COVID-19 vaccination anti-cancer impact on the PI3K/AKT signaling pathway in MC4L2 mice models.

The most promising method of containing the COVID-19 pandemic is considered to be vaccination against SARS-CoV-2 infection. However, research on the relationship between vaccination against COVID-19 and cancer has primarily examined induced immunity rather than the disease itself. Considering that breast cancer is the most common cancer among women, the main goal of this study was to examine the impact of the Sinopharm and AstraZeneca vaccination on tumor characteristics such as tumor size, important tumor markers, tumor-infiltrating lymphocytes, metastasis to vital organs, and investigation of the PI3K/AKT signaling pathway, and the expression levels of relevant genes (PTEN, mTOR, AKT, PI3K, GSK3, and FoxO1) of the luminal B (MC4L2) mouse model. The tumor size of the mice was measured and monitored every two days, and after thirty days, the mice were euthanized. Remarkably, after vaccination, all vaccinated mice showed a decrease in the size of their tumor and an increase in the number of lymphocytes that had invaded the tumors. Tumor marker levels (VEGF, Ki-67, MMP-2/9), CD4/CD8 ratio, metastasis to vital organs, hormone receptors (ER, PR, and HER-2), and expression of genes related to the advancement of the PI3K/AKT signaling pathway were lower in vaccinated mice. Our research showed that the COVID-19 vaccine can have an anti-cancer effect by slowing the tumor progression and metastasis.

Anti-MUC1 nanobody can synergize the Tamoxifen and Herceptin effects on breast cancer cells by inducing ER, PR and HER2 overexpression.

INTRODUCTION: One of the most pressing concerns associated with breast cancer-targeted therapies is resistance to Tamoxifen and Herceptin. Such drug resistance is usually characterized by reduced expression of certain cell surface receptors. Some biological regimens can induce perceptible overexpression of these receptors in favor of drug responsiveness. MATERIAL AND METHODS: In this research, drug-responsive MCF-7 and SKBR-3, along with drug-resistant MCF-7R (Tamoxifen resistant) and JIMT-1 (Herceptin resistant) breast cancer cell lines in 2D and 3D cultures were exposed to anti-MUC1 nanobody and then assessed for their ER, PR, and HER2 gene and protein expression using qRT-PCR and immunofluorescent staining analyses. Cell viability and the synergistic relationships of combination treatments were determined with MTT assay followed by CompuSyn software. Apoptotic cells were evaluated with Annexin V/propidium Iodide (PI) and acridine orange/ethidium bromide (AO/EB) staining. RESULTS: Anti-MUC1 exposure elevated the expression levels of ER (42 folds), PR (18.5 folds), and HER2 (4.7 folds). As a result of co-treatment, the IC50 levels for Tamoxifen and Herceptin were reduced by up to 10 and 3 folds, respectively. MCF-7R cells responded positively to Tamoxifen, as evidenced by a 5-fold reduction in the IC50 and enhanced apoptosis. CONCLUSION: The ER, PR, and HER2 overexpression after MUC1 blocking could signal drug hypersensitization and facilitate drug resistance management.

P53 status, and G2/M cell cycle arrest, are determining factors in cell-death induction mediated by ELF-EMF in glioblastoma.

The average survival of patients with glioblastoma is 12-15 months. Therefore, finding a new treatment method is important, especially in cases that show resistance to treatment. Extremely low-frequency electromagnetic fields (ELF-EMF) have characteristics and capabilities that can be proposed as a new cancer treatment method with low side effects. This research examines the antitumor effect of ELF-EMF on U87 and U251 glioblastoma cell lines. Flowcytometry determined the viability/apoptosis and distribution of cells in different phases of the cell cycle. The size of cells was assessed by TEM. Important cell cycle regulation genes mRNA expression levels were investigated by real-time PCR. ELF-EMF induced apoptosis in U87cells much more than U251 (15% against 2.43%) and increased G2/M cell population in U87 (2.56%, p value < 0.05), and S phase in U251 (2.4%) (data are normalized to their sham exposure). The size of U87 cells increased significantly after ELF-EMF exposure (overexpressing P53 in U251 cells increased the apoptosis induction by ELF-EMF). The expression level of P53, P21, and MDM2 increased and CCNB1 decreased in U87. Among the studied genes, MCM6 expression decreased in U251. Increasing expression of P53, P21 and decreasing CCNB1, induction of cell G2/M cycle arrest, and consequently increase in the cell size can be suggested as one of the main mechanisms of apoptosis induction by ELF-EMF; furthermore, our results demonstrate the possible footprint of P53 in the apoptosis induction by ELF-EMF, as U87 carry the wild type of P53 and U251 has the mutated form of this gene.

Cross-talk between non-ionizing electromagnetic fields and metastasis; EMT and hybrid E/M may explain the anticancer role of EMFs.

Recent studies have shown that non-ionizing electromagnetic fields (NIEMFs) in a specific frequency, intensity, and exposure time can have anti-cancer effects on various cancer cells; however, the underlying precise mechanism of action is not transparent. Most cancer deaths are due to metastasis. This important phenomenon plays an inevitable role in different steps of cancer including progression and development. It has different stages including invasion, intravasation, migration, extravasation, and homing. Epithelial-mesenchymal transition (EMT), as well as hybrid E/M state, are biological processes, that involve both natural embryogenesis and tissue regeneration, and abnormal conditions including organ fibrosis or metastasis. In this context, some evidence reveals possible footprints of the important EMT-related pathways which may be affected in different EMFs treatments. In this article, critical EMT molecules and/or pathways which can be potentially affected by EMFs (e.g., VEGFR, ROS, P53, PI3K/AKT, MAPK, Cyclin B1, and NF-кB) are discussed to shed light on the mechanism of EMFs anti-cancer effect.

Anti-cancer effect of COVID-19 vaccines in mice models.

AIMS: Without any doubt, vaccination was the best choice for Coronavirus disease 2019 (COVID-19) pandemic control. According to the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO), people with cancer or a history of cancer have a higher risk of dying from Covid-19 than ordinary people; hence, they should be considered a high-priority group for vaccination. On the other hand, the effect of the Covid-19 vaccination on cancer is not transparent enough. This study is one of the first in vivo studies that try to show the impact of Sinopharm (S) and AstraZeneca (A) vaccines on breast cancer, the most common cancer among women worldwide. MATERIALS AND METHODS: Vaccination was performed with one and two doses of Sinopharm (S1/S2) or AstraZeneca (A1/A2) on the 4T1 triple-negative breast cancer (TNBC) mice model. The tumor size and body weight of mice were monitored every two days. After one month, mice were euthanized, and the existence of Tumor-infiltrating lymphocytes (TILs) and expression of the important markers in the tumor site was assessed. Metastasis in the vital organs was also investigated. KEY FINDINGS: Strikingly, all of the vaccinated mice showed a decrease in tumor size and this decrease was highest after two vaccinations. Moreover, we observed more TILs in the tumor after vaccination. Vaccinated mice demonstrated a decrease in the expression of tumor markers (VEGF, Ki-67, MMP-2/9), CD4/CD8 ratio, and metastasis to the vital organs. SIGNIFICANCE: Our results strongly suggest that COVID-19 vaccinations decrease tumor growth and metastasis.

Reactive oxygen species, the trident of Neptune in the hands of hecate; role in different diseases, signaling pathways, and detection methods.

Free radicals are highly reactive molecules with short lifetime which are now well accepted to act as regulators for different signaling pathways and hence can affect various cellular processes. Furthermore, they play pivotal role in different physiological/pathophysiological processes including homeostasis, metabolism, immunity, proliferation, differentiation, and cancer. Meanwhile, free radicals play a positive role in pathogen resistance that any imbalances in their productions/regulation could be harmful to cell macromolecules such as proteins, lipids, and nucleic acids and finally cells' fate, which may be results in different diseases. Some modalities, especially in cancer therapy, are based on ROS elevation/decreasing. Based on the inevitable importance of ROS various detection methods have been developed. These methods should have fundamental criteria including cell-permeability and physiological pH compatibility. In this review first we will bring up about different free radicals, their role in diseases, and underlying signaling pathways; after that various detection methods with their pros and cons will be discussed.

Cellular stress response to extremely low-frequency electromagnetic fields (ELF-EMF): An explanation for controversial effects of ELF-EMF on apoptosis.

Impaired apoptosis is one of the hallmarks of cancer, and almost all of the non-surgical approaches of eradicating tumour cells somehow promote induction of apoptosis. Indeed, numerous studies have stated that non-ionizing non-thermal extremely low-frequency magnetic fields (ELF-MF) can modulate the induction of apoptosis in exposed cells; however, much controversy exists in observations. When cells are exposed to ELF-EMF alone, very low or no statistically significant changes in apoptosis are observed. Contrarily, exposure to ELF-EMF in the presence of a co-stressor, including a chemotherapeutic agent or ionizing radiation, can either potentiate or inhibit apoptotic effects of the co-stressor. In our idea, the main point neglected in interpreting these discrepancies is "the cellular stress responses" of cells following ELF-EMF exposure and its interplay with apoptosis. The main purpose of the current review was to outline the triangle of ELF-EMF, the cellular stress response of cells and apoptosis and to interpret and unify discrepancies in results based on it. Therefore, initially, we will describe studies performed on identifying the effect of ELF-EMF on induction/inhibition of apoptosis and enumerate proposed pathways through which ELF-EMF exposure may affect apoptosis; then, we will explain cellular stress response and cues for its induction in response to ELF-EMF exposure; and finally, we will explain why such controversies have been observed by different investigators.

DNMT1 and miRNAs: possible epigenetics footprints in electromagnetic fields utilization in oncology.

Many studies were performed to unravel the effects of different types of Electromagnetic fields (EMFs) on biological systems. Some studies were conducted to exploit EMFs for medical purposes mainly in cancer therapy. Although many studies suggest that the EMFs exposures can be effective in pre-clinical cancer issues, the treatment outcomes of these exposures on the cancer cells, especially at the molecular level, are challenging and overwhelmingly complicated yet. This article aims to review the epigenetic mechanisms that can be altered by EMFs exposures with the main emphasis on Extremely low frequency electromagnetic field (ELF-EMF). The epigenetic mechanisms are reversible and affected by environmental factors, thus, EMFs exposures can modulate these mechanisms. According to the reports, ELF-EMF exposures affect epigenetic machinery directly or through the molecular signaling pathways. ELF-EMF in association with DNA methylation, histone modification, miRNAs, and nucleosome remodeling could affect the homeostasis of cancer cells and play a role in DNA damage repairing, apoptosis induction, prevention of metastasis, differentiation, and cell cycle regulation. In general, the result of this study shows that ELF-EMF exposure probably can be effective in cancer epigenetic therapy, but more molecular and clinical investigations are needed to clarify the safe and specific dosimetric characteristics of ELF-EMF in practice.

Anti-cancer impact of Hypericin in B-CPAP cells: Extrinsic caspase dependent apoptosis induction and metastasis obstruction.

Thyroid cancer is the most common type of endocrine-related cancer. According to the literature, its incidence is not very high, but its rate increasing especially in developed countries. With this regard, finding approaches to prevent, and exert anti-tumor activity with the least side effects on the normal cells at the next step after diagnosis is demanded. Herbal medicine is a branch of integrative oncology that seems to be a practically beneficial goddess for cancer treatment in many cases. Here we utilized Hypericin (HYP) to investigate its anti-tumor (apoptotic and anti-metastatic) activity on B-CPAP (a thyroid cancer cell line) and cytotoxicity on TPC-1 (thyroid cancer cell line with wild type TP53) cell lines. To assess whether HYP may exert preventive and anti-tumor effects and does not have a potential side effect, we dubbed the experiments on the fibroblast cells (as a normal cell line). Cytotoxicity and kind of cellular death were examined by MTT and AnnexinV/PI respectively. Extrinsic/intrinsic apoptosis pathway induction was clarified by western blotting on pro/cleaved caspases 9, 8, and 3. According to our data HYP induces an extrinsic apoptosis pathway and no other types (necroptosis, necrosis, etc.) in B-CPAP cells. Moreover, CDH1 mRNA expression calculated to be up-regulated, and that of LGALS3 down-regulated in the B-CPAP cell line after treatment. Besides tumor cytotoxic activity, we suggest that HYP impedes with invasion and/or metastasis process.

Necroptosis triggered by ROS accumulation and Ca2+ overload, partly explains the inflammatory responses and anti-cancer effects associated with 1Hz, 100 mT ELF-MF in vivo.

Whereas the anti-neoplastic activity of extremely low frequency magnetic fields (ELF-EMF) is well-documented in literature, little is known about its underlying anti-cancer mechanisms and induced types of cell death. Here, for the first time, we reported induction of necroptosis, a specific type of programed necrotic cell death, in MC4-L2 breast cancer cell lines following a 2 h/day exposure to a 100 Hz, 1 mT ELF-EMF for five days. For in vivo assessment, inbred BALB/c mice bearing established MC-4L2 tumors were exposed to 100 mT, 1 Hz ELF-EMF 2 h daily for a period of 28-day, following which tumors were dissected and fixed for evaluation of tumor biomarkers expression and types of cell death induced using TUNEL assay, Immunohistochemistry and H&E staining. Peripheral blood samples were also collected for assessing pro-inflammatory cytokine profile following exposure. An exaggerated proinflammatory response evident form enhancement of IFN-γ (4.8 ± 0.24 folds) and TNF-α (3.1 ± 0.19 folds) and number of tumors infiltrating lymphocytes (TILs), specially CD8+ Th cells (~20 folds), proposed occurrence of necroptosis in vivo. Meanwhile, exposure could effectively suppress tumor growth and expression of Ki-67, CD31, VEGFR2 and MMP-9. In vitro studies on ELF-EMF exposed MC-4L2 cells demonstrated a meaningful increase in phosphorylation of RIPK1/RIPK3/MLKL proteins and cleavage of caspase-9/caspase-3, confirming occurrence of both necroptosis and apoptosis. Complementary in vitro studies by treating ELF-EMF exposed MC-4L2 cells with verapamil (a calcium channel inhibitor), N-acetyl cysteine (a ROS scavenger) or calcium chloride confirmed the role of elevated intracellular calcium and ROS levels in ELF-EMF induced necroptosis.

Hypericin induces apoptosis in K562 cells via downregulation of Myc and Mdm2.

BACKGROUND: Nowadays, some studies have shown the effect of hypericin on cancer cells. However, considering the cytotoxicity of this plant and signs of anticancer activity in the plant, unfortunately, there is still no proper treatment for leukemia cancer cells. Therefore, the present study aims to evaluate the anticancer effect of hypericin in the treatment of leukemia cancer and its possible mechanism of action. METHODS: In this study, the K562 cell line was treated with different concentrations of hypericin for 24 and 48 h. Detection of cell death was performed by 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-tetrazolium bromide assay. The rate of cell apoptosis was measured by Annexin V/propidium iodide assay using flow cytometry. The expression of Bax, Bcl2, Myc, Mdm2, and P53 genes was evaluated by real-time polymerase chain reaction test, and immunocytochemistry (ICC) analysis was used for further evaluation of P53. RESULTS: The results showed that hypericin has a dose-dependent cytotoxic effect on the K562 (in much less dose compared with cisplatin). According to flow cytometry results, cell apoptosis after exposure to hypericin for 24 h was 53%, and ICC analysis on p53 confirmed this. Furthermore, after 24 h of exposure to hypericin with IC50 concentration, the expression of P53 and Bax genes increased and the expression of the Bcl2, Myc, and Mdm2 gene decreased. CONCLUSION: The results showed that hypericin exerts its cytotoxicity on K562 cancer cells by downregulating Mdm2 and Myc. Based on the data acquired from the present study and many investigations till now, hypericin can be a good option for leukemia cancer cells treatment.

Transcriptome analysis evinces anti-neoplastic mechanisms of hypericin: A study on U87 glioblastoma cell line.

AIMS: Hypericin (HYP) from Hypericum perforatum has cytotoxic effects on a variety of malignant cell types, but the pattern of gene expression mediating the effect is largely unknown. Here we sought to analyze the response of U87 glioblastoma (GBM) cell lines in response to HYP. MATERIALS AND METHODS: U87 cell line was treated by HYP. Cytotoxicity was assessed using MTT and Annexin V/PI assays. Gene expression profile was obtained using high-throughput sequencing. Enrichment analysis was performed on differentially expressed genes (DEGs). Upstream transcription factors and microRNAs regulating DEGs were predicted. The effects of DEGs on survival of GBM patients were calculated. Protein-protein interaction analysis was conducted to obtain key altered genes. The possible effect of HYP treatment on immunity response was evaluated. KEY FINDINGS: The IC50 of HYP on U87 cell line was determined to be 1.5 µg/ml. The main type of cell death was apoptosis. A total of 312 DEGs were found. Affected Gene Ontology terms and pathways were identified. Analysis of upstream modulators of DEGs pointed out to transcription factors that significantly overlap with GBM stem cell transcription factor. Survival analysis suggested that HYP works best for the mesenchymal subtype patients. Tumor infiltration analysis predicted that HYP may affect Treg and macrophage infiltration in vivo. Using expression pattern of GBM patients and HYP-induced DEGs we suggested Fedratinib as a complementary drug to HYP. SIGNIFICANCE: Our study represents the response of U87 cell line to HYP, with analyses on survival, transcription factors and personalization according to GBM subtype.

Verapamil Inhibits Mitochondria-Induced Reactive Oxygen Species and Dependent Apoptosis Pathways in Cerebral Transient Global Ischemia/Reperfusion.

The prefrontal cortex is the largest lobe of the brain and is consequently involved in stroke. There is no comprehensive practical pharmacological strategy for ameliorating prefrontal cortex injury induced by cerebral ischemia. Therefore, we studied the neuroprotective properties of verapamil (Ver) on mitochondrial dysfunction and morphological features of apoptosis in transient global ischemia/reperfusion (I/R). Ninety-six Wistar rats were allocated into four groups: control, I/R, I/R+Ver (10 mg/kg twice 1 hour prior to ischemia and 1 hour after reperfusion phase), and I/R+NaCl (vehicle). Animals were sacrificed, and mitochondrial dysfunction parameters (i.e., mitochondrial swelling, mitochondrial membrane potential, ATP concentration, ROS production, and cytochrome c release), antioxidant defense (i.e., superoxide dismutase, malondialdehyde, glutathione peroxidase, catalase, and caspase-3 activation), and morphological features of apoptosis were determined. The results showed that mitochondrial damage, impairment of antioxidant defense system, and apoptosis were significantly more prevalent in the I/R group in comparison with the other groups. Ver decreased mitochondrial damage by reducing oxidative stress, augmented the activity of antioxidant enzymes in the brain, and decreased apoptosis in the I/R neurons. The current study confirmed the role of oxidative stress and mitochondrial dysfunction in I/R progression and indicated the possible antioxidative mechanism of the neuroprotective activities of Ver.

Hypericin Induces Apoptosis in AGS Cell Line with No Significant Effect on Normal Cells.

It is of great importance to find an effective approach that not only eliminates gastric cancer cells but also do exhibits significant side effect to normal cells. Some studies have shown the effectiveness of hypericin against cancer cells. In this study, we evaluated the anti-cancer effect of Hypericin in the treatment of gastric cancer. In this study, the AGS cell line was exposed to different concentrations of hypericin for 24 and 48 h. Evaluation of cell death was done by MTT assay. The rate of apoptosis was measured by flow cytometry assay using Annexin V/ Propidium Iodide. The expression rate of Bcl2, p53 and Bax genes was evaluated by Real-time PCR test, and immunocytochemistry (ICC) analysis and western blotting was used for further evaluation of p53. MTT assay test showed that hyepricin induces 50% cell death in the concentration of 1 (µg/mL) and 0.5 (µg/mL) at 24 h and 48 h post-treatment, respectively, however no similar effect seen on fibroblast cells. Annexin/PI test revealed that cell apoptosis after exposure to hypericin for 24 h was 74%. Real-time PCR showed that expression level of Bax, p53 and Bax genes increases and Bcl2 gene decreases in AGS cell lines after treatment by hypericin. ICC analysis and western blotting for p53 confirmed these data. The results of this study indicated that hypericin has the potential to be introduced as an effective treatment for gastric cancer. Therefore, it seems that this substance has potential to be utilized as anti-cancer drug.

Hypericin Exerts Detrimental Effect on Huh-7 As a Delegacy of Hepatocellular Carcinoma: A P53 Dependent Pathway.

BACKGROUND: Hepatocellular carcinoma is the most common type of liver cancer which arises from the main cells in the liver. We address many studies investigating anti-cancer role of hypericin, however the proposing corresponding molecular pathway seems to be still a debate. Therefore, the present study aimed to evaluate the apoptotic effect of hypericin on the Huh7 as the liver cancer cell line and its relation with the gate keeper gene P53. MATERIALS AND METHODS: In this study, the Huh7 cell line and fibroblast cells (as control group) were treated with different concentrations of hypericin for 24 and 48 hours. Detection of cell death was performed by MTT assay and flow cytometry. The expression of bax, bcl2 and p53 mRNAs was evaluated by Real-time PCR. Also, Immunocytochemistry (ICC) analysis was used for further evaluation of P53expression. RESULTS: The results showed that hypericin has a dose-dependent cytotoxic effect on the Huh7 cell line, with no or marginal effect on fibroblastic cells. According to flow cytometry results, about 53%cells underwent apoptosis after exposure to LD50 of hypericin for 24 hours. Real-time PCR data demonstrated that the pro-apoptotic genes Bax and P53 expression level increased. Expectedly ICC results confirmed the up-regulation of P53 proteins in treated samples. CONCLUSION: Our results indicate the cytotoxicity of hypericin on Huh7 cells by affecting the expression of the gate keeper gene P53; furthermore it is suggested that this herb can be utilized simultaneously with modalities targeting P53 up-regulation or related molecular pathways.

Investigating curcumin potential for diabetes cell therapy, in vitro and in vivo study.

AIMS: An important obstacle on the way of cell-based therapy is the risk of tumorigenicity in the patients benefit from these transplanted cells due to undifferentiated cells which participate in transplantation. Curcumin, the main compound of spice turmeric -as one of the natural products-was demonstrated to possess effective anti-cancer properties, with no significant effect on normal cells in dose and/or time-dependent manner. Furthermore many studies have been accomplished using curcumin for diabetes treatment. Therefore in this study we examined the efficacy of IPCs treated with curcumin in vivo. MAIN METHODS: Differentiation efficiency investigated by flowcytometry. RNA extraction and real-time PCR performed for important genes in IPC differentiation and tumorigenesis including Insulin, Nestin, Ngn3, Pdx1, P21, and P53. Finally we investigated the efficiency of these differentiated and treated cells in diabetic rats. KEY FINDINGS: Our data indicates that nanocurcumin -in a specific dose-reduces the expression of Nestin with no significant effect on insulin expression in mRNA and protein level. Besides blood glucose level of diabetic rats which treated with DNC + cells, decreased from average 350 (mg/dI) to 100 (mg/dI). Checking out the pancreases of these rats, demonstrated that their endocrine segment was rebuilt. Moreover hematoxylin & eosin staining and IF results revealed that the Langerhans Islands were reformed. SIGNIFICANCE: IPCs' which treated with DNC were able to efficiently control the blood glucose level in diabetic rats which these cells were transplanted to them. Hence Curcumin has the potential to be employed in this kind of cell therapy.

Hypericin Induces Apoptosis in MDA-MB-175-VII Cells in Lower Dose Compared to MDA-MB-231.

BACKGROUND: Breast cancer is the major cause of death from cancer among women around the world. Given the drug resistance in the treatment of this disease, it is very important to identify new therapies and anticancer drugs. Many studies demonstrated that hypericin could induce apoptosis in different cancer cell lines; however, the underlying mechanism is not well understood yet. Therefore, this study aimed to evaluate the anticancer effect of hypericin in two breast cancer cell lines, one with wild type P53 and the other with mutant P53. METHODS: In this study, the MDA-MB-231 and MDA-MB-175-VII cell lines were treated with different concentrations of hypericin for 24 and 48 hours. The measurement of cell death was performed by MTT assay. The cell apoptosis rate was measured using annexin V/propidium iodide assay through flow cytometry. The level of expression in P21 and P53 genes was evaluated by real time PCR. Immunocytochemistry (ICC) analysis was performed for P21 (direct target for P53 protein) to confirm the results. RESULTS: The results showed that hypericin could have dose-dependent cytotoxic effects on the MDA-MB-231 and MDA-MB-175-VII cell lines, and its cytotoxicity is much higher in the latter cells. According to flow cytometry results, 86% of MDA-MB-175-VII cells underwent apoptosis with IC50 dose of hypericin for MDA-MB-231 cells after 24 hours. Moreover, after 24 hours of exposure to hypericin with MDA- MB-231 IC50 concentration, the expression of P53 and P21 genes upregulated in MDA-MB-175-VII much more than MDA-MB-231 when both cell lines were treated with 24 hours IC50 dose of MDA-MB-231. The ICC analysis on P21 confirmed that by treating both cell lines with MDA-MB-231 IC50 dose of hypericin for 24 hours, this protein is overexpressed much more in MDA-MB-175-VII cells. CONCLUSION: The results of this study demonstrated that hypericin's apoptotic and cytotoxic effects on cancer cells may be mediated via P53 overexpression, cell cycle arrest and the subsequent apoptosis. Therefore, it is of great importance to consider that hypericin would have better impact on cells or tumors with wild type P53.

Cytotoxic and Apoptogenic Effects of Cyanidin-3-Glucoside on the Glioblastoma Cell Line.

OBJECTIVE: Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary cerebral tumor. The median survival time is 15 months despite maximum treatment because the tumor is resistant to most therapeutic modalities. Several studies have indicated chemopreventive and chemotherapeutic activity of cyanidin-3-glucoside (C3G) as an anthocyanin component. We aimed to illustrate the cytotoxic and apoptogenic effects of C3G in the U87 cell line (human GBM cell line). METHODS: Cytotoxic activity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium assay after treatment with C3G at different concentrations in the U87 cell line. Cisplatin was used as a positive control for 24 and 48 hours. The percentage of apoptotic cells was determined using an Annexin V/propidium iodide assay, and the expression of bax, bcl2, and p53 genes was assessed using real-time polymerase chain reaction. RESULTS: Treatment of U87 cells with 40 µg/mL of C3G resulted in 32% apoptotic cells after 24 hours. To further confirm that C3G treatment induced apoptosis in U87 cells, RNA expression of bax, bcl2, and p53 genes was investigated after treatment. Real-time polymerase chain reaction indicated that the expression of bax and p53 increased, whereas the expression of bcl2 decreased. CONCLUSIONS: C3G had an apoptogenic effect in the GBM cell line. New information regarding the therapeutic effects of C3G in GBM could ultimately lead to the production of new drugs.

MicroRNA-Mediated Post-Transcriptional Regulation of Epithelial to Mesenchymal Transition in Cancer.

Epithelial to mesenchymal transition (EMT) program participates in tissue repair, embryogenesis and numerous pathological conditions, particularly cancer progression and tumor metastasis. A highly complex and strongly controlled post-transcriptionally regulated network of microRNAs (miRNAs) regulates the EMT process. miRNAs are critical parts of the post-transcriptional regulation of gene expression. A set of miRNAs target multiple components of major signaling pathways and downstream effectors of EMT. miRNAs associated with this process are involved in controlling tumor progression and invasiveness either as oncogenes or as tumor suppressors. Since several miRNAs directly affect EMT-related master regulators, they have been discovered to have the potential to be used as biomarkers or targets in EMT-based pathological conditions such as cancer. Therefore, comprehensive understanding of miRNA-EMT correlation with tumor metastatic spread may provide improvements to diagnostic tools or therapeutics for cancer. This review summarizes our current knowledge about some of these important miRNAs and focuses on their specific roles in regulation of the EMT process in cancer.

Comparison of in Vitro Cytotoxicity and Apoptogenic Activity of Magnesium Chloride and Cisplatin as Conventional Chemotherapeutic Agents in the MCF-7 Cell Line.

Breast cancer is the most common malignancy and also the second leading cause of cancer death among women and also in women that have a high mortality. Previous studies showed that magnesium (Mg) has cytotoxic effects on malignant cell lines. However, the anti-cancer effects of Mg on MCF-7 breast cancer cells are uncertain. This study was aimed at the comparison of the cytotoxic effect of Mg salt (MgCl2) and cisplatin on MCF-7 cells and fibroblasts (as normal cells). After treatment with various concentrations of MgCl2, and cisplatin as a positive control for 24 and 48 hours (h), cytotoxicity activity was measured by MTT assay. In addition, apoptosis was determined by annexin V/propidium iide assay. Both cisplatin and the MgCl2 exhibited dose-dependent cytotoxic effects in the MCF-7 cell line, although the LD50 of the Mg was significantly higher when compared to cispaltin (40 µg/ml vs. 20 µg/ml). Regarding annexin V/propidium results, treatment of MCF-7 cells with LD50 concentrations of cisplatin and Mg showed 59% and 44% apoptosis at 24h, respectively. Finally, the results indicated that Mg has cytotoxic effects on MCF-7 cells, but less than cisplatin as a conventional chemotherapeutic agent. However, regarding the side effects of chemotherapy drugs, it seems that Mg can be considered as a supplement for the treatment of breast cancer.