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Purpose: CD44 plays a pivotal role through tumorigenesis by regulating cancer cell metastasis, stemness, and chemosensitivity and is considered a promising therapeutic target for human cancers, including colorectal cancer (CRC). Therefore, the present research aimed to examine the simultaneous therapeutic effect of CD44 silencing and 5-fluorouracil (5-FU) on in vitro tumorigenesis of CRC cells. Methods: CD44 expression was initially evaluated in TCGA datasets and CRC tissues. Furthermore, functional analysis was performed on HT-29 CRC cells overexpressing CD44. The cells were transfected with CD44 siRNA and then treated with 5-FU. Consequently, to explore the combination therapy effect on cell viability, migration, apoptosis, and chromatin fragmentation, we performed MTT assay, scratch assay, Annexin V/PI staining and DAPI staining assays, respectively. The spheroid and colony formation assays were further employed to investigate stemness features. The gene expression at protein and mRNA levels were explored using western blotting and qPCR. Results: Our findings illustrated that CD44 was significantly overexpressed in CRC tissues compared to normal samples. The suppression of CD44 considerably promoted the chemosensitivity of HT-29 cells to 5-FU by apoptosis induction. Also, the combination therapy led to overexpression of apoptotic genes, including P53, caspase-3, and caspase-9, as well as downregulation of AKT1 expression. Furthermore, CD44 suppression, separately or combined with 5-FU, hindered stemness properties in HT-29 cells via downregulation of Sox2 and Nanog expression. Besides, the combination therapy remarkably downregulated MMPs and suppressed CRC cell migration. Conclusion: Considering its involvement in chemosensitivity to 5-FU, CD44 could be suggested as a potential target for improving the efficiency of CRC chemotherapy. [ABSTRACT FROM AUTHOR]

Abnormal vasculature is one of the most conspicuous traits of tumor tissue, largely contributing to tumor immune evasion. The deregulation mainly arises from the potentiated pro-angiogenic factors secretion and can also target immune cells' biological events, such as migration and activation. Owing to this fact, angiogenesis blockade therapy was established to fight cancer by eliminating the nutrient and oxygen supply to the malignant cells by impairing the vascular network. Given the dominant role of vascular-endothelium growth factor (VEGF) in the angiogenesis process, the well-known anti-angiogenic agents mainly depend on the targeting of its actions. However, cancer cells mainly show resistance to anti-angiogenic agents by several mechanisms, and also potentiated local invasiveness and also distant metastasis have been observed following their administration. Herein, we will focus on clinical developments of angiogenesis blockade therapy, more particular, in combination with other conventional treatments, such as immunotherapy, chemoradiotherapy, targeted therapy, and also cancer vaccines. 64SciJHJrfLYaKT285oK4U Video abstract [ABSTRACT FROM AUTHOR]

Purpose: To investigate the downregulation of high mobility group AT-hook 2 (HMGA2) expression by small interfering RNAs (siRNAs) in PC3 prostate cancer cell line. HMGA2 belongs to the non-histone chromatin-binding protein family that serves as a crucial regulator of gene transcription. The overexpression of this gene is positively correlated with various prostate cancer (PC)-related properties. Thus, HMGA2 is an emerging target in PC treatment. This study aimed to examine the impact of siRNAs targeting HMGA2 on the viability, migration, and apoptosis processes of the PC3 PC cell line. Methods: siRNA transfection was conducted with a liposome-mediated approach. The mRNA and protein expression levels for HMGA2 are evaluated by real-time polymerase chain reaction (qRT-PCR) and western blot analysis. The cytotoxic properties of HMGA2-siRNA were measured by MTT assay on PC3 cells. The migration of PC3 cells was measured by implementing a wound-healing assay. Apoptosis measurement was also quantified by TUNEL assay. Results: Transfection with siRNA significantly decreased both mRNA and protein levels of the HMGA2 gene in a dose-dependent manner after 48 hours. Also, we demonstrated that the knockdown of HMGA2 led to a reduction in cell viability, migration ability, and enhanced apoptosis of PC3 cells in vitro. Conclusion: Our findings recommend that the specific siRNA of HMGA2 may efficiently be able to decrease PC progression. Therefore, it may be a promising adjuvant treatment in PC. [ABSTRACT FROM AUTHOR]

Purpose: Gastric cancer (GC) is one of the main causes of death from diseases, especially in developing countries. MicroRNAs (miRNAs) are important modulators of the messenger RNAs expression. Among these miRNAs, MiR-143 is a tumor suppressor miRNA and its irregular expression has been revealed in a diversity of malignancies such as GC. Methods: In this study, we have attempted to restore the miR-143 expression in MKN-45 cells by introducing pCMV-miR-143 plasmid vectors. The consequences of exogenous expression of miR-143 on cell proliferation and migration were assessed by MTT and scratch tests, respectively. In addition, the DAPI staining assay was applied for apoptosis quantification. Following miR- 143 transfection, the changes in K-Ras, C-Myc, MMP9, Bax, caspase-3, and caspase-9 mRNA levels were assessed. Results: The results indicated that the enhanced expression of miR-143 had negative effects on MKN-45 cells proliferation and invasion. Moreover, decreased expressions of K-Ras, MMP9, and C-Myc and up-regulation of Bax, caspase-3, and caspase-9 as downstream targets of miR- 143 were recognized. Conclusion: These experimental results indicate that reversing the miR-143 expression, by novel techniques, including miRNA replacement could be considered as an efficient approach to reduce cell survival and metastasis. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most common cancers and its incidence is rising around the world. Various studies suggest that miR‐330 acts as a tumor‐suppressor microRNA (miRNA) in different types of cancers, but precisely how has remained unclear. In this study, we investigate miR‐330 expression in lung cancer patient samples, as well as in vitro, by studying how normalization of miR‐330 expression affects lung cancer cellular phenotypes such as viability, apoptosis, proliferation, and migration. We establish that low miR‐330 expression predicts poor lung cancer prognosis. Stable restoration of reduced miR‐330 expression in lung cancer cells reduces cell viability, increases the fraction of apoptotic cells, causes G2/M cell cycle arrest, and inhibits cell migration. These findings are substantiated by increased mRNA and protein expression of markers for apoptosis via the intrinsic pathway, such as caspase 9, and decreased mRNA and protein expression of markers for cell migration, such as vimentin, C‐X‐C chemokine receptor type 4, and matrix metalloproteinase 9. We showed that reduced miR‐330 expression predicts poor lung cancer survival and that stable restoration of miR‐330 expression in lung cancer cells has a broad range of tumor‐suppressive effects. This indicates that miR‐330 is a promising candidate for miRNA replacement therapy for lung cancer patients. [ABSTRACT FROM AUTHOR]

The use of liposomes as drug carriers improves the therapeutic efficacy of anticancer drugs, while at the same time reducing side effects. Hyaluronic acid (HA) is recognized by the CD44 receptor, which is overexpressed in many cancer cells. In this study, we developed HA‐modified liposomes encapsulating 5‐fluorouracil (5‐FU) and tested them against a CD44 expressing colorectal cell line (HT29) and a non‐CD44 expressing hepatoma cell line. The average size of 5‐FU‐lipo and 5‐FU‐lipo‐HA nanoparticles were 112 ± 28 and 144 ± 77 nm, respectively. The 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium (MTT) assay showed selective cancer cell death depending on the CD44 expression in a time‐dependent manner. Apoptosis assays and cell‐cycle analysis indicated that G0/G1 arrest occurred. The colony formation study revealed that cells treated with 5‐FU‐lipo and 5‐FU‐lipo‐HA had reduced colony formation. Quantitative reverse‐transcription polymerase chain reaction study showed that the oncogenic messenger RNA and microRNA levels were significantly reduced in the 5‐FU‐lipo‐HA‐treated group, while tumor suppressors were increased in that group. We suggest that optimal targeted delivery and release of 5‐FU into colorectal cancer cells, renders them susceptible to apoptosis, cell‐cycle arrest, and decreased colony formation. [ABSTRACT FROM AUTHOR]

MiR-145 is a tumor suppressor miRNA that its ubiquitously expressed in the body but in numerous types of cancers such as GC, its expression became reduced or sometimes ceased in many subjects. This study aimed at restoring the function of the miR-145 in MKN-45 cells and investigating the function of this miRNA in proliferation, apoptosis, and migration of GC cells. MKN-45 cells were transfected using the PCMV-miR-145 plasmid vector. The MTT, DAPI staining, and wound healing assays were applied to estimate the impacts of ectopic expression of miR-145 in vitro. Moreover, alterations in the expression levels of K-Ras, c-Myc, caspase-3, caspase-9, Bax, Bcl-2, and MMP-9 mRNA were measured by qRT-PCR analysis. The findings designated that high expression of miR-145 reduced the proliferation and migration and increased the apoptosis of the MKN-45 cells. These effects occur with concurrent suppression of c-Myc, K-Ras, Bcl-2, and MMP-9 as well as induction of caspase-3, caspase- 9, and Bax expression. Exogenous miR-145 influences multiple oncogenic pathways and can be regarded as a promising avenue of future therapeutic interventions for GC therapy. [ABSTRACT FROM AUTHOR]

One of the major obstacles in the treatment of cancer is resistance to standard chemotherapeutic drugs. According to the numerous reports, miR‐200c is involved in many cancers, especially gastric cancer, and also miR‐200c has been known as an effective factor in the elimination of chemotherapy resistance. The purpose of this study was to explore the potential function and mechanism of miR‐200c and cisplatin in the inhibition of migration and induction of apoptosis in gastric cancer cells. In this study, first, miR‐200c mimics and LNA‐anti‐miR‐200c were transfected into KATOIII cells. Moreover, 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay results revealed that increased miR‐200c expression and cisplatin can more inhibited the proliferation of KATOIII cells. MiR‐200c overexpression inhibited the movement of KATOIII cells in wound healing assay. Subsequently, miR‐200c/cisplatin could suppress colony formation in KATOIII cells. To identify a potential miR‐200c target, we investigated the effect of miR‐200c modulation on RhoE, PTEN, VEGFR, and MMP9 expression levels. Increased miR‐200c expression caused a reduction in VEGFR and MMP9 mRNA and protein, suggesting that VEGFR and MMP9 are targets of miR‐200c. In addition, reverse‐transcription polymerase chain reaction assays showed that RhoE is target gene of miR‐200c and LNA‐anti‐miR‐200c suppressed the expression of PTEN. Flow cytometry and 4′,6‐diamidino‐2‐phenylindole staining analysis indicated that miR‐200c increased the cisplatin‐induced apoptosis which may be associated with suppression of RhoE expression in KATOIII cells, also cell‐cycle analysis showed the arrest of cell‐cycle progression at the G2 phase. These data demonstrated that miR‐200c functioned as a suppressor gene in KATOIII cells. Also, miR‐200c can be a potential therapeutic approach to overcome chemoresistance during cisplatin chemotherapy. [ABSTRACT FROM AUTHOR]

During breast cancer progression, tumor cells acquire multiple malignant features. The transcription factors and cell cycle regulators high mobility group A2 (HMGA2) and BTB and CNC homology 1 (Bach‐1) are overexpressed in several cancers, but the mechanistic understanding of how HMGA2 and Bach‐1 promote cancer development has been limited. We found that HMGA2 and Bach‐1 are overexpressed in breast cancer tissues and their expression correlates positively in tumors but not in normal tissues. Individual HMGA2 or Bach‐1 knockdown downregulates expression of both proteins, suggesting a mutual stabilizing effect between the two proteins. Importantly, combined HMGA2 and Bach‐1 knockdown additively decrease cell proliferation, migration, epithelial‐to‐mesenchymal transition, and colony formation, while promoting apoptotic cell death via upregulation of caspase‐3 and caspase‐9. First the first time, we show that HMGA2 and Bach‐1 overexpression in tumors correlate positively and that the proteins cooperatively suppress a broad range of malignant cellular properties, such as proliferation, migration, clonogenicity, and evasion of apoptotic cell death. Thus, our observations suggest that combined targeting of HMGA2 and Bach1 may be an effective therapeutic strategy to treat breast cancer. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a common and highly malignant neoplasm, ranking as the fourth most frequent cause of cancer-related deaths worldwide. Recently, non-human oncolytic viruses such as Peste des petits ruminants virus (PPRV) are considered as a potent candidate in the viral therapy of cancer. In the current study, the apoptotic effects of matrix (M) protein of PPRV was investigated on SW480 CRC cells. The M gene was cloned into the pcDNA™3.1/Hygro(+) expression vector and transfected into the cancer cells. The cytotoxic effects of the M protein on SW480 cells were confirmed using MTT assay. Furthermore, flow cytometry results showed that the M protein induces apoptosis in 91 % of CRC cells. Interestingly, the expression of the M gene in SW480 cells led to the up-regulation of genes including Bax , p53 , and Caspase-9 , as well as an increase in the Bax/Bcl-2 ratio. By using bioinformatics modeling, we hypothesized that the M protein could interact with Bax factor through its BH3-like motif and could further activate the intrinsic apoptosis pathway. Ultimately, this study provided the first evidence of the pro-apoptotic activity of PPRV M protein indicating its possible development as a promising novel anti-cancer agent. [Display omitted] [ABSTRACT FROM AUTHOR]

Erlotinib (ELT) as a small molecule with poor solubility, poor bioavailability, and instability in gastrointestinal environment, has been considered as a therapeutic agent for Non-Small-Cell Lung Cancer (NSCLC) therapy through oral administration. In the present study, ELT-liposome and ELT-NLCs were successfully prepared and characterized by assessment of the particle size, zeta potential (ZP), polydispersity index (PDI), encapsulation efficiency (EE), and drug loading (DL). DAPI staining and Flow cytometry techniques were employed to probe anticancer activities of the optimal formulations. The obtained results indicated that the average size of optimized ELT-NLCs was 109 ± 2 nm, while the optimal formulation of ELT-liposome was 130 ± 4 nm. In addition, the values of EE, DL, and cellular uptake were higher in ELT-NLCs than ELT-liposome. Moreover, the stability of ELT-NLCs and ELT-liposome were not significantly changed (P > 0.05) within storage time. The results of anti-cancer assessment indicated that ELT-NLCs caused more cell viability reduction than ELT-liposome and free ELT. According to the Flow cytometry and DAPI staining results, the exposed A549 cells with ELT-NLCs had more rates of apoptosis than ELT-liposome. The obtained data from this study clearly showed that ELT-NLCs had better anti-cancer activity than ELT-liposome, which may be related to the effective nano particle size, PDI, EE, and DL of ELT-NLCs. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic adenocarcinoma has a high prevalence all over the world. Most of the therapeutic approaches failed as a result of tumor invasion and rapid metastasis. Several natural plants have been shown to have promising therapeutic effects. Thus, the aim of this study was to investigate the cytotoxic activity of Eryngium billardieri against PANC-1 cancer cell lines. Methods: Dimethylthiazole diphenyltetrazolium bromide assay (MTT assay) and flow cytometry were used to assess the cytotoxicity of E. billardieri extracts against PANC-1 cancer cell lines. Quantitative Polymerase Chain Reaction (qPCR) was conducted to investigate the expression levels of Bcl2- associated X protein (BAX) and cyclin D1. Results: The results of the MTT assay showed that E. billardieri extracts had cytotoxic effects on PANC- 1 cancer cell lines. Moreover, the findings from the gene expression confirmed the over expression of Bax, and under expression of cyclin D1 following treatment with dichloromethane (DCM) and n-hexane (n- hex) extracts in cancer cells (P < 0.05). Interestingly, the flow cytometry results showed that DCM and n- hex extracts of E. billardieri induced apoptosis in PANC- 1 cancer cell lines. Conclusion: The results of this study demonstrated that DCM and n- hex extracts of E. billardieri significantly induce apoptosis by increasing Bax and decreasing cyclin D1 mRNA expression. Therefore, E. billardieri may be regarded as a novel approach for treatment of pancreatic cancer as a result of its promising apoptotic and cytotoxic properties. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the serious human health problems and many researchers have focused on identifying new therapeutic agents and effective therapies. Recently, herbal medicines have been used for the treatment of various diseases such as cancer. This research aimed to investigate the potential anti-tumoral activity and clarify the respective mechanisms of Anacyclus pyrethrum plant extract on the A549 lung cancer cell line. To determine the cytotoxic effects of the Anacyclus pyrethrum extract on lung cancer cells, Trypan blue exclusion and MTT assay were performed. To show the induction of apoptosis by Anacyclus pyrethrum extract, flow cytometry assay was conducted. Quantitative real time PCR test was used to quantify the expressions of Bcl-2, Caspase-3, − 8, and − 9 genes, which are involved in apoptosis regulation. Also, cell cycle analysis was conducted by using flow cytometry. The Anacyclus pyrethrum plant extract could significantly inhibit lung cancer cell (A549) proliferation. Flow cytometry assay demonstrated that Anacyclus pyrethrum induced apoptosis. The messenger RNA (mRNA) expression levels of Caspase-3 and Caspase-9 were significantly upregulated by Anacyclus pyrethrum treatment, while the Bcl-2 gene was downregulated. The flow cytometry confirmed that cell cycle arrest occurred at the G1 phase. Our experiment showed that Anacyclus pyrethrum plant extract could considerably inhibit lung cancer cell growth by inducing of the intrinsic apoptosis pathway. Therefore, it may be a useful agent for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Anticancer drugs resistance is a complex process that arises from altering in the drug targets. Advances in the DNA microarray, proteomics technology and the development of targeted therapies provide the new strategies to overcome the drug resistance. Although a design of the new chemotherapy agents is growing quickly, effective chemotherapy agent has not been discovered against the advanced stage of cancer (such as invasion and metastasis). The cancer cell resistance against the anticancer agents can be due to many factors such as the individual's genetic differences, especially in tumoral somatic cells. Also, the cancer drug resistance is acquired, the drug resistance can be occurred by different mechanisms, including multi-drug resistance, cell death inhibiting (apoptosis suppression), altering in the drug metabolism, epigenetic and drug targets, enhancing DNA repair and gene amplification. In this review, we outlined the mechanisms of cancer drug resistance and in following, the treatment failures by common chemotherapy agents in the different type of cancers. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer is the most frequent malignancy diagnosed in women both in developed and developing countries. Natural products especially those from herbal origin have high potential in producing drug components with a source of novel structures. The present study was designed to explore the cytotoxic effects and the cell death mechanism of Scrophularia atropatana extracts. Methods: MTT assay was employed to evaluate the cytotoxic activity of the extracts of S. atropatana on the MCF-7 as well as non-malignant cells. Furthermore, induction of apoptosis was evaluated by TUNEL assay, cell death detection ELISA, DNA fragmentation test, western blotting and Real Time PCR. Results: In vitro exposures of the MCF-7 cells with different concentration of S. atropatana extract significantly inhibited their growth and viability and induced apoptosis in the MCF-7 cells. Cleavage PARP protein, decrease in the mRNA expression levels of bcl-2 and increase expression of Caspase-3 and Caspase-9 mRNA, highlights that the induction of apoptosis was the main mechanism of cell death. Moreover the expression study of Caspase-9 mRNA showed that, the extracts have induced apoptosis via intrinsic mitochondrial pathway. Conclusion: Our results demonstrated that dichloromethane extract of Scrophularia atropatana has an apoptotic effects and it can be developed as anticancer agents. [ABSTRACT FROM AUTHOR]

The transcription factor high mobility group protein A2 (HMGA2) plays an important role in the pathogenesis of some cancers including breast cancer. Polyamidoamine dendrimer generation 4 is a kind of highly branched polymeric nanoparticle with surface charge and highest density peripheral groups that allow ligands or therapeutic agents to attach it, thereby facilitating target delivery. Here, methotrexate (MTX)- modified polyamidoamine dendrimer generation 4 (G4) (G4/MTX) was generated to deliver specific small interface RNA (siRNA) for suppressing HMGA2 expression and the consequent effects on folate receptor (FR) expressing human breast cancer cell lines (MCF-7, MDA-MB-231). We observed that HMGA2 siRNA was electrostatically adsorbed on the surface of the G4/MTX nanocarrier for constructing a G4/MTX-siRNA nano-complex which was verified by changing the final particle size and zeta potential. The release of MTX and siRNA from synthesized nanocomplexes was found in a time- and pH-dependent manner. We know that MTX targets FR. Interestingly, G4/MTX-siRNA demonstrates significant cellular internalization and gene silencing efficacy when compared to the control. Besides, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay demonstrated selective cell cytotoxicity depending on the FR expressing in a dose-dependent manner. The gene silencing and protein downregulation of HMGA2 by G4/MTX-siRNA was observed and could significantly induce cell apoptosis in MCF-7 and MDA-MB-231 cancer cells compared to the control group. Based on the findings, we suggest that the newly developed G4/MTX-siRNA nano-complex may be a promising strategy to increase apoptosis induction through HMGA2 suppression as a therapeutic target in human breast cancer. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common women's malignancy in the world and, for subgroups of patients, treatment outcomes remain poor. Thus, more effective therapeutic strategies are urgently needed. MicroRNAs (miRNAs) have emerged as promising therapeutic tools and targets, as they play significant roles in regulating key cellular processes by suppressing gene expression. However, additive opportunities involving miRNAs have been underexplored. For example, both miR-34a and miR-200c individually suppress the development of different types of cancer, but the cellular effects of their combined actions remain unknown. Here, we show that miR-34a and miR-200c levels are reduced in breast tumors compared to adjacent normal tissues and that this additively predicts poor patient survival. In addition, in cell lines, miR-34a and miR-200c additively induce apoptosis and cell cycle arrest, while also inhibiting proliferation, invasion, migration, stemness and epithelial-to-mesenchymal transition (EMT). Mechanistically, both miRNA-34a and miR-200c directly target HIF1-α and subsequently downregulate VEGFR, MMP9 and CXCR4, although combined miRNA-34a and miR-200c delivery suppresses mouse xenograft tumor development as effectively as individual delivery. We establish a model, supported by in vitro and clinical data, which collectively suggest that the co-delivery of miR-34a and miR-200c represents a promising novel therapeutic strategy for breast cancer patients. [ABSTRACT FROM AUTHOR]

L-asparaginase is an enzyme capable of hydrolyzing the asparagine to aspartic acid and ammonia. L-asparaginase is widely used in the treatment of acute lymphoblastic leukemia (ALL) and other cancers. Here, for the first time, the effects of a novel yeast L-asparaginase from Yarrowia lipolytica were studied on human lung (A549) and breast cancer (MCF7) cell lines as the solid cancer cell lines in terms of cell growth and metastasis inhibition. Functional analysis showed the L-asparagine deprivation mediated anti-proliferation effects by apoptosis induction and changes in the expression of target genes involved in apoptosis and migration pathways. The qRT-PCR analysis showed the higher expression levels of pro-apoptosis genes, including Bax, P53, caspase 3, caspase 8, and down-regulation of Bcl-2 anti-apoptotic gene in treated cells. On the other hand, there was no increase in ROS production in the treated cells. However, L-asparaginase treatment was able to significantly induce autophagy activation in A549 cells. Besides, wound healing assay showed that L-asparaginase could considerably inhibit the migration of A549 and MCF7 cells. Taken together, our results suggested that Yarrowia lipolytica L-asparaginase might be considered for enzyme therapy against breast and lung cancers. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common type of malignancy in women. A subset of breast cancers show resistance to endocrine-based therapies. The estrogen receptor (ER) plays a critical role in developing hormone-dependent BC. Loss of ER contributes to resistance to tamoxifen therapy and may contribute to mortality. Thus, it is crucial to overcome this problem. Here, using luciferase reporter assays, qRT-PCR, and Western blot analyses, we demonstrate that the microRNA miR-486–5p targets HMGA1 mRNA, decreasing its mRNA and protein levels in ER-positive (ER+) BC cells. Consistently, miR-486–5p is significantly downregulated, whereas HMGA1 is considerably upregulated in ER+ BC samples. Remarkably, while both miR-486–5p and tamoxifen individually cause G2/M cell cycle arrest, combination treatment synergistically causes profound cell death, specifically in tamoxifen-resistant ER+ cells but not in tamoxifen-sensitive ER+ cells. Combined treatment with miR-486–5p and tamoxifen also additively reduces cell migration, invasion, colony formation, mammary spheroid formation and a CD24-CD44+ cell population, representing decreased cancer stemness. However, these phenomena are independent of the tamoxifen responsiveness of the ER+ BC cells. Thus, miR-486–5p and tamoxifen exhibit additive and synergistic tumor-suppressive effects, most importantly causing profound cell death specifically in tamoxifen-resistant BC cells. Therefore, our work suggests that combining miR-486–5p replacement therapy with tamoxifen treatment is a promising strategy to treat endocrine therapy-resistant BC. [ABSTRACT FROM AUTHOR]

To protect tissues and the organism from disease, potentially harmful cells are removed through programmed cell death processes, including apoptosis and necroptosis. These types of cell death are critically controlled by microRNAs (miRNAs). MiRNAs are short RNA molecules that target and inhibit expression of many cellular regulators, including those controlling programmed cell death via the intrinsic (Bcl-2 and Mcl-1), extrinsic (TRAIL and Fas), p53-and endoplasmic reticulum (ER) stress-induced apoptotic pathways, as well as the necroptosis cell death pathway. In this review, we discuss the current knowledge of apoptosis and necroptosis pathways and how these are impaired in cancer cells. We focus on how miRNAs disrupt apoptosis and necroptosis, thereby critically contributing to malignancy. Understanding which and how miRNAs and their targets affect cell death pathways could open up novel therapeutic opportunities for cancer patients. Indeed, restoration of pro-apoptotic tumor suppressor miRNAs (apoptomiRs) or inhibition of oncogenic miRNAs (oncomiRs) represent strategies that are currently being trialed or are already applied as miRNA-based cancer therapies. Therefore, better understanding the cancer type-specific expression of apoptomiRs and oncomiRs and their underlying mechanisms in cell death pathways will not only advance our knowledge, but also continue to provide new opportunities to treat cancer. Image 1 • MicroRNA as regulatory molecules in the intrinsic and extrinsic apoptosis pathway. • MicroRNAs as regulatory molecules in apoptosis by targeting p53. • MicroRNA regulate ER stress-induced apoptosis. • MicroRNA regulate programmed necrotic cell death. [ABSTRACT FROM AUTHOR]

The aim of this study is to determine the behavior of relative expression of Bcl-2, caspase-8, caspase-9, and caspase-3 genes of/in SK-MEL-3 cancer cells and explore molecular mechanisms responsible for the apoptosis response during an in vitro photodynamic therapy (PDT) with Zinc Phthalocyanine (ZnPc) using different doses of the light source. In this study, firstly the cytotoxic effects of ZnPc-PDT on SK-MEL-3 cells were evaluated. By irradiating the laser, ZnPc induced a significant amount of apoptosis on SK-MEL-3 cells in three IC 50 s including 0.064 ± 0.01, 0.043 ± 0.01, and 0.036 ± 0.01 μg/mL at the doses of 8, 16, and 24 J/cm 2 , respectively. Moreover, flow cytometry and QRT-PCR experiments were done. The high percentage of apoptotic cells was seen in the early apoptosis stage. The expression of Bcl-2 and caspase-8 genes at all doses of laser experienced an obvious reduction in comparison to the control group. On the other hand, although the expression of caspase-9 and caspase-3 genes remains almost constant at 8 J/cm 2 , but they faced an increment at 16 and 24 J/cm 2 doses. These data reveal caspase-dependent apoptosis in high and caspase-independent apoptosis in low doses of laser. Based on the results of present work, it can be suggested that the dose of the light source is a key factor in induction of caspase-dependent and caspase-independent apoptosis pathways following PDT. [ABSTRACT FROM AUTHOR]

[Display omitted] • BSA coated Pt nanoparticles was applied as both radiosensitizer and drug carrier. • In terms of morphology, nanoparticles appeared to be homogenous and monodispersed. • The results disclosed that designed nanoplatform due to the presence of Pt and BSA had ability to kill cancer cells effectively. Bovine serum albumin (BSA) coated platinum (Pt) nanoparticles (Pt@BSA NPs) were synthesized, followed by the conjugation of an anticancer drug (MTX) with the aim of chemoradiation therapy. The physical and chemical properties of Pt@BSA-MTX were evaluated by DLS, FESEM, STEM, UV–Vis and XRD. A release study was performed in the presence and absence of the proteinase K enzyme. In terms of morphology, nanoparticles appeared to be monodispersed and spherical. The size of nanoparticles was 7.4 ± 1.4 nm. Release behavior of Pt@BSA-MTX depended significantly on enzyme presence which accelerated and promoted the release of MTX. The improved chemoradiation was demonstrated in vitro using MTT, colony formation and apoptosis assays on mouse breast carcinoma cells (4T1). It was concluded that the combination of a nanoradiosensitizer with a chemotherapeutic agent resulted in superior anticancer activity after X-ray exposure. [ABSTRACT FROM AUTHOR]

Mitogen-activated protein kinase (MAPK) signal transduction, as a highly conserved signaling pathway, is reported to be involved in various biological events, including metabolic reprogramming, cell proliferation, survival, and differentiation. Mutations in key molecules involved in MAPK/ERK signaling and dysregulation of this pathway are very common events in various human malignancies, which make the MAPK signaling a crucial signaling pathway participating in the regulation of glucose uptake by malignant cells and tumorigenesis. MicroRNAs (miRNAs), as small non-coding RNAs, are critical regulators of gene expression that play key roles in cancer initiation and progression. On the other hand, these small RNAs mutually regulate the MAPK signaling which is often overexpressed in the case of cancer progression; suggesting that crosstalk between miRNAs and this signaling pathway plays a pivotal role in the development of human cancers. Some miRNAs such as miR-20b, miR-34c-3p, miR-152, miR-181a, and miR-302b through inhibiting MAPK signaling, and miR-193a-3p, miR-330-3p, and miR-592 by activating this signaling pathway, play imperative roles in tumorigenesis. Therefore, in this review, we aimed to focus on the interplay between miRNAs and MAPK signaling in the various steps of tumorigenesis, including metabolic regulation, cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. [Display omitted] [ABSTRACT FROM AUTHOR]