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Aims Acute myeloid leukemia (AML) initiation and progression have been attributed to subpopulations of self-renewing leukemia stem cells (LSCs), which contribute to progression, recurrence and therapeutic resistance in leukemia. Osteopontin (OPN) plays an important role in promoting survival and drug resistance in LSCs. The aim of this study was to explore OPN roles in modulating curcumin-mediated LSC enrichment and survival in AML cell lines and primary CD34 +/CD38 − bone-marrow-derived AML cells. Materials and methods The growth inhibitory effects of curcumin (CUR) were evaluated by MTT assay in U937 and CD34 + KG-1 AML cell lines as well as primary CD34 +/CD38 − bone-marrow derived AML cells isolated by MACS technique. The proportion of LSC markers (CD34, CD38 and CD123) were evaluated by flow cytometry. The expression levels of OPN, AKT, mTOR, PTEN, β-catenin and NF-κB were investigated by qRT-PCR. Short interfering RNA (siRNA) against OPN was used in AML cells incubated with or without CUR. Key findings Proportions of CD34 +/CD38 −/CD123 + and CD34 +/CD38 +/CD123 + LSCs compartment co-expressing an increased level of OPN could be enriched in AML cell lines and in patient's primary cells by CUR treatment. The expression levels of AKT, mTOR, PTEN, and β-catenin and NF-κB1, were also significantly up-regulated concurrently with OPN in the enriched CD34 + AML cells. Significance The increased in CUR-mediated OPN level is involved in a complex interplay of various signaling pathways resulting in cytoprotection and enrichment of CD34 + LSC compartment in CUR-treated AML cells. AKT/mTOR/PTEN/β-catenin/NF-kB signaling pathways may play roles in modulating OPN-mediated LSC cell survival and enrichment. [ABSTRACT FROM AUTHOR]

Highlights: [•] ATO treatment decreases proliferation of neuroblastoma SK-N-BE(2) and SK-N-MC cells. [•] Inhibition of PI3K or MAPK sensitizes NB cells to low doses of ATO. [•] Inhibition of PI3K and MAPK act synergistically with ATO in I-type NB cells. [•] Different subtypes of NB require different treatments. [ABSTRACT FROM AUTHOR]

Highlights: [•] hGH producing breast cancer cell line did not have inhibitory effect against the cytotoxicity of ATO. [•] Autocrine hGH increase sensitivity of mammary carcinoma cell to ATO-induced apoptosis. [•] ATO counteracts with hGH at transcriptional levels of genes involved in survival. [•] c-Myc may be an important common target of both hGH and ATO. [•] ATO treatment may be beneficial for treatment of patients with hGH positive tumors. [Copyright &y& Elsevier]

Abstract: In this study, we were aimed to evaluate the probable effect of the crud extract of Silybum marianum, with high polyphenolic content, on experimental nonalcoholic steatohepatitis (NASH). To induce NASH, a methionine and choline deficient (MCD) diet was given to N-Mary rats for 8 weeks. After NASH development, MCD-fed rats were divided into two groups: MCD groups received MCD diet and MCD+S group was fed MCD diet plus crude extract of S. marianum orally for 3 weeks. Control group was fed a normal diet for 11 weeks. Finally, all rats were sacrificed. Plasma alanine amino transferase (ALT) and aspartate amino transferase (AST) levels were evaluated. In addition, the following hepatic factors were also evaluated: liver histology, malondialdehyde (MDA) and reduced glutathione (GSH) contents, gene expressions of TNF-α and TGF-β and immunoblot evaluations of caspase-3, ERK/p-ERK, JNK/pJNK and p38/pp38. Histopathological evaluations of the liver samples revealed that treatment with the S. marianum extract has abated the severity of NASH among the MCD-fed rats. Also, a significant reduction was observed in the sera ALT and AST activities. In addition, the extract caused dramatic reduction in the elevated hepatic TNF-α and TGF-β mRNA and MDA levels along with an increase in the GSH content. Moreover, the plant extract treatments significantly lowered activation of procaspase-3 to active caspase-3 and also lowered the phosphorylated form of JNK among the same group of rats. These results suggest that the S. marianum crude extract beneficial effects on NASH are mainly due to its antioxidant and anti-inflammatory activities. [Copyright &y& Elsevier]

Reactive oxygen species (ROS) are essential mediators of crucial cellular processes including apoptosis, proliferation, survival and cell cycle. Their regulatory role in cancer progression has seen in different human malignancies such as acute myeloid leukemia (AML). AML patients suffer from high resistance of the tumors against routine therapeutics including ATO. ATO enhance reactive oxygen species levels and induce apoptosis and suppresses proliferation in AML cells. However, some pathways such as JAK2/STAT3 ease anti-tumor activity of ATO by reducing reactive oxygen species amount and protecting the cell from apoptosis. In the present study, we use ruxolitinib (potent JAK2 inhibitor) to increase the sensitivity of AML cells to ATO treatment. We test, the effect of this combination on metabolic activity, proliferation, colony formation, cell cycle distribution, apoptosis, oxidative stress and DNA damage. Our results showed that combination of ATO with ruxolitinib synergistically reduced metabolic activity, proliferation and survival of AML cell lines. This combination induced G1/S cell cycle arrest because of reactive oxygen species elevation and GSH reduction. Besides, enhancement of reactive oxygen species increased apoptosis rate in combination samples. We uncovered that the synergistic anti-tumor effect of ATO and ruxolitinib in AML cells mediates via reactive oxygen species elevation and DNA damage. Overall, our results show that the combinatorial therapy of AML cells is more effective than solo-targeted therapy. [ABSTRACT FROM AUTHOR]

• The present study reviews macrophage phagocytosis regulation in response to tumors. • This review outlines recent advances of modulating macrophage phagocytosis in cancers. • We concentrate on the emerging role of CAR-engineered macrophages against solid tumors. • We reviewed the exploit of nanoparticles in macrophages-mediated anticancer effects. Immunotherapy has been developing at an unprecedented speed with promising therapeutic outcomes in the wide spectrum of cancers. Up until now, most immunotherapies have focused on adaptive immunity; however, investigating the potential of macrophage phagocytosis and consequent adaptive immune cross-priming has led to a growing interest in exploiting macrophages in cancer therapy. In light of the positive evidence from preclinical studies and early clinical data, targeting macrophage phagocytosis has become a promising therapeutic strategy. Here, we review therapies based on harnessing and amplifying macrophage phagocytosis, such as blocking phagocytosis checkpoints and exploiting nanoparticles as efficient approaches in elevating macrophages-mediated phagocytosis. The present study introduces CAR-macrophage as the state-of-the-art modality serving as the bridge between the innate and adaptive immune system to mount a superior anti-tumor response in the treatment of cancer. We also take a look at the recent reports of therapies based on CAR-engineered macrophages with the hope of providing a future research direction for expanding the application of CAR-macrophage therapy. [ABSTRACT FROM AUTHOR]

Numerous links exist between inflammation and tumor development. Toll-like receptor 4 (TLR4) expression by tumor cells can be a contributing factor that promotes tumor cell proliferation, survival, migration, and metastasis. In this study, we explored the impact of TLR4 inhibition using TAK-242, a specific inhibitor of TLR4, on the invasion properties of ovarian (A2780CP, 2008C13, SKOV3, and A2780S) and breast (MCF7, SKBR3, MDA-MB-231, and BT-474) cancer cell lines. Six out of eight cell lines expressed TLR4 and its downstream mediators (MyD88, NF-ĸB1, and RELB), indicating that these cell lines could be proper candidates for the TLR4 inhibition. TAK-242 induced a cytotoxic effect on all tested cell lines; however, a different cell sensitivity pattern was noticeable. Interestingly, in the TLR4-expressing cell lines, there was a significant correlation between the TLR4/MyD88 expressions and the cancer cell response to TAK-242: the higher the expression, the higher the IC 50. To the best of our knowledge, no study has addressed the effects of TAK-242 on invasive abilities of cancer cells and our study suggests for the first time that TAK-242 could considerably decrease invasion properties of ovarian and breast cancer cell lines. We found that not only did TAK-242 reduce the enzymatic activity of MMP2 and MMP9, but also down-regulated gene expressions of epithelial-mesenchymal transition (EMT)-related genes. In sum, it seems that targeting TLR4 using TAK-242 possesses novel promising potential in cancer treatment strategies and may prevent invasion in patients suffering from ovarian and breast cancers, especially in those with over-expression of TLR4. [ABSTRACT FROM AUTHOR]

Abstract Telomerase-mediated immortalization and proliferation of tumor cells is a promising anti-cancer treatment strategy and development of potent telomerase inhibitors is believed to open new window of treatments in human malignancies. In the present study, we found that BIBR1532, a small molecule inhibitor of human telomerase, exerted cytotoxic effects on a panel of human cancer cells spanning from solid tumors to hematologic malignancies; however, as compared with solid tumors, leukemic cells were more sensitive to this inhibitor. This was independent of molecular status of p53 in the leukemic cells. The results of a miRNA PCR array revealed that BIBR1532-induced cytotoxic effects in NB4, the most sensitive cell line, was coupled with alteration in a substantial number of cancer-related miRNAs. Interestingly, most of these miRNAs were found to act as tumor suppressors with validated targets in cell cycle or nuclear factor (NF)-κB–mediated apoptosis. In accordance with a bioinformatics analysis, our experimental studies showed that BIBR1532-induced apoptosis is mediated, at least partly, by inhibition of NF-κB. Moreover, we found that the alteration in the expression of miRNAs was coupled with the alteration in the cell cycle progression. To sum up with, a straightforward interpretation of our results is that telomerase inhibition using BIBR1532 not only induced CDKN1A-mediated G1 arrest in NB4, but also resulted in a caspase-3-dependent apoptotic cell death mostly through suppression of NF-κB axis. [ABSTRACT FROM AUTHOR]

Abstract While a batch of efforts are fastened on synthesizing the novel targeted anti-cancer agents, recent investigations have achieved a breakthrough in identifying a favorable anti-tumor activity for some supportive drugs, which their safety have been confirmed thus far. The results of the present study highlighted the efficacy of Aprepitant, an oral antagonist of the neurokinin-1 receptor (NK1R), against both APL (NB4) and pre-B ALL (Nalm-6) cell lines; however, a differential sensitivity pattern was found in these cells. To the best of our knowledge, this is the first time that the molecular mechanisms of resistance to Aprepitant have been investigated and, herein, we proposed that the effectiveness of Aprepitant could be overshadowed, at least partially, through over-activated nuclear factor-κB in Nalm-6 pre-B ALL cells. In contrast to Nalm-6, the cytotoxic property of Aprepitant in NB4 was divulged at the lower concentrations. Of particular interest, we found that the cytotoxicity of the inhibitor became even more evident in the synergistic experiments, where an enhanced reduction in viability was noted after treatment of NB4 cells with ATO-plus-Aprepitant. The stimulatory effect of NK1R inhibition on ATO cytotoxicity is probably mediated through up-regulation of p73, which can subsequently engage p21 and NF-κB pathway via transcriptional suppression of c-Myc. Taken together, the present study suggests that inhibition of NK1R using Aprepitant, either alone or in combination with chemotherapeutic drugs, could be a novel therapeutic strategy for the treatment of acute leukemia, especially APL, that may be clinically accessible in the near future. [ABSTRACT FROM AUTHOR]

Glioblastoma multiform (GBM) accounts for the most common form of primary brain tumors with very limited survival rate. Drug resistance is the main challenges for good prognosis of GBM patients. Arsenic trioxide (ATO) as a multifunctional drug has been investigated for the treatment of several solid tumors. Amplification/overexpression of the epidermal growth factor receptor (EGFR) gene as a signature genetic abnormality of GBM tumors can be a chemoresistance mechanism. In this study, we use erlotinib as an EGFR inhibitor to increase the sensitivity of GBM cell lines to ATO treatment. We evaluate the effects of this combination on metabolic activity, viability, cell proliferation, colony formation, cell cycle distribution, migration, oxidative stress and reactive oxygen species production. Our results showed that combination of ATO with erlotinib synergistically reduced metabolic activity, proliferation and colony forming potential in treated GBM cell lines. This combination induced G2/M cell cycle arrest. We also found that wound-healing rate were suppressed only after combination treatment. In addition, apoptotic cell death and reactive oxygen species content significantly increased after combination treatment. The combination of ATO and erlotinib considerably interfere with survival and migration of treated GBM cell lines through cell cycle arrest and reactive oxygen species production. Present study uncovered that EGFR inhibition could overcome the resistance of glioblastoma cells to ATO treatment. [ABSTRACT FROM AUTHOR]

The intertwining between cancer pathogenesis and perturbation of multitude signaling pathways ushered the cancer therapeutic approaches into an unbounded route of targeted therapies. For the nonce and among the plethora of promising inhibitors, intense interest has focused on small molecules targeting different component of PI3K axis. Intrigued by the constant activation of PI3K in leukemia, this study aimed to investigate the effects of BKM120, as the excelled member of pan PI3K inhibitors, in a panel of hematologic malignant cell lines. The resulting data showed that BKM120 exerted a concentration-dependent growth suppressive effect; however, IC 50 values varied among the tested cells. Our results outlined that the blockage of PI3K in NB4, as the most sensitive cell line, resulted in a caspase-3-dependent apoptosis probably through NFκB-mediated suppression of c-Myc and hTERT. As far we are aware, to date, there have been no reports of BKM120 effect on enzymatic repression of telomerase, and this study represents for the first time that the anti-proliferative effect of the inhibitor on NB4 is mediated by down-regulation of telomerase; shedding new light on the novel mechanism of action of BKM120. [ABSTRACT FROM AUTHOR]

Background The Hypermethylation of Ras association domain family (RASSF) often plays a key role in malignant progression of solid tumors; however, their impact on the prognosis and survival of adult ALL patients remain elusive. Methods The frequency of the promoter methylation pattern of RASSF6 and RASSF10 were analyzed in the peripheral blood (PB) samples taken at the time of diagnosis of 45 ALL patients. The methylation-specific PCR (MSP) assay was used to detect the DNA methylation patterns. Results RASSF6 was frequently hypermethylated in patients diagnosed with pre-B-ALL (90.9%) and B-ALL (87.5%), followed by T-ALL (66.7%); whereas, RASSF10 methylation was more confined to T-ALL (80%) as compared to B-ALL (25%) and pre-B ALL (9.1%) patients. Moreover, hypermethylation of RASSF6 was significantly associated with a poor prognosis and shorter overall survival (OS) in patients with pre-B-ALL (log-rank test; P = 0.041). Conclusion RASSF6 and RASSF10 were frequently hypermethylated in the samples at the time of diagnosis of adult ALL patients. Our study represents the first report of methylation of RASSF6 at a high frequency in patients with pre-B ALL. Furthermore, hypermethylation of RASSF6 was significantly associated with inferior overall survival in pre-B ALL patients. It may suggest that the frequent epigenetic inactivation of RASSF6 plays an important role in the pathogenesis and progression of pre-B-ALL. [ABSTRACT FROM AUTHOR]

The impressive advances carried out in designing pharmacological strategies with the aim of telomerase inhibition in cancers emerged a consensus that telomerase-targeted therapies could be exciting prospect in repertoire of future cancer strategies. The results of the present study indicated that targeting telomerase using an oligonucleotide-based molecule against human telomerase RNA template (hTR ASODN) reduced the survival rate of NB4 cells and induced a caspase-3-dependent apoptosis. Our finding was even noticeable in the synergistic experiments, where we found an enhanced reduction in the viability of the cells after short-term treatment with ATO in combination with the inhibitor. The resulting data delineated that short-term treatment of the cells with hTR ASODN either as single agent or in combination with ATO resulted in apoptotic cell death through activation of DNA damage response via up-regulation of p73 and ATM coupled with down-regulation of c-Myc. Moreover, we found that induction of p21 and subsequent disturbance of the death promoter to death repressor genes may contribute to the enhanced growth suppressive effect of the drugs combination. Overall, our findings support the idea that telomerase activity may have pivotal role in attenuating ATO effectiveness and combination of ATO with telomerase inhibitor seems to be a novel promising strategy, which may increase APL cure rates. [ABSTRACT FROM AUTHOR]

Genetic and laboratory experiments have brought remarkable advances in management of human malignancies, which not only revolutionized the understanding of the disease, but also led to development of novel and effective targeted therapies against specific deregulated pathways. This study aimed to investigate anti-cancer effects of Idelalisib, a potent PI3K-δ inhibitor, in a panel of hematological cell lines. The resulting data showed that Idelalisib decreased cell survival in all the tested cell lines; however, as compared to NB4, viability of other cell lines, irrespective of their molecular characteristics or even the compensatory activation of MEK/ERK pathway, was inhibited at higher concentrations. This study suggests for the first time that there is a significant correlation between relative response to Idelalisib and basal expression levels of anti-apoptotic genes, in particular survivin and MCL-1. Intriguingly, we found that Idelalisib-induced apoptosis in NB4, as the most sensitive cell line with the lowest expression level of the aforementioned genes, is executed probably via alteration in the transcriptional level of apoptosis-related genes coupled with p21-mediated caspase-3 activation. Moreover, the lower concentrations of Idelalisib combined with arsenic trioxide (ATO) produced synergistic anti-cancer effect in APL-derived NB4 cells. Overall, due to the pharmacologic safety of Idelalisib and its broad clinical effectiveness in chronic lymphoproliferative disorders, our study suggests that this inhibitor is a promising agent for the treatment of acute promyelocytic leukemia, either as single agent or in a combined-modality strategy. [ABSTRACT FROM AUTHOR]

Aims Cell cycle dysregulation is important in tumorigenesis. Transcriptional silencing of cell cycle regulatory genes, due to DNA methylation, is a common epigenetic event in malignancies. As 2 O 3 has been shown to induce cell cycle arrest and also to be a potential hypomethylating agent. Our study aimed to investigate DNA methylation patterns of cell cycle regulatory genes promoters, the effects of Arsenic trioxide (As 2 O 3 ) on the methylated genes and cell cycle distribution in colorectal cancer (CRC) cell lines. Main methods The methylation-specific PCR (MSP) and/or restriction enzyme-based methods were used to study the promoter methylation patterns of 24 cell cycle regulatory genes in CRC cell lines. Gene expression level and cell cycle distribution were determined by Real-time PCR and flow cytometric analyses, respectively. Key findings Our methylation analysis indicated that only promoters of RBL1 (p107), CHFR and p16 genes were aberrantly methylated in three cell lines. As 2 O 3 significantly decreased DNA methylation in promoter regions of these genes and restored their expression. We found that As 2 O 3 significantly reduced the expression of DNA methyltransferase 1 (DNMT1) and increased arsenic methyltransferase (AS3MT). Furthermore, As 2 O 3 altered transcriptional activity of several unmethylated cell cycle regulatory genes including cyclin B 1, E1, D1, GADD45A and p21. Cell cycle flow cytometry analysis showed As 2 O 3 induced G2/M arrest in all three cell lines. Significance These data suggest that demethylation and alteration in the expression level of the cell cycle-related genes may be possible mechanisms in As 2 O 3 -induced cell cycle arrest in colorectal cancer cells. [ABSTRACT FROM AUTHOR]

Increasing number of genetic and cancer biology studies indicated a prominent role for tachykinin NK 1 receptor (NK 1 R) in cancer cell growth and survival. Considering the fact that neoplastic lymphoid precursors in acute lymphoblastic leukemia (ALL) carry a three- to four-fold NK 1 R expression as compared to normal lymphocytes, using NK 1 R antagonist seems to be noteworthy in the treatment of ALL patients. In this study, we found that inhibition of NK 1 R with aprepitant, a selective high-affinity antagonist of the human NK 1 R, exerts cytotoxic and anti-proliferative effects against pre-B ALL-derived Nalm-6 cells either as single drug or in combination with doxorubicin. Our data showed that treatment of the cells with the inhibitor resulted in apoptotic cell death, at least partly, through abrogation of PI3K/Akt pathway, as revealed by the reduction of phospho/total Akt ratio. In agreement with the inhibitory effect on Akt, we also found that aprepitant increased the expression level of p21 and p27, which in turn leads to the induction of G1 cell cycle arrest. Overall, this study recommends mechanistic pathways by which inhibition of NK 1 R can augment apoptotic cell death through a plausible p53-dependent pathway rather than NF-κB-depended mechanism in pre-B ALL cells; however, further studies are needed to better characterize the application of NK 1 R inhibition in clinical cancer treatment. [ABSTRACT FROM AUTHOR]

Complex interplay of intracellular signaling networks, spanning from the extracellular environment to the nucleus, orchestrate normal cell growth and survival. Dysregulation of such signals contributes to malignant transformation, thereby giving the cancer cells a survival advantage, but also could be exploited for new anticancer interventions. The aim of this study was to investigate the effects of pan class-I PI3K inhibitor NVP-BKM120 on two distinct acute leukemia cell lines, NB4 (with mutant p53) and Nalm-6 (with wild-type p53). Our data highlighted the efficacy of the inhibitor against APL and pre B ALL cell lines; however, we failed to find an obvious correlation between p53 status and the sensitivity of leukemic cells to NVP-BKM120. Real-time PCR analysis revealed a significant up-regulation of p53 target genes in Nalm-6 cells, indicating a p53-dependent mechanism involved in NVP-BKM120 cytotoxicity. On the other hand, cytotoxic effects in mutant p53-expressing NB4 cells seem to be mediated mostly by the inhibition of the PI3K/Akt/NF-κB axis. In conclusion, we suggest NVP-BKM120 induces apoptosis through p53-dependent and -independent mechanisms, indicating the potential application of the inhibitor in both wild-type and deficient p53-expressing leukemic cells. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (ATO), a traditional Chinese medicine, has long been of biomedical interest and is largely used for treatment of a broad spectrum of cancers. Melatonin, a naturally occurring indoleamine synthesized in the pineal gland, has been considered as a biomarker for endocrine-dependent tumors, particularly breast cancer. An increasing number of studies indicate that melatonin could be an attractive candidate for combined therapy due to its anti-oxidant and cytotoxic activities. The aim of this study was to investigate the potentiating effect of melatonin on ATO-induced apoptosis in estrogen receptor (ER)-positive breast cancer cell line, MCF-7. Our data highlighted for the first time that pre-treating MCF-7 cells with physiological concentration of melatonin substantially augmented the cytotoxic effects of ATO as compared with either agent alone. Real-time PCR analysis revealed that apoptosis induction by the drugs combination was associated with increased p53 transcriptional activity followed by the elevated molecular ratio of Bax/Bcl-2. Moreover, induced p21, subsequent G1 cell cycle arrest and transcriptional suppression of survivin-mediated c-Myc and hTERT expression may contribute in the enhanced growth suppressive effect of ATO-plus-melatonin. Due to the safety profile of melatonin, our study suggests that using melatonin in combination with ATO might provide insight into a novel adjuvant therapy and may confer advantages for breast cancer treatment. [ABSTRACT FROM AUTHOR]

Glioblastoma (GB) is the most aggressive type of brain tumor. Rapid progression, active angiogenesis, and therapy resistance are major reasons for its high mortality. Elevated expression of members of the vascular endothelial growth factor (VEGF) family suggests that anti-VEGF therapies may be potent anti-glioma therapeutic approaches. Here, we evaluated the anti-tumor activity of cediranib, a pan inhibitor of the VEGF receptors, on GB cells. Anti-proliferative effects of cediranib were determined using MTT, crystal-violet staining, clonogenic and anoikis resistance assays. Apoptosis induction was assessed by Annexin V/PI staining and Western blot analysis and aggressive abilities of GB cells were investigated using cell migration/invasion assays and zymography. Small-interfering RNA (siRNA)-mediated Knockdown was used to study resistance mechanisms. The anti-proliferative and apoptotic effects of cediranib in combination with radiotherapy, temozolomide, bevacizumab were also evaluated using MTT, Annexin V/PI staining and Western blot analysis for cleaved PARP-1. Cediranib reduced GB cell proliferation, induced apoptotic cell death and inhibited the aggressive abilities of GB cells. Cediranib synergistically increased the anti-proliferative and apoptotic effects of radiotherapy and bevacizumab and augmented the sensitivity of GB cells to temozolomide chemotherapy. In addition, knockdown of MET and AKT potentiated cediranib sensitivity in cediranib-resistant GB cells. These findings suggest that cediranib, alone or in combination with other therapeutics, is a promising strategy for the treatment of GB and provide a rationale for further investigation of the therapeutic potential of cediranib for the treatment of this fatal malignancy. [ABSTRACT FROM AUTHOR]

Abstract: Since all-trans retinoic acid (ATRA) has shown promising results in differentiation therapy, the present study was designed to investigate the effects of ATRA on thyroid carcinoma and to evaluate the effectiveness of ATRA in redifferentiation induction of thyroid carcinoma. Therefore, we investigated cell growth rate, morphological and nuclear: cytoplasmic ratio, adherent-dependent growth, response to chemotherapy drug following differentiation, T3 and T4 measurement, and critical genes expression pattern. Papillary cell line showed more growth inhibition by ATRA, in addition, mesenchymal and spindle-shape of 8305C cells changed to polygonal. Additionally, high nuclear: cytoplasmic ratio of anaplastic decreased significantly. Redifferentiation significantly suppressed the anchorage-dependent growth in the both cell lines in a dose-dependent manner, potentiated the arsenic trioxide (ATO) effects in anaplastic and papillary cell lines. Furthermore, reduction in the expression of stemness, and invasion related genes was observed in the both cell lines. Altogether, ATRA treatment could hold the aggressive behavior of thyroid carcinoma in restraint and/or potentiate the effect of chemotherapy drug ATO. [Copyright &y& Elsevier]

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with the highest mortality rate and a poor 5-year survival rate. The majority of the cases are diagnosed in advanced stages when the disease has spread, which makes the tumor inoperable. Due to the antigenic essence of lung tumor cells, immunotherapy is a novel area and has exhibited remarkable results in this malignancy. Immune checkpoint inhibitors are inhibitory molecules that disrupt immune checkpoint signaling pathways whether in the immune cells or tumor cells. Tremelimumab and ipilimumab (CTLA-4 blockers), pembrolizumab and nivolumab (PD-1 blockers), and durvalumab, avelumab, and atezolizumab (PD-L1 blockers) are FDA-approved and improve the survival and objective response of NSCLC patients. Despite this, over-stimulation of the immune system via the immune checkpoint therapy is a double-edged sword that causes a spectrum of adverse events from moderate to life-threatening. Nanomedicine considerably impacts the way of diagnosis and treatment of tumors to overcome treatment-related challenges. Accordingly, nanoparticle-based immune checkpoint inhibitor therapy increases the local concentration of immune checkpoint inhibitors while reduces the side effects, which result in boosting the anti-tumor immunity against various types of malignancies, including NSCLC. The current review provides comprehensive information about immune checkpoint therapy in NSCLC, their efficacy, and their safety profile. Besides, recent advances in nanoparticle-based immune checkpoint therapy and its limitation are discussed. [ABSTRACT FROM AUTHOR]

Ovarian cancer, characterized by rapid growth and asymptomatic development in the early stage, is the fifth common cancer in women. The deregulated expression of c-Myc in more than 50% of human tumors including ovarian cancer makes this oncogenic master transcription factor a potential therapeutic target for cancer treatment. In the present study, we evaluated the anti-tumor effects of 10058-F4, a small molecule c-Myc inhibitor, on ovarian cancer cells. We found that 10058-F4 not only inhibited the proliferation and clonal growth of ovarian cancer cells but also enhanced the cytotoxic effects of chemotherapeutic drugs. Our results also revealed that c-Myc inhibition using 10058-F4 increased the intracellular reactive oxygen species production coupled with suppressed expression of hTERT. RT-qPCR analysis indicated that 10058-F4 enhanced the mRNA levels of the forkhead box O (FOXO) family of transcription factors, including FOXO1, 3, and 4. Moreover, 10058-F4 induced G1 cell cycle arrest in 2008C13 ovarian cancer cells, along with increased expression of some key targets of FOXOs involved in the regulation of cell cycle such as p15, p21, p27, and GADD45A. The results of our study also showed that the 10058-F4-induced apoptosis in 2008C13 cell line was associated with the upregulation of FOXO downstream genes, including PUMA, Bim, and FasL. In conclusion, our results, for the first time, suggest that the anti-tumor effects of 10058-F4 in ovarian cancer cells might be mediated through upregulation of FOXO transcription factors and their key target genes involved in G1 cell cycle arrest, apoptosis, and autophagic cell death. [Display omitted] [ABSTRACT FROM AUTHOR]

Due to its potent anti-tumor activity, well-investigated pharmacokinetic properties and safety profile, disulfiram (DSF) has emerged as a promising candidate for drug repurposing in cancer therapy. Although several molecular mechanisms have been proposed for its anti-cancer effects, the precise underlying mechanisms remain unclear. In the present study, we showed that DSF inhibited proliferation of cancer cells by inducing reactive oxygen species (ROS) production, a G1 cell cycle arrest and autophagy. Moreover, DSF triggered apoptosis via suppression of the anti-apoptotic protein survivin. To elucidate the mechanisms for the anti-proliferative activities of DSF, we applied a 2-DE combined with MALDI-TOF-MS/MS analysis to identify differentially expressed proteins in breast cancer cells upon treatment with DSF. Nine differentially expressed proteins were identified among which, three candidates including calmodulin (CaM), peroxiredoxin 1 (PRDX1) and collagen type I alpha 1 (COL1A1) are involved in the regulation of the AKT signaling pathway. The results of western blot analysis confirmed that DSF inhibited p-AKT, suggesting that DSF induces its anti-tumor effects via AKT blockade. Moreover, we found that DSF increased the mRNA levels of FOXO1 , FOXO3 and FOXO4 , and upregulated the expression of their target genes involved in G1 cell cycle arrest, apoptosis and autophagy. Finally, DSF potentiated the anti-proliferative effects of well-known chemotherapeutic agents such as arsenic trioxide (ATO), doxorubicin, paclitaxel and cisplatin. Altogether, these findings provide mechanistic insights into the anti-growth activities of DSF. • Disulfiram (DSF) significantly inhibits the growth and survival of cancer cells. • Nine differentially expressed proteins were identified upon treatment with DSF. • DSF induces antitumor effects via blockade of AKT phosphorylation. • DSF increases the mRNA levels of FOXO1, FOXO3, FOXO4 and their key target genes. • DSF enhances the cytotoxic effects of a wide range of chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

[Display omitted] • MSC therapy can attenuate cytokine storm and enhance alveolar fluid clearance. • MSC-derived EVs impede cytokine overproduction leading to immunity reconstitution. • Exosomes seem to be safer as they cannot form a tumor or lead to emboli formation. • Source of MSC, administration route, and optimal dose should be carefully evaluated. • Clinical-grade production and stability during MSC preparation are major challenges. In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan city, Hubei province, China. Rapidly escalated into a worldwide pandemic, it has caused an unprecedented and devastating situation on the global public health and society economy. The severity of recent coronavirus disease, abbreviated to COVID-19, seems to be mostly associated with the patients' immune response. In this vein, mesenchymal stromal/stem cells (MSCs) have been suggested as a worth-considering option against COVID-19 as their therapeutic properties are mainly displayed in immunomodulation and anti-inflammatory effects. Indeed, administration of MSCs can attenuate cytokine storm and enhance alveolar fluid clearance, endothelial recovery, and anti-fibrotic regeneration. Despite advantages attributed to MSCs application in lung injuries, there are still several issues __foremost probability of malignant transformation and incidence of MSCs-related coagulopathy__ which should be resolved for the successful application of MSC therapy in COVID-19. In the present study, we review the historical evidence of successful use of MSCs and MSC-derived extracellular vesicles (EVs) in the treatment of acute respiratory distress syndrome (ARDS). We also take a look at MSCs mechanisms of action in the treatment of viral infections, and then through studying both the dark and bright sides of this approach, we provide a thorough discussion if MSC therapy might be a promising therapeutic approach in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Despite the remarkable anti-proliferative effects of Arsenic trioxide (ATO) in breast cancer cells, the requirement of high, toxic concentrations to induce apoptosis may cause serious side effects in patients. In the present study, we aimed to use BIBR1532, an hTERT inhibitor, in combination with ATO to sensitize MCF7 and MDA-231 cells to lower concentrations of ATO. Breast cancer cell lines MCF7 and MDA-231 were cultured and treated with different doses of ATO and BIBR1532 for 48 h and its effects on cell survival and proliferation were analyzed by MTT, crystal violet staining, colony formation assay, cell cycle, AnnexinV/PI and Real-time PCR tests. ATO and BIBR1532 synergistically inhibited proliferation and colony-forming ability of breast cancer cells. Besides, BIBR1532 augmented ATO-induced cytotoxic effects via triggering G1 cell cycle arrest and induction of apoptosis coupled with the down-regulation of NF-κB target genes that were involved in cell cycle progression (e.g. CCND1 and CDK6) and prevention of apoptosis such as Bcl-2, Bcl-xl, c-IAP2, and Survivin Respectively. Moreover, ATO-BIBR1532 significantly reduced the mRNA expression level of RELA, NFKB1, and several validated target genes of the NF-κB signaling pathway including NFKBIA, VEGFC, c-Myc, and hTERT. The combination of ATO and BIBR1532 synergistically induced its anti-proliferative effect in breast cancer cells by targeting the two key cancer-related pathways, hTERT and NF-κB, and disrupting their feed-forward loop at the same time which result in the reduction of NF-κB transcriptional activity and subsequent down-regulation of its target genes. [ABSTRACT FROM AUTHOR]

Prostate Cancer is the second cause of cancer-related death in men and development of metastatic castration-resistant prostate cancer (mCRPC) is the major reason for its high mortality rate. Despite various treatments, all patients succumb to resistant disease, suggesting that there is a pressing need for novel and more efficacious treatments. Members of the vascular endothelial growth factor (VEGF) family play key roles in the tumorigenesis of mCRPC, indicating that VEGF-targeted therapies may have potential anti-tumor efficacy in this malignancy. However, due to compensatory activation of other family members, clinical trials with single-targeted VEGF inhibitors were discouraging. Here, we determined the anti-neoplastic activity of Cediranib, a pan-VEGF receptor inhibitor, in the mCRPC cell lines. Anti-growth effects of Cediranib were studied by MTT and BrdU cell proliferation assays and crystal violet staining. Annexin V/PI, radiation therapy and cell motility assays were carried out to examine the effects of Cediranib on apoptosis, radio-sensitivity and cell motility. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were conducted to determine the molecular mechanisms underlying the anti-tumor activity of Cediranib. Cediranib decreased cell viability and induced apoptosis via inhibition of the anti-apoptotic proteins. Combination with Cediranib synergistically increased Docetaxel sensitivity and potentiated the effects of radiation therapy. Furthermore, Cediranib impaired cell motility via decrease in the expression of the epithelial-to-mesenchymal transition markers. These findings suggest that Cediranib may have anti-tumor activity in mCRPC cells and warrant further investigation on the therapeutic activity of this pan-VEGF receptor inhibitor in mCRPC. [ABSTRACT FROM AUTHOR]

Gastric adenocarcinoma (GAC), the most common malignancy of the stomach, is the fourth most common and the second cause of cancer-related death worldwide. Although HER family plays a cardinal role in tumorigenesis of GAC, trastuzumab is the only approved anti-HER drug for this malignancy and development of resistance to trastuzumab is inevitable. Additionally, single-targeted HER inhibitors have demonstrated limited activity in GAC. Hence, there is a pressing need to devise more efficacious anti-HER therapeutic strategies. Here, we examined the anti-tumor activity of neratinb, a pan-HER inhibitor, on GAC cells. Anti-proliferative effects of neratinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and anoikis resistance and wound healing assays were carried out to examine the effects of neratinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) analyses were applied to further investigate the anti-tumor activity of neratinib. We found that neratinib sensitized GAC cells to 5FU, carboplatin and oxaliplatin. Moreover, we found that neratinib was synergistic with trametinib (an approved MEK inhibitor) and foretinib (a c-MET inhibitor) and potentiated radio-sensitivity of GAC cells. Furthermore, we found that neratinib diminished GAC cell proliferation along with downregulation of FOXM1 and its targets. Additionally, neratinib induced apoptosis along with upregulation of pro-apoptotic and downregulation of anti-apoptotic genes. Treatment with neratinib attenuated invasive ability of GAC cells as shown by reduced anoikis resistance, downregulation of EMT markers, and reduced width in scratch assay. Our findings indicate that neratinib provides the therapeutic potential in the treatment of GAC. [ABSTRACT FROM AUTHOR]