Sanguinarine Induces Apoptosis in Papillary Thyroid Cancer Cells via Generation of Reactive Oxygen Species.

Sanguinarine (SNG), a natural compound with an array of pharmacological activities, has promising therapeutic potential against a number of pathological conditions, including malignancies. In the present study, we have investigated the antiproliferative potential of SNG against two well-characterized papillary thyroid cancer (PTC) cell lines, BCPAP and TPC-1. SNG significantly inhibited cell proliferation of PTC cells in a dose and time-dependent manner. Western blot analysis revealed that SNG markedly attenuated deregulated expression of p-STAT3, without affecting total STAT3, and inhibited growth of PTC via activation of apoptotic and autophagy signaling cascade, as SNG treatment of PTC cells led to the activation of caspase-3 and caspase-8; cleavage of PARP and activation of autophagy markers. Further, SNG-mediated anticancer effects in PTC cells involved the generation of reactive oxygen species (ROS) as N-acetyl cysteine (NAC), an inhibitor of ROS, prevented SNG-mediated antiproliferative, apoptosis and autophagy inducing action. Interestingly, SNG also sensitized PTC cells to chemotherapeutic drug cisplatin, which was inhibited by NAC. Finally, SNG suppressed the growth of PTC thyrospheres and downregulated stemness markers ALDH2 and SOX2. Altogether, the findings of the current study suggest that SNG has anticancer potential against PTC cells as well its derived cancer stem-like cells, most likely via inactivation of STAT3 and its associated signaling molecules

The Role of Extracellular Vesicles as Modulators of the Tumor Microenvironment, Metastasis and Drug Resistance in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide, with high morbidity and mortality rates. A number of factors including modulation of the tumor microenvironment, high metastatic capability, and resistance to treatment have been associated with CRC disease progression. Recent studies have documented that tumor-derived extracellular vesicles (EVs) play a significant role in intercellular communication in CRC via transfer of cargo lipids, proteins, DNA and RNAs to the recipient tumor cells. This transfer influences a number of immune-related pathways leading to activation/differentiation/expression of immune cells and modulation of the tumor microenvironment that plays a significant role in CRC progression, metastasis, and drug resistance. Furthermore, tumor-derived EVs are secreted in large amounts in biological fluids of CRC patients and as such the expression analysis of EV cargoes have been associated with prognosis or response to therapy and may be a source of therapeutic targets. This review aims to provide a comprehensive insight into the role of EVs in the modulation of the tumor microenvironment and its effects on CRC progression, metastasis, and drug resistance. On the other hand, the potential role of CRC derived EVs as a source of biomarkers of response and therapeutic targets will be discussed in detail to understand the dynamic role of EVs in CRC diagnosis, treatment, and management

Is there a role for the pharmacist in screening for metabolic syndrome?

Evidence for a pharmacist role in the screening of MetS has been shown to be effective in at risk populations. Despite migrants being an at risk group for the development of MetS, no literature has described screening of migrants by pharmacists. The aim of this research was therefore to identify the impact of the pharmacist role in screening migrants on arrival in a Middle Eastern country and following 24 months of residency in the Middle East. This was a prospective longitudinal observational study. Migrants aged 18–65 years were informed about the research by pharmacists and consented to participate. Baseline screening for MetS risk factors was conducted. Parameters included glycated haemoglobin (HbA1c), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), blood pressure (BP) and waist circumference (WC). All migrants with identified metabolic abnormalities at this screening stage were referred to physicians by the pharmacist for further management. Migrants with normal metabolic parameters at baseline were invited to be re-screened by pharmacists. This will allow identification of an increase in any incidence of MetS, and will allow for earlier intervention and management. Of the 1379 identified migrants, 460 consented to participate; 70% were men and 82.2% (378) were Asians. Pharmacist-led screening revealed 13.9% (64) with abnormal BP, 6.7% (31) with pre-diabetes, 21.4% (91) with elevated TG, 25% (115) with low HDL–C and 47% (219) with high WC. 16% (75) were found to have MetS and were referred to the physician for follow-up. These participants were consequently identified as at risk for development of MetS at a much earlier stage. A total of 199 migrants with normal metabolic parameters will be followed-up following 24 months of residency in the Middle East. Throughout the study, migrants with metabolic abnormalities were referred by pharmacists to physicians for further management. The study indicates that pharmacist screening is effective for early identification and potential early management of MetS in this migrant population

Anticancer activity of Neosetophomone B by targeting AKT/SKP2/MTH1 axis in leukemic cells

Neosetophomone B (NSP–B), a meroterpenoid fungal secondary metabolite, was investigated for its anticancer potential in leukemic cell lines (K562 and U937). NSP-B treatment of leukemic cells suppressed cell viability by triggering apoptotic cell death. Apoptosis induced by NSP-B is triggered by mitochondrial signaling and caspase activation. Additionally, NSP-B treatment of leukemic cells causes AKT's inactivation accompanied by downregulation of SKP2 oncogene and MTH1 with a concomitant increase of p21Cip1and p27Kip1. Furthermore, NSP-B causes suppression of antiapoptotic proteins, including cIAP1, cIAP2, XIAP, survivin and BCl-XL. Overall, NSP-B reduces cell viability by mitochondrial and caspase-dependent apoptosis. The inhibition of AKT and SKP2 axis could be a promising therapeutic target for leukemia treatment.This work was supported by grant funded by the Medical Research Center (MRC), Hamad Medical Corporation, Doha, Qatar (MRC-01-21-301). The authors thank Qatar National Library for open access support of this article

Network pharmacology, molecular simulation, and binding free energy calculation-based investigation of Neosetophomone B revealed key targets for the treatment of cancer

In the current study, Neosetophomone B (NSP–B) was investigated for its anti-cancerous potential using network pharmacology, quantum polarized ligand docking, molecular simulation, and binding free energy calculation. Using SwissTarget prediction, and Superpred, the molecular targets for NSP-B were predicted while cancer-associated genes were obtained from DisGeNet. Among the total predicted proteins, only 25 were reported to overlap with the disease-associated genes. A protein-protein interaction network was constructed by using Cytoscape and STRING databases. MCODE was used to detect the densely connected subnetworks which revealed three sub-clusters. Cytohubba predicted four targets, i.e., fibroblast growth factor , FGF20, FGF22, and FGF23 as hub genes. Molecular docking of NSP-B based on a quantum-polarized docking approach with FGF6, FGF20, FGF22, and FGF23 revealed stronger interactions with the key hotspot residues. Moreover, molecular simulation revealed a stable dynamic behavior, good structural packing, and residues’ flexibility of each complex. Hydrogen bonding in each complex was also observed to be above the minimum. In addition, the binding free energy was calculated using the MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) and MM/PBSA (Molecular Mechanics/Poisson-Boltzmann Surface Area) approaches. The total binding free energy calculated using the MM/GBSA approach revealed values of −36.85 kcal/mol for the FGF6-NSP-B complex, −43.87 kcal/mol for the FGF20-NSP-B complex, and −37.42 kcal/mol for the FGF22-NSP-B complex, and −41.91 kcal/mol for the FGF23-NSP-B complex. The total binding free energy calculated using the MM/PBSA approach showed values of −30.05 kcal/mol for the FGF6-NSP-B complex, −39.62 kcal/mol for the FGF20-NSP-B complex, −34.89 kcal/mol for the FGF22-NSP-B complex, and −37.18 kcal/mol for the FGF23-NSP-B complex. These findings underscore the promising potential of NSP-B against FGF6, FGF20, FGF22, and FGF23, which are reported to be essential for cancer signaling. These results significantly bolster the potential of NSP-B as a promising candidate for cancer therapy

Sanguinarine Induces Apoptosis Pathway in Multiple Myeloma Cell Lines via Inhibition of the JaK2/STAT3 Signaling.

Sanguinarine (SNG), a benzophenanthridine alkaloid, has displayed various anticancer abilities in several vivo and studies. However, the anticancer potential of SNG is yet to be established in multiple myeloma (MM), a mostly incurable malignancy of plasma cells. In this study, we aimed to investigate the potential anti-proliferative and pro-apoptotic activities of SNG in a panel of MM cell lines (U266, IM9, MM1S, and RPMI-8226). SNG treatment of MM cells resulted in a dose-dependent decrease in cell viability through mitochondrial membrane potential loss and activation of caspase 3, 9, and cleavage of PARP. Pre-treatment of MM cells with a universal caspase inhibitor, Z-VAD-FMK, prevented SNG mediated loss of cell viability, apoptosis, and caspase activation, confirming that SNG-mediated apoptosis is caspase-dependent. The SNG-mediated apoptosis appears to be resulted from suppression of the constitutively active STAT3 with a concomitant increase in expression of protein tyrosine phosphatase (SHP-1). SNG treatment of MM cells leads to down-regulation of the anti-apoptotic proteins including cyclin D, Bcl-2, Bclxl, and XIAP. In addition, it also upregulates pro-apoptotic protein, Bax. SNG mediated cellular DNA damage in MM cell lines by induction of oxidative stress through the generation of reactive oxygen species and depletion of glutathione. Finally, the subtoxic concentration of SNG enhanced the cytotoxic effects of anticancer drugs bortezomib (BTZ) by suppressing the viability of MM cells via induction of caspase-mediated apoptosis. Altogether our findings demonstrate that SNG induces mitochondrial and caspase-dependent apoptosis, generates oxidative stress, and suppresses MM cell lines proliferation. In addition, co-treatment of MM cell lines with sub-toxic doses of SNG and BTZ potentiated the cytotoxic activity. These results would suggest that SNG could be developed into therapeutic agent either alone or in combination with other anticancer drugs in MM

Bioinformatics Analysis Reveals FOXM1/BUB1B Signaling Pathway as a Key Target of Neosetophomone B in Human Leukemic Cells: A Gene Network-Based Microarray Analysis

Abnormal expression of Forkhead box protein M1 (FOXM1) and serine/threonine kinase Budding uninhibited by benzimidazoles 1 (BUB1B) contributes to the development and progression of several cancers, including chronic myelogenous leukemia (CML). However, the molecular mechanism of the FOXM1/BUB1B regulatory network and the role of Neosetophomone-B (NSP-B) in leukemia remains unclear. NSP-B, a meroterpenoid fungal secondary metabolite, possesses anticancer potential in human leukemic cells lines; however, the underlying mechanism has not been elucidated. The present study aimed to explore the role of NSP-B on FOXM1/BUB1B signaling and the underlying molecular mechanism of apoptosis induction in leukemic cells. We performed gene expression profiling of NSP-B-treated and untreated leukemic cells to search for differentially expressed genes (DEGs). Interestingly BUB1B was found to be significantly downregulated (logFC -2.60, adjusted p = 0.001) in the treated cell line with the highest connectivity score among cancer genes. Analysis of TCGA data revealed overexpression of BUB1B compared to normal in most cancers and overexpression was associated with poor prognosis. BUB1B also showed a highly significant positive correlation with FOXM1 in all the TCGA cancer types. We used human leukemic cell lines (K562 and U937) as an in vitro study model to validate our findings. We found that NSP-B treatment of leukemic cells suppressed the expression of FOXM1 and BUB1B in a dose-dependent manner. In addition, NSP-B also resulted in the downregulation of FOXM1-regulated genes such as Aurora kinase A, Aurora kinase B, CDK4, and CDK6. Suppression of FOXM1 either by siRNA or NSP-B reduced BUB1B expression and enhanced cell survival inhibition and induction of apoptosis. Interestingly combination treatment of thiostrepton and NSP-B suppressed of cell viability and inducted apoptosis in leukemic cells via enhancing the activation of caspase-3 and caspase-8 compared with single-agent treatment. These results demonstrate the important role of the FOXM1/BUB1B pathway in leukemia and thus a potential therapeutic target.Medical Research Center Grant no; MRC-01-21-301 (SU), Hamad Medical Corporation, Doha Qatar. The publication of this article was funded by the Qatar National Library

Role of non-coding RNA networks in leukemia progression, metastasis and drug resistance.

Early-stage detection of leukemia is a critical determinant for successful treatment of the disease and can increase the survival rate of leukemia patients. The factors limiting the current screening approaches to leukemia include low sensitivity and specificity, high costs, and a low participation rate. An approach based on novel and innovative biomarkers with high accuracy from peripheral blood offers a comfortable and appealing alternative to patients, potentially leading to a higher participation rate.Recently, non-coding RNAs due to their involvement in vital oncogenic processes such as differentiation, proliferation, migration, angiogenesis and apoptosis have attracted much attention as potential diagnostic and prognostic biomarkers in leukemia. Emerging lines of evidence have shown that the mutational spectrum and dysregulated expression of non-coding RNA genes are closely associated with the development and progression of various cancers, including leukemia. In this review, we highlight the expression and functional roles of different types of non-coding RNAs in leukemia and discuss their potential clinical applications as diagnostic or prognostic biomarkers and therapeutic targets

Sanguinarine mediated apoptosis in Non-Small Cell Lung Cancer via generation of reactive oxygen species and suppression of JAK/STAT pathway

Effective treatment of lung cancer remains a significant clinical challenge due to its multidrug resistance and side effects of the current treatment options. The high mortality associated with this malignancy indicates the need for new therapeutic interventions with fewer side effects. Natural compounds offer various benefits such as easy access, minimal side effects, and multi-molecular targets and thus, can prove useful in treating lung cancer. Sanguinarine (SNG), a natural compound, possesses favorable therapeutic potential against a variety of cancers. Here, we examined the underlying molecular mechanisms of SNG in Non-Small Cell Lung Cancer (NSCLC) cells. SNG suppressed cell growth and induced apoptosis via downregulation of the constitutively active JAK/STAT pathway in all the NSCLC cell lines. siRNA silencing of STAT3 in NSCLC cells further confirmed the involvement of the JAK/STAT signaling cascade. SNG treatment increased Bax/Bcl-2 ratio, which contributed to a leaky mitochondrial membrane leading to cytochrome c release accompanied by caspase activation. In addition, we established the antitumor effects of SNG through reactive oxygen species (ROS) production, as inhibiting ROS production prevented the apoptosis-inducing potential of SNG. In vivo xenograft tumor model further validated our in vitro findings. Overall, our study investigated the molecular mechanisms by which SNG induces apoptosis in NSCLC, providing avenues for developing novel natural compound-based cancer therapies

Sanguinarine Induces Apoptosis Pathway in Multiple Myeloma Cell Lines via Inhibition of the JaK2/STAT3 Signaling

Sanguinarine (SNG), a benzophenanthridine alkaloid, has displayed various anticancer abilities in several vivo and in vitro studies. However, the anticancer potential of SNG is yet to be established in multiple myeloma (MM), a mostly incurable malignancy of plasma cells. In this study, we aimed to investigate the potential anti-proliferative and pro-apoptotic activities of SNG in a panel of MM cell lines (U266, IM9, MM1S, and RPMI-8226). SNG treatment of MM cells resulted in a dose-dependent decrease in cell viability through mitochondrial membrane potential loss and activation of caspase 3, 9, and cleavage of PARP. Pre-treatment of MM cells with a universal caspase inhibitor, Z-VAD-FMK, prevented SNG mediated loss of cell viability, apoptosis, and caspase activation, confirming that SNG-mediated apoptosis is caspase-dependent. The SNG-mediated apoptosis appears to be resulted from suppression of the constitutively active STAT3 with a concomitant increase in expression of protein tyrosine phosphatase (SHP-1). SNG treatment of MM cells leads to down-regulation of the anti-apoptotic proteins including cyclin D, Bcl-2, Bclxl, and XIAP. In addition, it also upregulates pro-apoptotic protein, Bax. SNG mediated cellular DNA damage in MM cell lines by induction of oxidative stress through the generation of reactive oxygen species and depletion of glutathione. Finally, the subtoxic concentration of SNG enhanced the cytotoxic effects of anticancer drugs bortezomib (BTZ) by suppressing the viability of MM cells via induction of caspase-mediated apoptosis. Altogether our findings demonstrate that SNG induces mitochondrial and caspase-dependent apoptosis, generates oxidative stress, and suppresses MM cell lines proliferation. In addition, co-treatment of MM cell lines with sub-toxic doses of SNG and BTZ potentiated the cytotoxic activity. These results would suggest that SNG could be developed into therapeutic agent either alone or in combination with other anticancer drugs in MM