD gene and protein expression increased in combination cases compared to pre-chemotherapy and single drug treatments. Conclusion: The elevated levels of cytotoxicity in more effective combinations could be related to a different mechanism apart from DPD mediating effects or high DPD level in the remaining resistance cells (drug-insensitive cells), which should be investigated in subsequent studies.

Association of Delta-6-Desaturase Expression with Aggressiveness of Cancer, Diabetes Mellitus, and Multiple Sclerosis: A Narrative Review

Background: The phosphatidylinositol 3-kinase/ protein kinase B /mammalian target of rapamycin (PI3K/Akt/ mTOR) signaling regulates multiple cellular processes and organizes cell proliferation, survival, and differentiation with the available nutrients, in particular, fatty acids. Polyunsaturated fatty acids (PUFAs) are cytotoxic to cancer cells and play a critical role in the treatment of multiple sclerosis (MS) and diabetes mellitus (DM). PUFAs are produced in the body by desaturases and elongases from dietary essential fatty acids (EFAs), primarily involving delta-6-desaturase (D6D). D6D is a rate-limiting enzyme for maintaining many aspects of lipid homeostasis and normal health. D6D is important to recognize the mechanisms that regulate the expression of this enzyme in humans. A lower level of D6D was seen in breast tumors compared to normal tissues. Interestingly, the elevated serum level of D6D was seen in MS and DM, which explains the critical role of D6D in inflammatory diseases. Methods: We searched databases of PubMed, Web of Science (WOS), Google Scholar, Scopus and related studies by predefined eligibility criteria. We assessed their quality and extracted data. Results: Regarding the mTOR signaling pathway, there is remarkable contributions of many inflammatory diseases to attention to common metabolic pathways are depicted. Of course, we need to have the insights into each disorder and their pathological process. The first step in balancing the intake of EFAs is to prevent the disruption of metabolism and expression of the D6D enzyme. Conclusions: The ω6 and ω3 pathways are two major pathways in the biosynthesis of PUFAs. In both of these, D6D is a vital bifunctional enzyme desaturating linoleic acid or alpha-linolenic acid. Therefore, if ω6 and ω3 EFAs are given together in a ratio of 2: 1, the D6D expression will be down-regulated and normalized.

Anti-cancer effects of chemotherapeutic agent; 17-AAG, in combined with gold nanoparticles and irradiation in human colorectal cancer cells.

OBJECTIVE: The present study evaluated the anti-cancer effects of irradiation (Ir) alone, Ir after heat shock protein 90 inhibitor; 17-allylamino-17-demethoxygeldanamycin (17-AAG) and gold nanoparticle (GNP) treatments in human colorectal cancer cell line (HCT-116), with the targeting of related mechanisms. METHODS: Water-soluble tetrazolium salt-1 assay was utilized to study the cytotoxic effects of 17-AAG, GNP, Ir in single and combination cases on the cell viability of HCT-116 cells. The cells were examined with DNA fragmentation electrophoresis and evaluated for apoptosis induction. Caspase-3 expression as a critical apoptosis element in protein level was detected by western blotting. RESULTS: Treatment with 17-AAG in a dose dependent manner for 24 h inhibited the cellular viability of HCT-116 cells. GNP at a dose of 70 µM had the lowest cytotoxic effects and was thus selected for combination treatment studies. Based on the results, GNP at a dose of 70 µM did not have a significant effect on cellular viability of HCT-116. In contrast, the evaluation of double and triple combinations, GNP with Ir (2 Gy of 6 MV X-ray radiation) and 17-AAG in double combinations induced significant cytotoxicity. Both DNA damage pattern and caspase-3 protein upregulation were present in Ir,GNP/17-AAG,GNP and Ir,17-AAG combinations compared to single treatments. Furthermore, in the three combination of GNP,Ir,17-AAG, radiosensitization effects (increased caspase-3 expression) occurred with a minimum concentration of 17-AAG. CONCLUSION: According to the results of this study, 17-AAG as chemotherapeutic agent in combination with Ir and GNP exerts noticeable anti-cancer effects, inhibited cell viability, and increased apoptosis occurrence by upregulating caspase-3 expression. It is suggested that these combinations should be more evaluated as a promising candidate for colorectal cancer treatment. Graphical abstract Anti-cancer effects of chemotherapeutic agent; 17-AAG, in combined with gold nanoparticles and irradiation in human colorectal cancer cells.

A molecular basis for the synergy between 17­allylamino­17­demethoxy geldanamycin with Capecitabine and Irinotecan in human colorectal cancer cells through VEFG and MMP-9 gene expression.

Anti-proliferative, anti-metastatic and anti-angiogenic effects of 17­allylamino­17­demethoxy geldanamycin (17-AAG) were studied alone and in combination with Capecitabine (Cap) and/or Irinotecan (IR) on HT-29 human colorectal carcinoma cells. Expression of MMP-9 (matrix metalloproteinase­9) and VEGF (vascular endothelial growth factor) mRNA was analyzed by real-time PCR method. The study was further followed by wound scratch assay for migration assessment. Nitric oxide content, Malondialdehyde generation and total anti-oxidant capacity were also assessed. Results showed significant differences between mono- and double therapy (p < 0.05). Combination of 17-AAG with IR or Cap resulted in synergistic effect (Combination Index < 1). Among double combination groups only Cap/17-AAG showed significant differences in MMP-9 and VEGF genes expression and wound healing assay. Moreover, a significant decrease of wound area in our triple combination group was obtained, indicating the antagonistic effect. IR/17-AAG and IR/Cap double combination groups resulted in down-regulation of MMP-9 and VEGF mRNA expression, respectively. Significant generation of MDA and decrease in TAC values have been observed in all our tested groups, however, the IR/17-AAG combination was the only group that could elevate NO concentration, significantly. Our findings demonstrated potent anti-angiogenesis and anti-metastatic effects for 17-AAG when it is provided in double combination especially with Cap, suggesting a new protocol in colorectal cancer combination therapy. These findings may indicate that down-regulation of VEGF and MMP-9 genes is directly related to angiogenesis and metastasis.

The Sources of Essential Fatty Acids for Allergic and Cancer Patients; a Connection with Insight into Mammalian Target of Rapamycin: A Narrative Review

Background: Disturbance in essential fatty acids (EFA) metabolism plays a key role in autoimmune diseases, but EFA supplementation with sources of borage, evening primrose, hemp seed and fish oils was not effective in atopic and cancer diseases, as that seen in the case of multiple sclerosis. It seems that two complexes of the mammalian target of rapamycin (mTOR) signaling, mTORC1 and mTORC2, are congruent with the two bases of the Traditional Iranian Medicine (TIM) therapy, Cold and Hot nature, which are essential for the efficacy of functional oils for controlling immune responses in autoimmune diseases. Methods: We searched PubMed database, Web of Science (WOS), Google Scholar, Scopus and selected studies by predefined eligibility criteria. We then assessed their quality and extracted data. Results: The oils controlled by Cold or Hot nature may be helpful in maintaining homeostasis and preventing autoimmune diseases. In summary, studies of randomized controlled trials for allergy and cancer patients found no improvement in the signs or response to tests, despite a remarkable change in EFA fractions in the blood by supplementation with sources of borage, evening primrose, hemp seed and fish oils. In contrast, portulaca oleracea oil exhibited protective effects by anti-inflammatory properties via the PI3K/Akt/mTORC2 pathway with a deviation immune response to Th1 to treat atopic diseases and cancer. Conclusions: According to the concept of Traditional Iranian Medicine therapy, in contrast to Cold-nature oils, EFA supplementation with the sources of Hot-nature oilsis not suitable for the treatment of atopic and cancerous diseases.

Cytotoxic effects of the newly-developed chemotherapeutic agents 17-AAG in combination with oxaliplatin and capecitabine in colorectal cancer cell lines.

The use of heat shock protein 90 inhibitors like 17-allylamino-17-demethoxy-geldanamycin (17-AAG) has been recently introduced as an attractive anticancer therapy. It has been shown that 17-AAG may potentiate the inhibitory effects of some classical anticolorectal cancer (CRC) agents. In this study, two panels of colorectal carcinoma cell lines were used to evaluate the effects of 17-AAG in combination with capecitabine and oxaliplatin as double and triple combination therapies on the proliferation of CRC cell lines. HT-29 and all HCT-116 cell lines were seeded in culture media in the presence of different doses of the mentioned drugs in single, double, and triple combinations. Water-soluble tetrazolium-1 (WST-1) assay was used to investigate cell proliferation 24 h after treatments. Then, dose-response curves were plotted using WST-1outputs, and IC50 values were determined. For double and triple combinations respectively 0.5 × IC50 and 0.25 × IC50 were used. Data was analyzed with the software CompuSyn. Drug interactions were analyzed using Chou-Talalay method to calculate the combination index (CI).The data revealed that 17-AAG shows a potent synergistic interaction (CI < 1) with oxaliplatin and capecitabine in double combinations (0.5 × IC50) in both cell lines. In the case of triple combinations, the findings showed an antagonistic interaction (CI > 1) in HT-29 and a synergistic effect (CI < 1) in HCT-116 (0.25 × IC50) cell lines. It was concluded that double combinations of 17-AAG with oxaliplatin or capecitabine might be effective against HCT-116 and HT-29 cell lines. However, in triple combinations, positive results were seen only against HCT-116. Further investigation is suggested to confirm the effectiveness of these combinations in clinical trials.

Toxicity of Cisplatin-Loaded Poly Butyl Cyanoacrylate Nanoparticles in a Brain Cancer Cell Line: Anionic Polymerization Results

Cancer is one of the most important issues in modern medicine and the most common cause of death after cardiovascular diseases in many countries. Brain cancer is one of the most common causes of cancer death among men and women, ranking third. Chemotherapeutic drugs that aim to prevent uncontrolled proliferation of cells in tissues of the body and induce apoptosis of tumor cells are prominent candidates for development. Since cisplatin has an apoptosisinducing role, it is widely used as an anticancer agent. In this research, toxicity of cisplatin was studied with the C6 rat glioma cell lined using the MTT method. In addition, nanoparticles underwent SEM microscopic imaging. Particle average size, size distribution, polydispersity index (PDI) and zeta potential of poly butyl cyanoacrylate nanoparticles were found to be 222 nm, 0.470 ± 0.04 and 5.1 ± 0.2 mV, respectively. The results showed that nanoconjugates of cisplatin have more cytotoxic effects on C6 cells than the free drug (P<0.05), pointing to an enhanced potential of the synthesized nano-particles as a new nanocarrier for chemotherapy.