Publications by authors named "Mohamed Saeed"

73 Publications

Anti-inflammatory and tight junction protective activity of the herbal preparation STW 5-II on mouse intestinal organoids.

Phytomedicine 2021 May 6;88:153589. Epub 2021 May 6.

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany. Electronic address:

Background: Irritable bowel syndrome (IBS) is a functional bowel disorder, in which recurrent abdominal pain is associated with defecation or a change in bowel habits. STW 5-II is a combination of six medicinal herbs with a clinically proven efficacy in managing IBS.

Aim: This study aims to establish an in vitro IBS model using mouse intestinal organoids and to explore the anti-inflammatory and tight junction protective activities of the multi-herbal preparation STW 5-II.

Methods: Intestinal organoids were cultured in 1:1 Matrigel™ and medium domes. Inflammation and tight junction disruption were induced by a cocktail of cytokines (TNFα, IFNγ, IL-1β, IL-6) and bacterial proteins (LPS, flagellin). Organoids were treated with different concentrations of STW 5-II, and its multi-target activity was assessed using microarray analyses, RT-qPCR, immunofluorescence, western blot, immunohistochemistry, and a FITC permeability assay. In addition, we analyzed the expression of pNF-κB, pSTAT1, iNOS and ZO-1. In silico analyses were conducted to predict and identify the active components that may be responsible in mediating the multi-target anti-inflammatory activity of STW 5-II.

Results: An organoid based IBS model was successfully established. STW 5-II effectively reduced the cytokines-induced overexpression of the pro-inflammatory mediators pNF-κB, pSTAT1 and iNOS. Moreover, STW 5-II attenuated cytokine-mediated downregulation of the tight junction protein, ZO-1. This finding was confirmed by a FITC permeability assay. In silico analyses revealed a promising inhibitory activity of some isolated compounds from STW 5-II against NF-κB, STAT1 and iNOS.

Conclusion: STW 5-II possesses multiple anti-inflammatory as well as tight junction protective activities that could explain its clinically proven efficacy in managing IBS symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phymed.2021.153589DOI Listing
May 2021

Xylochemical Synthesis and Biological Evaluation of Shancigusin C and Bletistrin G.

Molecules 2021 May 27;26(11). Epub 2021 May 27.

Department of Chemistry, Organic Chemistry Section, Johannes Gutenberg University, Duesbergweg 10-14, 55128 Mainz, Germany.

The biological activities of shancigusin C () and bletistrin G (), natural products isolated from orchids, are reported along with their first total syntheses. The total synthesis of shancigusin C () was conducted by employing the Perkin reaction to forge the central stilbene core, whereas the synthesis of bletistrin G () was achieved by the Wittig olefination followed by several regioselective aromatic substitution reactions. Both syntheses were completed by applying only renewable starting materials according to the principles of xylochemistry. The cytotoxic properties of shancigusin C () and bletistrin G () against tumor cells suggest suitability as a starting point for further structural variation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules26113224DOI Listing
May 2021

Identification of novel drug resistance mechanisms by genomic and transcriptomic profiling of glioblastoma cells with mutation-activated EGFR.

Life Sci 2021 May 12:119601. Epub 2021 May 12.

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany. Electronic address:

Aims: Epidermal growth factor receptor (EGFR) is not only involved in carcinogenesis, but also in chemoresistance. We characterized U87.MGΔEGFR glioblastoma cells with constitutively active EGFR due to deletion at the ligand binding domain in terms of gene expression profiling and chromosomal aberrations. Wild-type U87.MG cells served as control.

Materials And Methods: RNA sequencing and network analyses (Ingenuity Pathway Analysis) were performed to identify novel drug resistance mechanisms related to expression of mutation activated EGFR. Chromosomal aberrations were characterized by multicolor fluorescence in situ hybridization (mFISH) and array comparative genomic hybridization (aCGH).

Key Findings: U87.MGΔEGFR cells presented much more chromosomal aberrations, amplifications and deletions than wild-type U87.MG cells. Still, both cell lines were near-triploid. Numerous genes were overexpressed in U87.MGΔEGFR cells, some of which have been already linked to drug resistance. PXDN, which is associated with epithelial mesenchymal transition, was the most upregulated gene (901.8-fold). TENM1 was 331.6-fold upregulated, and it was previously reported to modulate neural development. EGFR-AS1 (161.2-fold upregulated) has been reported to increase the EGFR mRNA stability and its expression - in accordance with that of EGFR - was upregulated (85.5-fold). In addition to well-known resistance genes, numerous novel genes and genomic aberrations were identified. ANGPT2 upregulation and CPM downregulation were validated by Western blotting.

Significance: Transcriptomics and genomics analyses in U87.MGΔEGFR cells unraveled a range of novel drug resistance mechanisms including apoptosis, DNA repair, ferroptosis, glutathione related gene activities, heat shock, oxidative stress, transcription factor activities, which may have important implications for future treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2021.119601DOI Listing
May 2021

Thickness-modulated lateral MoS diodes with sub-terahertz cutoff frequency.

Nanoscale 2021 May;13(19):8940-8947

School of Engineering Science, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada.

Thickness-modulated lateral MoS2 diodes with an extracted benchmark cutoff frequency (fc) of up to 126 GHz are implemented and fully characterised. Fabricated diodes demonstrate an on-off current ratio of more than 600 and a short circuit current responsivity at zero-bias of 7 A/W. The excellent performance achieved in our device is attributed to reduced contact resistance from using In/Au contacts and low junction capacitance due to the lateral device structure. In addition, the use of multilayer MoS2 crystals enabled relatively high current flow. Small- and large-signal models are extracted from DC and RF characterisation of the fabricated diode prototype. Extracted compact models are compared to the measured DC and S-parameters of the diode, demonstrating excellent matching between models and measurements. The presented diode is suitable for switching circuits and high frequency applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1nr00089fDOI Listing
May 2021

Identification of novel compounds against three targets of SARS CoV-2 coronavirus by combined virtual screening and supervised machine learning.

Comput Biol Med 2021 06 30;133:104359. Epub 2021 Mar 30.

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany. Electronic address:

Coronavirus disease 2019 (COVID-19) is a major threat worldwide due to its fast spreading. As yet, there are no established drugs available. Speeding up drug discovery is urgently required. We applied a workflow of combined in silico methods (virtual drug screening, molecular docking and supervised machine learning algorithms) to identify novel drug candidates against COVID-19. We constructed chemical libraries consisting of FDA-approved drugs for drug repositioning and of natural compound datasets from literature mining and the ZINC database to select compounds interacting with SARS-CoV-2 target proteins (spike protein, nucleocapsid protein, and 2'-o-ribose methyltransferase). Supported by the supercomputer MOGON, candidate compounds were predicted as presumable SARS-CoV-2 inhibitors. Interestingly, several approved drugs against hepatitis C virus (HCV), another enveloped (-) ssRNA virus (paritaprevir, simeprevir and velpatasvir) as well as drugs against transmissible diseases, against cancer, or other diseases were identified as candidates against SARS-CoV-2. This result is supported by reports that anti-HCV compounds are also active against Middle East Respiratory Virus Syndrome (MERS) coronavirus. The candidate compounds identified by us may help to speed up the drug development against SARS-CoV-2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.compbiomed.2021.104359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008812PMC
June 2021

Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion.

Arch Toxicol 2021 03 30;95(3):959-974. Epub 2021 Jan 30.

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.

TP53 (p53) is a pivotal player in tumor suppression with fifty percent of all invasive tumors displaying mutations in the TP53 gene. In the present study, we characterized colon cancer cells (HCT116 p53 ) with TP53 deletion, a sub-line derived from HCT116-p53  cells. RNA sequencing and network analyses were performed to identify novel drug resistance mechanisms. Chromosomal aberrations were identified by multicolor fluorescence in situ hybridization (mFISH) and array comparative genomic hybridization (aCGH). Numerous genes were overexpressed in HCT116 p53  cells: RND3/RhoE (235.6-fold up-regulated), DCLK1 (60.2-fold up-regulated), LBH (31.9-fold up-regulated), MYB (28.9-fold up-regulated), TACSTD2 (110.1-fold down-regulated), NRIP1 (81.5-fold down-regulated) and HLA-DMB (69.7-fold down-regulated) are among the identified genes with potential influence on multidrug resistance (MDR) and they are associated with cancer progression and tumorigenesis, according to previously published studies. Probably due to TP53 deletion, disturbances in DNA repair and apoptosis are leading to aberrancies in cellular and organismal organization, ultimately increasing tumorigenesis and cancer progression potential. With NFκB, PI3K and HSP70, being at the center of merged protein network, and TH1-2 pathways, being among the influenced pathways, it can be speculated that the inflammatory pathway contributes to a resistance phenotype together with cell cycle regulation and heat-shock response. HCT116-p53  cells have more chromosomal aberrations, gains and losses in copy numbers than HCT116-p53  cells. In conclusion, numerous genomic aberrations, which might be associated with yet unknown drug resistance mechanisms, were identified. This may have important implications for future treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00204-021-02979-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904745PMC
March 2021

Identification of metastasis-related genes by genomic and transcriptomic studies in murine melanoma.

Life Sci 2021 Feb 21;267:118922. Epub 2020 Dec 21.

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany. Electronic address:

Aims: We systematically characterized metastatic murine B16-F10 melanoma, a sub-line derived from murine melanoma B16-F1 cells.

Materials And Methods: RNA-sequencing and network analyses (Ingenuity Pathway Analysis) were performed to identify novel potential metastasis mechanisms. Chromosomal aberrations were identified by multicolor fluorescence in situ hybridization (mFISH) using all 21 murine whole chromosome painting probes.

Key Findings: Numerous genes were overexpressed in B16-F10 cells, some of which have been already described as being metastasis-linked. Nr5a1/sf1, a known prognostic marker for adrenal tumors, was 177-fold upregulated in B16-F10 cells compared to B16-F1 cells. Hoxb8 was 75-fold upregulated, which was previously associated with gastric cancer progression and metastasis. Ptk7, which is linked with tumorigenesis and metastasis of esophageal squamous carcinoma, was 67-fold upregulated. B16-F10 cells acquired additional chromosomal aberrations compared to B16-F1 cells, including dic(4)(pter->qter:qter->pter), +dic(6;15), +der(10)t(10;?1;16).

Significance: In addition to well-known metastatic genes, numerous novel genes and genomic aberrations were identified, which may serve as targets for treatment in the future. Transcriptomic and genetic analyses in B16-F10 cells unraveled a range of novel metastasis mechanisms, which may also have important implications for future treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2020.118922DOI Listing
February 2021

Drug repurposing using transcriptome sequencing and virtual drug screening in a patient with glioblastoma.

Invest New Drugs 2021 Jun 12;39(3):670-685. Epub 2020 Dec 12.

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 5512, Mainz, Germany.

Background Precision medicine and drug repurposing are attractive strategies, especially for tumors with worse prognosis. Glioblastoma is a highly malignant brain tumor with limited treatment options and short survival times. We identified novel BRAF (47-438del) and PIK3R1 (G376R) mutations in a glioblastoma patient by RNA-sequencing. Methods The protein expression of BRAF and PIK3R1 as well as the lack of EGFR expression as analyzed by immunohistochemistry corroborated RNA-sequencing data. The expression of additional markers (AKT, SRC, mTOR, NF-κB, Ki-67) emphasized the aggressiveness of the tumor. Then, we screened a chemical library of > 1500 FDA-approved drugs and > 25,000 novel compounds in the ZINC database to find established drugs targeting BRAF47-438del and PIK3R1-G376R mutated proteins. Results Several compounds (including anthracyclines) bound with higher affinities than the control drugs (sorafenib and vemurafenib for BRAF and PI-103 and LY-294,002 for PIK3R1). Subsequent cytotoxicity analyses showed that anthracyclines might be suitable drug candidates. Aclarubicin revealed higher cytotoxicity than both sorafenib and vemurafenib, whereas idarubicin and daunorubicin revealed higher cytotoxicity than LY-294,002. Liposomal formulations of anthracyclines may be suitable to cross the blood brain barrier. Conclusions In conclusion, we identified novel small molecules via a drug repurposing approach that could be effectively used for personalized glioblastoma therapy especially for patients carrying BRAF47-438del and PIK3R1-G376R mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10637-020-01037-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068653PMC
June 2021

Effect of ABC transporter expression and mutational status on survival rates of cancer patients.

Biomed Pharmacother 2020 Nov 12;131:110718. Epub 2020 Sep 12.

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany. Electronic address:

ATP-binding cassette (ABC) transporters mediate multidrug resistance in cancer. In contrast to DNA single nucleotide polymorphisms in normal tissues, the role of mutations in tumors is unknown. Furthermore, the significance of their expression for prediction of chemoresistance and survival prognosis is still under debate. We investigated 18 tumors by RNA-sequencing. The mutation rate varied from 27,507 to 300885. In ABCB1, three hotspots with novel mutations were in transmembrane domains 3, 8, and 9. We also mined the cBioPortal database with 11,814 patients from 23 different tumor entities. We performed Kaplan-Meier survival analyses to investigate the effect of ABC transporter expression on survival rates of cancer patients. Novel mutations were also found in ABCA2, ABCA3, ABCB2, ABCB5, ABCC1-6, and ABCG2. Mining the cBioPortal database with 11,814 patients from 23 different tumor entities validated our results. Missense and in-frame mutations led to altered binding of anticancer drugs in molecular docking approaches. The ABCB1 nonsense mutation Q856* led to a truncated P-glycoprotein, which may sensitize tumors to anticancer drugs. The search for ABC transporter nonsense mutations represents a novel approach for precision medicine.. Low ABCB1 mRNA expression correlated with significantly longer survival in ovarian or kidney cancer and thymoma. In cancers of breast, kidney or lung, ABC transporter expression correlated with different tumor stages and human populations as further parameters to refine strategies for more individualized chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2020.110718DOI Listing
November 2020

Identification of potential inhibitors targeting BRAF-V600E mutant melanoma cells.

J Am Acad Dermatol 2021 Apr 21;84(4):1086-1089. Epub 2020 Jul 21.

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaad.2020.07.069DOI Listing
April 2021

Putative molecular determinants mediating sensitivity or resistance towards carnosic acid tumor cell responses.

Phytomedicine 2020 Oct 29;77:153271. Epub 2020 Jun 29.

Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address:

Background: Carnosic acid (CA) is one of the main constituents in rosemary extract. It possesses valuable pharmacological properties, including anti-oxidant, anti-inflammatory, anti-microbial and anti-cancer activities. Numerous in vitro and in vivo studies investigated the anticancer profile of CA and emphasized its potentiality for cancer treatment. Nevertheless, the role of multidrug-resistance (MDR) related mechanisms for CA's anticancer effect is not yet known.

Purpose: We investigated the cytotoxicity of CA against known mechanisms of anticancer drug resistance (P-gp, ABCB5, BCRP, EGFR and p53) and determined novel putative molecular factors associated with cellular response towards CA.

Study Design: Cytotoxicity assays, bioinformatic analysis, flow cytometry and western blotting were performed to identify the mode of action of CA towards cancer cells.

Methods: The cytotoxicity to CA was assessed using the resazurin assays in cell lines expressing the mentioned resistance mechanisms. A pharmacogenomic characterization of the NCI 60 cell line panel was applied via COMPARE, hierarchical cluster and network analyses. Flow cytometry was used to detect cellular mode of death and ROS generation. Changes in proteins-related to apoptosis were determined by Western blotting.

Results: Cell lines expressing ABC transporters (P-gp, BCRP or ABCB5), mutant EGFR or p53 were not cross-resistant to CA compared to their parental counterparts. By pharmacogenomic approaches, we identified genes that belong to different functional groups (e.g. signal transduction, regulation of cytoskeleton and developmental regulatory system). These genes were predicted as molecular determinants that mediate CA tumor cellular responses. The top affected biofunctions included cellular development, cellular proliferation and cellular death and survival. The effect of CA-mediated apoptosis in leukemia cells, which were recognized as the most sensitive tumor type, was confirmed via flow cytometry and western blot analysis.

Conclusion: CA may provide a novel treatment option to target refractory tumors and to effectively cooperate with established chemotherapy. Using pharmacogenomic approaches and network pharmacology, the relationship between cancer complexity and multi-target potentials of CA was analyzed and many putative molecular determinants were identified. They could serve as novel targets for CA and further studies are needed to translate the possible implications to clinical cancer treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phymed.2020.153271DOI Listing
October 2020

Chemopreventive Property of Sencha Tea Extracts towards Sensitive and Multidrug-Resistant Leukemia and Multiple Myeloma Cells.

Biomolecules 2020 07 4;10(7). Epub 2020 Jul 4.

Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.

The popular beverage green tea possesses chemopreventive activity against various types of tumors. However, the effects of its chemopreventive effect on hematological malignancies have not been defined. In the present study, we evaluated antitumor efficacies of a specific green tea, sencha tea, on sensitive and multidrug-resistant leukemia and a panel of nine multiple myelomas (MM) cell lines. We found that sencha extracts induced cytotoxicity in leukemic cells and MM cells to different extents, yet its effect on normal cells was limited. Furthermore, sencha extracts caused G2/M and G0/G1 phase arrest during cell cycle progression in CCRF/CEM and KMS-12-BM cells, respectively. Specifically, sencha-MeOH/HO extracts induced apoptosis, ROS, and MMP collapse on both CCRF/CEM and KMS-12-BM cells. The analysis with microarray and COMPARE in 53 cell lines of the NCI panel revealed diverse functional groups, including cell morphology, cellular growth and proliferation, cell cycle, cell death, and survival, which were closely associated with anti-tumor effects of sencha tea. It is important to note that PI3K/Akt and NF-κB pathways were the top two dominant networks by ingenuity pathway analysis. We demonstrate here the multifactorial modes of action of sencha tea leading to chemopreventive effects of sencha tea against cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom10071000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407630PMC
July 2020

Identification of Novel Rare Transporter Mutations in Tumor Biopsies of Cancer Patients.

Cells 2020 01 26;9(2). Epub 2020 Jan 26.

Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, 55128 Mainz, Germany.

The efficiency of chemotherapy drugs can be affected by ATP-binding cassette (ABC) transporter expression or by their mutation status. Multidrug resistance is linked with ABC transporter overexpression. In the present study, we performed rare mutation analyses for 12 transporters related to drug resistance (ABCA2, -A3, -B1, -B2, -B5, -C1, -C2, -C3, -C4, -C5, -C6, -G2) in a dataset of 18 cancer patients. We focused on rare mutations resembling tumor heterogeneity of ABC transporters in small tumor subpopulations. Novel rare mutations were found in , but not in the other ABC transporters investigated. Diverse mutations were found, including nonsense mutations causing premature stop codons, and compared with the wild-type protein in terms of their protein structure. Nonsense mutations lead to truncated protein structures. Molecular docking and heat map analyses of /MRP1 pointed out that Lys498* appeared in a separate cluster branch due to the large deletion, leading to a massive disruption in the protein conformation. The resulting proteins, which are nonfunctional due to nonsense mutations in tumors, offer a promising chemotherapy strategy since tumors with nonsense mutations may be more sensitive to anticancer drugs than wild-type -expressing tumors. This could provide a novel tumor-specific toxicity strategy and a way to overcome drug resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9020299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072590PMC
January 2020

Retrospective study of small pet tumors treated with Artemisia annua and iron.

Int J Oncol 2020 Jan 25;56(1):123-138. Epub 2019 Nov 25.

Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, D‑55128 Rhineland‑Palatinate, Germany.

Artemisinin from Artemisia annua L. and its derivatives are well‑known antimalarial drugs. In addition, in vitro studies, in vivo studies and clinical trials have demonstrated that these drugs exhibit anticancer activity in human patients with cancer. Therefore, the aim of the present study was to investigate whether a phytotherapeutic A. annua preparation exerts anticancer activity in veterinary tumors of small pets. Dogs and cats with spontaneous cancer (n=20) were treated with standard therapy plus a commercial A. annua preparation (Luparte®) and compared with a control group treated with standard therapy alone (n=11). Immunohistochemical analyses were performed with formalin‑fixed paraffin‑embedded tumor biopsies to analyze the expression of transferrin receptor (TfR) and the proliferation marker Ki‑67 as possible biomarkers to assess treatment response of tumors to A. annua. Finally, the expression levels of TfR and Ki‑67 were compared with the IC50 values towards artemisinin in two dog tumor cells lines (DH82 and DGBM) and a panel of 54 human tumor cell lines. Retrospectively, the present study assessed the survival times of small animals treated by standard therapy with or without A. annua. A. annua treatment was associated with a significantly higher number of animals surviving >18 months compared with animals without A. annua treatment (P=0.0331). Using a second set of small pet tumors, a significant correlation was identified between TfR and Ki‑67 expression by immunohistochemistry (P=0.025). To further assess the association of transferrin and Ki‑67 expression with cellular response to artemisinin, the present study compared the expression of these two biomarkers and the IC50 values for artemisinin in National Cancer Institute tumor cell lines in vitro. Both markers were inversely associated with artemisinin response (P<0.05), and the expression levels of TfR and Ki‑67 were significantly correlated (P=0.008). In conclusion, the promising results of the present retrospective study warrant further confirmation by prospective studies in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ijo.2019.4921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910181PMC
January 2020

Comparison between tumors in plants and human beings: Mechanisms of tumor development and therapy with secondary plant metabolites.

Phytomedicine 2019 Nov 3;64:153081. Epub 2019 Sep 3.

Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz 55128, Germany. Electronic address:

Background: Human tumors are still a major threat to human health and plant tumors negatively affect agricultural yields. Both areas of research are developing largely independent of each other. Treatment of both plant and human tumors remains unsatisfactory and novel therapy options are urgently needed.

Hypothesis: The concept of this paper is to compare cellular and molecular mechanisms of tumor development in plants and human beings and to explore possibilities to develop novel treatment strategies based on bioactive secondary plant metabolites. The interdisciplinary discourse may unravel commonalities and differences in the biology of plant and human tumors as basis for rational drug development.

Results: Plant tumors and galls develop upon infection by bacteria (e.g. Agrobacterium tumefaciens and A. vitis, which harbor oncogenic T-DNA) and by insects (e.g. gall wasps, aphids). Plant tumors are benign, i.e. they usually do not ultimately kill their host, but they can lead to considerable economic damage due to reduced crop yields of cultivated plants. Human tumors develop by biological carcinogenesis (i.e. viruses and other infectious agents), chemical carcinogenesis (anthropogenic and non-anthropogenic environmental toxic xenobiotics) and physical carcinogenesis (radioactivity, UV-radiation). The majority of human tumors are malignant with lethal outcome. Although treatments for both plant and human tumors are available (antibiotics and apathogenic bacterial strains for plant tumors, cytostatic drugs for human tumors), treatment successes are non-satisfactory, because of drug resistance and the severe adverse side effects. In human beings, attacks by microbes are repelled by cellular immunity (i.e. innate and acquired immune systems). Plants instead display chemical defense mechanisms, whereby constitutively expressed phytoanticipin compounds compare to the innate human immune system, the acquired human immune system compares to phytoalexins, which are induced by appropriate biotic or abiotic stressors. Some chemical weapons of this armory of secondary metabolites are also active against plant galls. There is a mutual co-evolution between plant defense and animals/human beings, which was sometimes referred to as animal plant warfare. As a consequence, hepatic phase I-III metabolization and excretion developed in animals and human beings to detoxify harmful phytochemicals. On the other hand, plants invented "pro-drugs" during evolution, which are activated and toxified in animals by this hepatic biotransformation system. Recent efforts focus on phytochemicals that specifically target tumor-related mechanisms and proteins, e.g. angiogenic or metastatic inhibitors, stimulators of the immune system to improve anti-tumor immunity, specific cell death or cancer stem cell inhibitors, inhibitors of DNA damage and epigenomic deregulation, specific inhibitors of driver genes of carcinogenesis (e.g. oncogenes), inhibitors of multidrug resistance (i.e. ABC transporter efflux inhibitors), secondary metabolites against plant tumors.

Conclusion: The exploitation of bioactive secondary metabolites to treat plant or human tumors bears a tremendous therapeutic potential. Although there are fundamental differences between human and plant tumors, either isolated phytochemicals and their (semi)synthetic derivatives or chemically defined and standardized plant extracts may offer new therapy options to decrease human tumor incidence and mortality as well as to increase agricultural yields by fighting crown galls.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phymed.2019.153081DOI Listing
November 2019

Cytotoxicity of cucurbitacin E from Citrullus colocynthis against multidrug-resistant cancer cells.

Phytomedicine 2019 Sep 2;62:152945. Epub 2019 May 2.

Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address:

Background: Cucurbitacin E (CuE) is an oxygenated tetracyclic triterpenoid isolated from the fruits of Citrullus colocynthis (L.) Schrad.

Purpose: This study outlines CuE's cytotoxic activity against drug-resistant tumor cell lines. Three members of ABC transporters superfamily, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and ABCB5 were investigated, whose overexpression in tumors is tightly linked to multidrug resistance. Further factors of drug resistance studied were the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR).

Methods: Cytotoxicity assays (resazurin assays) were used to investigate the activity of Citrullus colocynthis and CuE towards multidrug resistant cancer cells. Molecular docking (In silico) has been carried out to explore the CuE's mode of binding to ABC transporters (P-gp, BCRP and ABCB5). The visualization of doxorubicin uptake was done by a Spinning Disc Confocal Microscope. The assessment of proteins expression was done by western blotting analysis. COMPARE and hierarchical cluster analyses were applied to identify, which genes correlate with sensitivity or resistance to cucurbitacins (CuA, CuB, CuE, CuD, CuI, and CuK).

Results: Multidrug-resistant cells overexpressing P-gp or BCRP were cross-resistant to CuE. By contrast, TP53 knock-out cells were sensitive to CuE. Remarkably, resistant cells transfected with oncogenic ΔEGFR or ABCB5 were hypersensitive (collateral sensitive) to CuE. In silico analyses demonstrated that CuE is a substrate for P-gp and BCRP. Immunoblot analyses highlighted that CuE targeted EGFR and silenced its downstream signaling cascades. The most striking result that emerged from the doxorubicin uptake by ABCB5 overexpressing cells is that CuE is an effective inhibitor for ABCB5 transporter when compared with verapamil. The COMPARE analyses of transcriptome-wide expression profiles of tumor cell lines of the NCI identified common genes involved in cell cycle regulation, cellular adhesion and intracellular communication for different cucurbitacins.

Conclusion: CuE represents a potential therapeutic candidate for the treatment of certain types of refractory tumors. To best of our knowledge, this is the first time to identify CuE and verapamil as inhibitors for ABCB5 transporter.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phymed.2019.152945DOI Listing
September 2019

Relationship between EGFR expression and subcellular localization with cancer development and clinical outcome.

Oncotarget 2019 Mar 8;10(20):1918-1931. Epub 2019 Mar 8.

Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.

Epidermal growth factor receptor (EGFR) as a prevalent oncogene regulates proliferation, apoptosis and differentiation and thereby contributes to carcinogenesis. Even though, the documentation on its clinical relevance is surprisingly heterogeneous in the scientific literature. Here, we systematically investigated the correlation of mRNA to survival time and pathological parameters by analyzing 30 datasets . Furthermore, the prognostic value of membrane-bound, cytoplasmic (mcEGFR) and nuclear expression (nEGFR) of EGFR was experimentally analyzed by immunohistochemical staining of 502 biopsies from 27 tumor types. We found that protein expression of EGFR showed better prognostic efficiency compared to mRNA, and that mcEGFR expression was positively correlated with nEGFR expression ( < 0.001). Unexpectedly, both mcEGFR and nEGFR expression were associated with low T stage ( < 0.001 and = 0.004; respectively). Moreover, positive mcEGFR was significantly related to high differentiation ( = 0.027). No significant correlation was found with any other pathological parameters. Collectively, our results imply that the oncogenic function of EGFR may be more related to nascent stages of carcinogenesis than to advanced and progressive tumors, which may as well explain at least partially the occurrence of secondary resistance against EGFR-directed therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.26727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443015PMC
March 2019

Collateral sensitivity of drug-resistant ABCB5- and mutation-activated EGFR overexpressing cells towards resveratrol due to modulation of SIRT1 expression.

Phytomedicine 2019 Jun 14;59:152890. Epub 2019 Mar 14.

Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany. Electronic address:

Background: In the drug discovery field, natural products deemed a precious source of novel lead compounds. They have the ability to bypass or overcome multidrug resistance (MDR) in cancer cells.

Purpose: In this study, the natural polyphenolic stilbene resveratrol (RES) has been studied for its cytotoxic activity toward MDR cancer cells.

Methods: Resazurin assay was used to investigate the cytotoxicity of RES not only against a panel of drug-resistant cancer cells overexpressing P-glycoprotein/ABCB1, BCRP/ABCG2, ABCB5 (ATP-binding cassette transporters), but also mutation-activated EGFR. The assessment of proteins expression was done by Western blot analysis. COMPARE and hierarchical cluster analyses were applied to identify, which genes correlate with sensitivity or resistance to RES. The NF-κB activation was evaluated using NF-kB reporter cells assay.

Results: Interestingly, MDR cells overexpressing ABCB5 and mutation-activated EGFR were collateral sensitive (CS) to RES. Our immunoblotting analysis highlighted that CS may be attributed to RES-induced sirtuin 1 (SIRT1) overexpression. Indeed, the SIRT1 inhibitor, sirtinol completely abolished CS to RES, indicating a causative role of SIRT1 for CS to RES. In addition, COMPARE and hierarchical cluster analyses of transcriptomic data indicated genes associated with diverse cellular mechanisms ranging from the immune response, inflammation signaling, and microtubule formation to cell migration. Searching for transcription factor binding motifs in the promoters of these genes pointed to NF-κB as one of the master regulators related to RES activity.

Conclusion: The findings demonstrate that RES alone or in combination with established chemotherapeutic agents might overcome the refractory tumors. This information may be immensely useful for the development of personalized treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phymed.2019.152890DOI Listing
June 2019

Kirschner Wires Versus Titanium Plates and Screws in Management of Unstable Phalangeal Fractures: A Randomized, Controlled Clinical Trial.

J Hand Surg Am 2019 Dec 23;44(12):1091.e1-1091.e9. Epub 2019 Feb 23.

Department of Orthopedic Surgery and Trauma, Suez Canal University Hospitals, Ismailia, Egypt.

Purpose: To compare clinical, radiological and functional outcomes of percutaneous K-wires and lateral titanium plates and screws in the management of unstable extra-articular proximal and middle phalangeal fractures.

Methods: In a randomized controlled clinical trial, 40 patients with unstable transverse, long oblique or spiral diaphyseal fractures of the proximal and middle phalanges were divided into 2 groups: the K-wire group (20 patients), which included 12 proximal and 8 middle phalangeal fractures fixed by percutaneous K-wires; and the plate group (20 patients), which included 13 proximal and 7 middle phalangeal fractures treated with open reduction and internal fixation with a lateral titanium plate and screws. The patients were observed for at least 6 months (mean [range], 6.9 [6-8] months). Results were evaluated by total active motion (TAM), grip strength, fracture union, pain assessed by visual analog scale and the Quick-Disabilities of the Arm, Shoulder, and Hand questionnaire, and complications.

Results: Clinical and radiological union was achieved in all patients except one in the K-wire group. Mean TAM was significantly better in the plate group than in the K-wire group. Both groups were similar in terms of postoperative loss of grip strength compared with the opposite healthy hand, and as assessed by visual analog scale and the Quick-Disabilities of the Arm, Shoulder, and Hand questionnaire. Fewer complications occurred in the plate group (2 of 20 patients) compared with the K-wire group (5 of 20 patients).

Conclusions: Fixation of unstable proximal and middle phalangeal fractures using a titanium plate and screws through a midlateral approach is a reliable and safe method for most fracture types and is associated with higher TAM and fewer complications.

Type Of Study/level Of Evidence: Therapeutic II.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhsa.2019.01.015DOI Listing
December 2019

Perspective on desalination discharges and coastal environments of the Arabian Peninsula.

Mar Environ Res 2019 Mar 10;145:1-10. Epub 2019 Feb 10.

Desalination Technologies Research Institute, Saline Water Conversion Corporation, PO BOX 8328, Al-Jubail, 31951, Saudi Arabia.

Two opposing views are held about the effects of desalination plants on coastal environments. One view is that brine discharged from desalination plants has minimal impact on the coastal environment. The other opinion claims that discharges from desalination plants pose a potential environmental hazard to coastal environments and particularly to those of the Arabian Gulf. The present study was carried out to determine whether negative environmental impacts could be detected in coastal waters of the Gulf and Red Sea near discharges from desalination plants in Saudi Arabia. Phytoplankton abundance, concentrations of chlorophyll a, nutrients, total suspended solids, trace metals, chlorination by-products, bacterial growth, and toxicity of effluents were assessed. Results indicate the brine discharges were not toxic to fish or brine shrimp. Mitigation of impacts from elevated temperature, salinity and chemicals in dual purpose plants is partly achieved by pre-dilution of brine reject stream with cooling water. Alternative pretreatment methods, chlorination and waste treatment are considered. There is accumulation of corrosion metals in sediments at the discharge site of a plant on the Gulf coast. However, their concentrations were within regulatory limits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.marenvres.2019.02.005DOI Listing
March 2019

Collateral sensitivity of natural products in drug-resistant cancer cells.

Biotechnol Adv 2020 Jan - Feb;38:107342. Epub 2019 Jan 29.

Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon.

Cancer chemotherapy is frequently hampered by drug resistance. Concepts to combine anticancer drugs with different modes of action to avoid the development of resistance did not provide the expected success in the past, because tumors can be simultaneously non-responsive to many drugs (e.g. the multidrug resistance phenotype). However, tumors may be specifically hypersensitive to other drugs - a phenomenon also termed collateral sensitivity. This seems to be a general biological mechanism, since it also occurs in drug-resistant Escherichia coli and Saccharomyces cerevisiae. Here, we give a timely and comprehensive overview on hypersensitivity in resistant cancer cells towards natural products and their derivatives. Since the majority of clinically established anticancer drugs are natural products or are in one way or another derived from them, it is worth hypothesizing that natural products may deliver promising lead compounds for the development of collateral sensitive anticancer drugs. Hypersensitivity occurs not only in classical ABC transporter-mediated multidrug resistance, but also in many other resistance phenotypes. Resistant cancers can be hypersensitive to natural compounds from diverse classes and origins (i.e. mitotic spindle poisons, DNA topoisomerase 1 and 2 inhibitors, diverse phytochemicals isolated from medicinal plants, (semi)synthetic derivatives of phytochemicals, antibiotics, marine drugs, recombinant therapeutic proteins and others). Molecular mechanisms of collateral sensitivity include (1) increased ATP hydrolysis and reactive oxygen species production by futile cycling during ABC transporter-mediated drug efflux, (2) inhibition of ATP production, and (3) alterations of drug target proteins (e.g. increased expression of topoisomerases and heat shock proteins, inhibition of Wnt/β-catenin pathway, mutations in β-tubulin). The phenomenon of hypersensitivity needs to be exploited for clinical oncology by the development of (1) novel combination protocols that include collateral sensitive drugs and (2) novel drugs that specifically exhibit high degrees of hypersensitivity in resistant tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biotechadv.2019.01.009DOI Listing
February 2020

Evaluating suitability of source water for a proposed SWRO plant location.

Heliyon 2019 Jan 9;5(1):e01119. Epub 2019 Jan 9.

Desalination Technologies Research Institute, Saline Water Conversion Corporation, PO Box 8328, Al-Jubail 31951, Saudi Arabia.

SWRO membranes are characterized by their ability to reject particles of larger than 0.001 μm diameter and approximately 200 molecular weight. This indicates the selectiveness of the SWRO membranes and the relative ease by which they can be clogged or fouled. For this reason, membrane filtration needs the cleanest possible feed water. Without extensive feed water purification, the reverse osmosis (RO) technology of simple filtration under pressure could be fraught with problems. The quality of source water determines the pretreatment regimen and consequently success or failure of a SWRO plant. The present study evaluated the suitability of source water for a proposed SWRO plant on the Gulf coast of Saudi Arabia. Various physico-chemical and biological parameters were assessed: temperature, pH, salinity, conductivity, total dissolved solids (TDS), silt density index (SDI), turbidity, total suspended solids (TSS), total hardness, total alkalinity, total organic carbon (TOC), dissolved carbohydrates and proteins, dissolved oxygen (DO), biochemical oxygen demand (BOD), chlorophyll-a, bacterial count, major ions, and trace metals. With the exception of total suspended solids, chemical and physicochemical variables measured in this study had concentrations typical of the Arabian Gulf water and seawater in general. Average TSS values were slightly higher than those reported for Gulf coastal waters, and more importantly they were highly variable. This variability may result in episodes of filtration problems for the SWRO plant. The plant should seek deeper sea water a distance from shore as the location of its intake. The study allowed recommendations for treatment options to assure more successful operation of the plant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.heliyon.2019.e01119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328354PMC
January 2019

Cytotoxicity of nimbolide towards multidrug-resistant tumor cells and hypersensitivity via cellular metabolic modulation.

Oncotarget 2018 Nov 6;9(87):35762-35779. Epub 2018 Nov 6.

Department of Pharmaceutical Biology, Johannes Gutenberg University, Mainz, Germany.

Nimbolide is considered a promising natural product in cancer prevention and treatment. However, it is not known yet, whether the different mechanisms of multidrug resistance (MDR) influence its anticancer activity. In this study, well-known MDR mechanisms (, , 5, , ) were evaluated against nimbolide. The P-glycoprotein (/)-overexpressing CEM/ADR5000 cell line displayed remarkable hypersensitivity to nimbolide, which was mediated through upregulation of the tumor suppressor, PTEN, and its downstream components resulted in significant downregulation in / mRNA and P-glycoprotein. In addition, nimbolide targeted essential cellular metabolic-regulating elements including HIF1α, FoxO1, MYC and reactive oxygen species. The expression of breast cancer resistance protein (BCRP) as well as epidermal growth factor receptor (EGFR) and mutant tumor suppressor did not correlate to nimbolide's activity. Furthermore, this paper looked for other molecular determinants that might determine tumor cellular response towards nimbolide. COMPARE and hierarchical cluster analyses of transcriptome-wide microarray-based mRNA expressions of the NCI 60 cell line panel were performed, and a set of 40 genes from different functional groups was identified. The data suggested NF-κB as master regulator of nimbolide's activity. Interestingly, was determined by COMPARE analysis to mediate sensitivity to nimbolide, which would be of great benefit in targeted therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.26299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254660PMC
November 2018

Biopiracy versus One-World Medicine-From colonial relicts to global collaborative concepts.

Phytomedicine 2019 Feb 11;53:319-331. Epub 2018 Jun 11.

Department of Chemistry, University of Nairobi, Nairobi, Kenya.

Background: Practices of biopiracy to use genetic resources and indigenous knowledge by Western companies without benefit-sharing of those, who generated the traditional knowledge, can be understood as form of neocolonialism.

Hypothesis: The One-World Medicine concept attempts to merge the best of traditional medicine from developing countries and conventional Western medicine for the sake of patients around the globe.

Study Design: Based on literature searches in several databases, a concept paper has been written. Legislative initiatives of the United Nations culminated in the Nagoya protocol aim to protect traditional knowledge and regulate benefit-sharing with indigenous communities. The European community adopted the Nagoya protocol, and the corresponding regulations will be implemented into national legislation among the member states. Despite pleasing progress, infrastructural problems of the health care systems in developing countries still remain. Current approaches to secure primary health care offer only fragmentary solutions at best. Conventional medicine from industrialized countries cannot be afforded by the impoverished population in the Third World. Confronted with exploding costs, even health systems in Western countries are endangered to burst. Complementary and alternative medicine (CAM) is popular among the general public in industrialized countries, although the efficacy is not sufficiently proven according to the standards of evidence-based medicine. CAM is often available without prescription as over-the-counter products with non-calculated risks concerning erroneous self-medication and safety/toxicity issues. The concept of integrative medicine attempts to combine holistic CAM approaches with evidence-based principles of conventional medicine.

Conclusion: To realize the concept of One-World Medicine, a number of standards have to be set to assure safety, efficacy and applicability of traditional medicine, e.g. sustainable production and quality control of herbal products, performance of placebo-controlled, double-blind, randomized clinical trials, phytovigilance, as well as education of health professionals and patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phymed.2018.06.007DOI Listing
February 2019

Identification of fatal outcome in a childhood nasopharyngeal carcinoma patient by protein expression profiling.

Int J Oncol 2018 Oct 19;53(4):1721-1731. Epub 2018 Jul 19.

Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, D-55128 Mainz, Germany.

Nasopharyngeal carcinoma (NPC) is a rare disease in children with good prognosis and high cure rate. Nevertheless, certain patients have an unfavorable prognosis due to development of refractory NPC that is unresponsive to any therapeutic strategies. The current study studies a case of a 17 years-old female with non-keratinizing NPC type IIb (T2N0M0), who passed away as a consequence of resistance to chemo-, radio- and β-interferon therapy, and to an allogenic stem cell transplantation. In order to identify factors that lead to treatment failure and fatal outcome, immunohistochemical analyses of different tumor biomarkers and hierarchical cluster analysis were performed and compared with those of eight other patients with NPC who experienced complete remission following conventional therapy. Hierarchical cluster analysis of the immunohistochemical results clearly demonstrated that staining for immunological factors (CD4, CD8 and CD56) distinguished this patient from the others. To further investigate a potential role of the immune system, lymphocytic infiltration was assessed in tumor tissue by evaluation of hematoxylin and eosin-stained tumor sections. Indeed, no tumor infiltrating lymphocytes (TILs) were observed in this NPC case, while 7 out of 8 of the other NPC samples contained variable TIL amounts. The view that immunodeficiency of the patient may be a factor in the fatal outcome of treatment is supported by the fact that this patient with NPC was not positive for Epstein-Barr virus markers and also infected by several other viruses and fungi (herpes simplex virus, human herpes virus 6, Varicella zoster virus, and Candida). In conclusion, the investigation of rare NPC cases with poor prognosis may provide an improved understanding of the molecular mechanisms involved in refractory tumors and identification of novel potential therapeutic targets for NPC in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ijo.2018.4491DOI Listing
October 2018

Synthesis of Thymoquinone-Artemisinin Hybrids: New Potent Antileukemia, Antiviral, and Antimalarial Agents.

ACS Med Chem Lett 2018 Jun 21;9(6):534-539. Epub 2017 Dec 21.

Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), Friedrich-Alexander University of Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, 91058 Erlangen, Germany.

A series of hybrid compounds based on the natural products artemisinin and thymoquinone was synthesized and investigated for their biological activity against the malaria parasite 3D7 strain, human cytomegalovirus (HCMV), and two leukemia cell lines (drug-sensitive CCRF-CEM and multidrug-resistant subline CEM/ADR5000). An unprecedented one-pot method of selective formation of C-10α-acetate starting from a 1:1 mixture of C-10α- to C-10β-dihydroartemisinin was developed. The key step of this facile method is a mild decarboxylative activation of malonic acid mediated by DCC/DMAP. Ether-linked thymoquinone-artemisinin hybrids stood out as the most active compounds in all categories, while showing no toxic side effects toward healthy human foreskin fibroblasts and thus being selective. They exhibited EC values of 0.2 μM against the doxorubicin-sensitive as well as the multidrug-resistant leukemia cells and therefore can be regarded as superior to doxorubicin. Moreover, they showed to be five times more active than the standard drug ganciclovir and nearly eight times more active than artesunic acid against HCMV. In addition, hybrids possessed excellent antimalarial activity (EC = 5.9/3.7 nM), which was better than that of artesunic acid (EC = 8.2 nM) and chloroquine (EC = 9.8 nM). Overall, most of the presented thymoquinone-artemisinin-based hybrids exhibit an excellent and broad variety of biological activities (anticancer, antimalarial, and antiviral) combined with a low toxicity/high selectivity profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.7b00412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004568PMC
June 2018

Betulinic Acid Exerts Cytotoxic Activity Against Multidrug-Resistant Tumor Cells via Targeting Autocrine Motility Factor Receptor (AMFR).

Front Pharmacol 2018 15;9:481. Epub 2018 May 15.

Medical and Clinical Affairs Phytomedicines, Steigerwald Arzneimittelwerk GmbH, Bayer Consumer Health, Darmstadt, Germany.

Betulinic acid (BetA) is a naturally occurring pentacyclic triterpene isolated from the outer bark of white-barked birch trees and many other medicinal plants. Here, we studied betulinic acid's cytotoxic activity against drug-resistant tumor cell lines. P-glycoprotein () and BCRP () are known ATP-binding cassette (ABC) drug transporters that mediating MDR. ABCB5 is a close relative to ABCB1, which also mediates MDR. Constitutive activation of the EGF receptor is tightly linked to the development of chemotherapeutic resistance. BetA inhibited P-gp, BCRP, ABCB5 and mutation activated EGFR overexpressing cells with similar efficacy as their drug-sensitive parental counterparts. Furthermore, the mRNA expressions of ABCB1, BCRP, ABCB5 and EGFR were not related to the 50% inhibition concentrations (IC) for BetA in a panel of 60 cell lines of the National Cancer Institute (NCI), USA. In addition to well-established MDR mechanisms, we attempted to identify other molecular mechanisms that play a role in mediating BetA's cytotoxic activity. For this reason, we performed COMPARE and hierarchical cluster analyses of the transcriptome-wide microarray-based mRNA expression of the NCI cell lines panel. Various genes significantly correlating to BetA's activity were involved in different biological processes, e.g., cell cycle regulation, microtubule formation, signal transduction, transcriptional regulation, chromatin remodeling, cell adhesion, tumor suppression, ubiquitination and proteasome degradation. Immunoblotting and analyses revealed that the inhibition of AMFR activity might be one of the mechanisms for BetA to overcome MDR phenotypes. In conclusion, BetA may have therapeutic potential for the treatment of refractory tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2018.00481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962668PMC
May 2018

Effect of negative pressure wound therapy on molecular markers in diabetic foot ulcers.

Gene 2018 Aug 11;667:56-61. Epub 2018 May 11.

Surgery Department, College of Medicine, Taif University, Al Taif, Saudi Arabia.

Diabetic foot ulcers are one of the most common complications of diabetes with high morbidity and mortality. Negative pressure wound therapy (NPWT) is one of the treatment modalities that facilitates the wound healing process; however, its molecular mechanism remains unclear. The aim of this study was to investigate the mechanism of action of NPWT in the treatment of diabetic foot ulcers via measuring the tissue expression of genes related to the wound healing process. The study included 40 patients with diabetic foot ulceration, 20 of them received NPWT and the other 20 were a control group treated with advanced moist therapy. Granulation tissue biopsies were obtained before and 10 days after treatment in both groups and subjected to real-time polymerase chain reaction to measure the mRNA expression of TGF-β1, VEGF, TNF-α, IL-1β, MMP-1, MMP-9 and TIMP-1 which are involved in the wound healing pathway. After 10 days of treatment with NPWT, the mRNA levels of IL-1β, TNF-α, MMP-1, and MMP-9 were significantly downregulated, while the levels of VEGF, TGF-β1 and TIMP-1 were significantly increased. Our study demonstrated that NPWT promotes wound healing in diabetic foot ulcers possibly by affecting growth factors, inflammatory cytokines, and matrix metalloproteinases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gene.2018.05.032DOI Listing
August 2018

Prevention of carcinogenesis and metastasis by Artemisinin-type drugs.

Cancer Lett 2018 08 8;429:11-18. Epub 2018 May 8.

Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Center for Biomedicine and Medical Technology Mannheim (CBTM), Ludolf-Krehl-Str. 6, 68135 Mannheim, Ruprecht-Karls University of Heidelberg, Germany. Electronic address:

Artemisia annua (sweet wormwood, qinhao) is an ancient Chinese herbal remedy for pyrexia. Nowadays, artemisinin (qinghaosu) and its derivatives belong to the standard therapies against malaria worldwide, and its discovery has led to the Nobel Prize in Physiology and Medicine to Youyou Tu in 2015. While most attention has been paid to the treatment of malaria, there is increasing evidence that Artemisinin-type drugs bear a considerable potential to treat and prevent cancer. Rather than reporting on therapy of cancer, this review gives a comprehensive and timely overview on the chemopreventive effects of artemisinin and its derivatives against carcinogenesis and metastasis formation, following the multistage model of carcinogenesis (initiation, promotion, progression). The favorable toxicity profile known from malaria studies indicates that artemisinin-type drugs may be safely applied to prevent carcinogenesis and cancer metastasis in human beings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2018.05.008DOI Listing
August 2018

Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by and Analyses.

Front Pharmacol 2018 16;9:355. Epub 2018 Apr 16.

Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University Mainz, Mainz, Germany.

Drug resistance is one of the main reasons of chemotherapy failure. Therefore, overcoming drug resistance is an invaluable approach to identify novel anticancer drugs that have the potential to bypass or overcome resistance to established drugs and to substantially increase life span of cancer patients for effective chemotherapy. Oridonin is a cytotoxic diterpenoid isolated from with anticancer activity. In the present study, we evaluated the cytotoxicity of oridonin toward a panel of drug-resistant cancer cells overexpressing ABCB1, ABCG2, or ΔEGFR or with a knockout deletion of TP53. Interestingly, oridonin revealed lower degree of resistance than the control drug, doxorubicin. Molecular docking analyses pointed out that oridonin can interact with Akt/EGFR pathway proteins with comparable binding energies and similar docking poses as the known inhibitors. Molecular dynamics results validated the stable conformation of oridonin docking pose on Akt kinase domain. Western blot experiments clearly revealed dose-dependent downregulation of Akt and STAT3. Pharmacogenomics analyses pointed to a mRNA signature that predicted sensitivity and resistance to oridonin. In conclusion, oridonin bypasses major drug resistance mechanisms and targets Akt pathway and might be effective toward drug refractory tumors. The identification of oridonin-specific gene expressions may be useful for the development of personalized treatment approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2018.00355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911471PMC
April 2018