Mahmoud Youns

Anticancer activity of new coumarin substituted hydrazide-hydrazone derivatives

Drug resistance is a major impediment for cancer treatment, to overcome it we designed and synthesized sixteen coumarins bearing hydrazide-hydrazone moiety and evaluated them against human drug-resistant pancreatic carcinoma (Panc-1) cells and drug-sensitive (hepatic carcinoma; Hep-G2 and leukemia; CCRF) cell lines in vitro. The 6-brominated coumarin hydrazide-hydrazone derivatives (BCHHD) 7c, 8c and 10c were more potent than doxorubicin (DOX) against resistant Panc-1 cells. BCHHD 7c showed significant cytotoxicity against all tested cells (IC50: 3.60-6.50 μM) on comparison with all other coumarin hydrazide-hydrazone derivatives (CHHD), whereas BCHHDs 8c and 10c showed significant antiproliferative activity only against resistant Panc-1 cells with IC50 of 2.02 μM and 2.15 μM, respectively. All the investigated BCHHDs were able to activate caspases 3/7 and they could induce apoptosis in resistant Panc-1 cells. Microarray analysis showed that BCHHD 7c induced the expression of apoptotic- and cell cycle arrest (G2/M)- genes in resistant Panc-1 cells. Moreover, BCHHD 7c induced the up-regulation of CDKN1A, DDIT4, GDF-15 and down-regulation of CDC2, CDC20, CDK2 genes. Based on our results, we conclude that 7c could be a potent anticancer drug to overcome drug resistance in cancer and it could be highly beneficial for patients in the clinic.

Gene expression profiling identifies novel key players involved in the cytotoxic effect of Artesunate on pancreatic cancer cells

Pancreatic cancer is one of the most aggressive human malignancies, with an extremely poor prognosis. The paucity of curative therapies has translated into an overall 5-year survival rate of less than 5%, underscoring a desperate need for new therapeutic options. Artesunate (ART), clinically used as anti-malarial agent, has recently revealed remarkable anti-tumor activity. However, the mechanisms underlying those activities in pancreatic cancer are not yet known. Here we evaluated the anti-tumor activity of Artesunate and the possible underlying mechanisms in pancreatic cancer. MiaPaCa-2 (poorly differentiated) and BxPC-3 (moderately differentiated) pancreatic cancer cell lines were treated with Artesunate and the effect was monitored by a tetrazolium-based assay (MTS) for evaluating cell viability and by flow cytometry and caspase 3/7 activation for apoptosis evaluation. In addition cDNA arrays were used to identify differentially expressed genes. The microarray data were then validated by RT-PCR and Western blotting. Moreover, pathways associated with these expression changes were identified using the Ingenuity Pathway Analysis. The expression analysis identified a common set of genes that were regulated by Artesunate in pancreatic cancer. Our results provide the first in vitro evidence for the therapeutic utility of Artesunate in pancreatic cancer. Moreover, we identified Artesunate as a novel topoisomerase IIalpha inhibitor that inhibits pancreatic cancer growth through modulation of multiple signaling pathways. The present analysis is a starting point for the generation of hypotheses on candidate genes and for a more detailed dissection of the functional role of individual genes for the activity of Artesunate in tumor cells.

Therapeutic and diagnostic applications of nanoparticles

Nanoparticles are sphere-like biocompatible materials made of inert silica, metal or crystals of a few nanometers in size. They are emerging as a novel class of therapeutics for cancer treatment. Being more selective and specific toward their targets, nanoparticles have the ability to enhance the anticancer effects and to simultaneously reduce systemic toxicity compared with conventional therapeutics. Furthermore, they offer the potential to overcome drug resistance leading to higher intracellular drug accumulation. Nowadays, nanotechnologies are applied to molecular diagnostics and incorporated in cutting-edge molecular diagnostic methods, such as DNA and protein microarray biochips. Nanotechnologies enable diagnosis at the single-cell and single-molecule levels. Recent progress in cancer nanotechnology raises exciting opportunities for specific drug delivery. The purpose of this review is to give an overview about different types of nanoparticles and to summarize the latest results regarding their diagnostic and therapeutic applications in the clinic with more focus on cancer treatment. Furthermore, we discuss opportunities, limitations, and challenges faced by therapeutic nanoparticles.

Chemical composition and biological activity of the essential oil obtained from Bupleurum marginatum (Apiaceae).

Objectives Bupleurum marginatum is a herb indigenous to the southern and southwestern part of China. It is widely used in many Chinese prescriptions. We aimed to investigate the chemical composition, antioxidant, anti‐inflammatory, antimicrobial and in‐vitro cytotoxic activity of the hydrodistilled and extracted essential oil from B. marginatum to validate some of its ethnopharmacologial uses.

Biological activity of the essential oil of Kadsura longipedunculata (Schisandraceae) and its major components

Objectives  The aim was to determine the chemical composition of the essential oil of Kadsura longipedunculata and the biological activity of the oil and its major components.

Toxicogenomics for the prediction of toxicity related to herbs from traditional Chinese medicine.

Toxicogenomics represents the integration of genomics and toxicology to investigate the interaction between genes and environmental stress in human health. It is a scientific field that studies how the genome is involved in responses to environmental stressors and toxicants. The patterns of altered gene expression that are caused by specific exposures or disease outcomes reveal how toxicants may act and cause disease. Nowadays, toxicogenomics faces great challenges in discriminating the molecular basis of toxicity. We do believe that advances in this field will eventually allow us to describe all the toxicological interactions that occur within a living system. Toxicogenomic responses of a toxic agent in one species (e.g., laboratory animals) may predict the mode of action in another species (e.g., humans) (predictive toxicology). Development and application of toxicogenomic databases and new bioinformatics tools are among the most important aspects of toxicogenomic research which will facilitate sharing and interpretation of the huge amount of biological information generated in this field. Medicinal herbs have played an important role in pharmacy from ancient to modern times. Nowadays, there is a revival of interest in medicinal plants and an increasing scientific interest in bioactive natural products. Medicinal herbs are usually considered to be nontoxic. However, the consumption of herbs could produce prominent toxic effects either due to inherent toxicity or to contaminants (heavy metals, microorganisms, pesticides, toxic organic solvents, radioactivity, etc.). Therefore, a critical assessment of their toxicity is an urgent issue. This review explores the field of toxicogenomics, pinpoints some of its research approaches and describes the challenges it faces. In particular, Chinese herbal preparations have been implicated.

Upregulation of extrinsic apoptotic pathway in curcumin‐mediated antiproliferative effect on human pancreatic carcinogenesis

Pancreatic cancer is one of the most lethal human cancers, with almost identical incidence and mortality rates. Curcumin, derived from the rhizome of Curcuma longa, has a long history of use as coloring agent and for a wide variety of disorders. Here, the antiproliferative activity of curcumin and its modulatory effect on gene expression of pancreatic cancer cell lines were investigated. The effect of curcumin on cellular proliferation and viability was monitored by sulphurhodamine B assay. Apoptotic effect was evaluated by flow cytometry and further confirmed by measuring amount of cytoplasmic histone‐associated DNA fragments. Analysis of gene expression was performed with and without curcumin treatment using microarray expression profiling techniques. Array results were confirmed by real‐time PCR. ingenuity pathway analysis (IPA) has been used to classify the list of differentially expressed genes and to indentify common biomarkergenes modulating the chemopreventive effect of curcumin. Results showed that curcumin induces growth arrest and apoptosis in pancreatic cancer cell lines. Its effect was more obvious on the highly COX‐2 expressing cell line. Additionally, the expression of 366 and 356 cancer‐related genes, involved in regulation of apoptosis, cell cycle, metastasis, was significantly altered after curcumin treatment in BxPC‐3 and MiaPaCa‐2 cells, respectively. Our results suggested that up‐regulation of the extrinsic apoptotic pathway was among signaling pathways modulating the growth inhibitory effects of curcumin on pancreatic cancer cells. Curcumin effect was mediated through activation of TNFR, CASP 8, CASP3, BID, BAX, and down‐regulation of NFκB, NDRG 1, and BCL2L10 genes. J. Cell. Biochem. 114: 2654–2665, 2013.

Traditional Chinese Medicines (TCMs) for Molecular Targeted Therapies of Tumours

Scientific progress in genetics, cell and molecular biology has greatly ameliorated our comprehensive understanding of the molecular mechanisms of neoplastic transformation and progression. The rapidly advancing identification of molecular targets in human cancers during the last decade has provided an excellent starting point for the development of novel therapeutics. A huge variety of potential molecular targets have been identified, many of which are already in the market for therapeutic purposes. It is now becoming possible to target pathways and/or molecules that are crucial in maintaining the malignant phenotype. Traditional Chinese medicine (TCM) is often considered as alternative or complementary medicine. TCM represents a holistic approach and lacks high-quality scientific evidence on its effectiveness. Therefore, it is frequently regarded with some scepticism by western academic medicine. In this review, we report that application of modern technologies allowed identification of novel molecular targets modulating the anti-tumour activity of natural products derived from TCM. Moreover, we tried to cross the bridge between TCM and Western modern medicine to be able to implement them for the sake of cancer patients.

Berberine Inhibits Cell Growth and Mediates Caspase-Independent Cell Death in Human Pancreatic Cancer Cells

Pancreatic cancer is one of the most aggressive human malignancies with an increasing incidence worldwide. In addition to the poor survival rates, combinations using gemcitabine as a backbone have failed to show any benefit beyond monotherapy. These facts underscore an urgent need for novel therapeutic options and motivated us to study the effect of berberine on pancreatic cancer cells. Here, we undertook an mRNA-based gene expression profiling study in order to get deeper insight into the molecular targets mediating the growth inhibitory effects of berberine on pancreatic cancer cells compared to normal ones. Twenty-four hours after treatment, berberine showed preferential selectivity toward pancreatic cancer cells compared to normal ones. Moreover, expression profiling and Ingenuity pathway analysis results showed that the cytotoxicity of berberine was accompanied with an activation of BRCA1-mediated DNA damage response, G1/S and G2/M cell cycle checkpoint regulation, and P53 signalling pathways. The activation of these signalling pathways might be explained by the fact that berberine intercalates DNA and induces DNA strand break through inhibition of topoisomerases and induction of DNA lesions.

Transcript profiling identifies novel key players mediating the growth inhibitory effect of NS-398 on human pancreatic cancer cells.

Pancreatic cancer is one of the most aggressive human malignancies with an increasing incidence worldwide. Despite an increase in the number of systemic treatments available for pancreatic cancer, the impact of therapy on the clinical course of the disease has been modest, underscoring an urgent need for new therapeutic options. Although selective cyclooxygenase-2 inhibitors have been demonstrated to have cancer-preventive effects, the mechanism of their effects is not clearly known. Moreover, there have been no unbiased studies to identify novel molecular targets of NS-398 regarding pancreatic cancer. Here we undertook a gene expression profiling study to identify novel molecular targets modulating the growth inhibitory effects of NS-398 on pancreatic cancer cell lines. Our mRNA-based gene expression results showed that the growth inhibitory effect of NS-398 was accompanied with an activation of G1/S and G2/M cell cycle regulation, P53 signalling, apoptotic, aryl hydrocarbon receptor and death receptor signalling pathways. Moreover, we reported, for the first time, that the growth inhibitory effect of NS-398 is mediated by down-regulation of RRM2, CTGF, MCM2 and PCNA and up-regulation of NAG-1 in all cell lines.