Showing papers by "John M. Pezzuto published in 2016"

Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents.

Abstract: Throughout history, natural products have played a dominant role in the treatment of human ailments. For example, the legendary discovery of penicillin transformed global existence. Presently, natural products comprise a large portion of current-day pharmaceutical agents, most notably in the area of cancer therapy. Examples include Taxol, vinblastine, and camptothecin. These structurally unique agents function by novel mechanisms of action; isolation from natural sources is the only plausible method that could have led to their discovery. In addition to terrestrial plants as sources for starting materials, the marine environment (e.g., ecteinascidin 743, halichondrin B, and dolastatins), microbes (e.g., bleomycin, doxorubicin, and staurosporin), and slime molds (e.g., epothilone B) have yielded remarkable cancer chemotherapeutic agents. Irrespective of these advances, cancer remains a leading cause of death worldwide. Undoubtedly, the prevention of human cancer is highly preferable to treatment. Cancer chemoprevention, the use of vaccines or pharmaceutical agents to inhibit, retard, or reverse the process of carcinogenesis, is another important approach for easing this formidable public health burden. Similar to cancer chemotherapeutic agents, natural products play an important role in this field. There are many examples, including dietary phytochemicals such as sulforaphane and phenethyl isothiocyanate (cruciferous vegetables) and resveratrol (grapes and grape products). Overall, natural product research is a powerful approach for discovering biologically active compounds with unique structures and mechanisms of action. Given the unfathomable diversity of nature, it is reasonable to suggest that chemical leads can be generated that are capable of interacting with most or possibly all therapeutic targets.

New heteroleptic palladium(II) dithiocarbamates: synthesis, characterization, packing and anticancer activity against five different cancer cell lines

Abstract: Two new heteroleptic palladium(II) complexes have been synthesized by reacting equimolar quantities of palladium(II) chloride, sodium 4-(2-methoxyphenyl)piperazine-1-carbodithioate and diphenyl-p-tolylphosphine (1) or tri-p-tolylphosphine (2). Complexes 1 and 2 have been characterized using elemental analysis, Fourier transform infrared spectroscopy, multinuclear NMR (1H, 13C and 31P) spectroscopy and single-crystal X-ray analysis. The latter technique confirms a pseudo square-planar geometry in which two adjacent positions are occupied by bidentate dithiocarbamate while chloro and substituted triphenylphosphine are present at the remaining two positions. The anticancer activity of both complexes against five different cancer cell lines (LU – human lung carcinoma, established at UIC, Department of Surgical Oncology; MCF7 – human breast adenocarcinoma, ATCC number HTB-22™; MDA-MB-231 – human breast adenocarcinoma, ATCC number HTB-26™; Hepa-1c1c7 – mouse liver hepatoma, ATCC number CRL-2026™; PC-3 – human prostate adenocarcinoma, ATCC number CRL-1435™) was determined by MTT assay, revealing 2 has higher activity than 1. A drug–calf thymus DNA binding study with UV–visible spectroscopy reveals a higher DNA binding affinity of 2 (3.511 × 104 M−1) than 1 (4.213 × 103 M−1). Density functional theory studies confirm the relatively more stable nature of 2 than 1. Copyright © 2016 John Wiley & Sons, Ltd.

Monofunctional platinum(II) dithiocarbamate complexes: synthesis, characterization and anticancer activity

Abstract: Heteroleptic platinum(II) dithiocarbamates, of general formula [Pt(DTC)LCl], where DTC = 4-(4-methoxyphenyl)piperazine-1-carbodithioate (1 and 2) and 4-(furan-2-carbonyl)piperazine-1-carbodithioate (3) and L = tri(4-flourophenylphosphine) (1 and 3) and tri(4-chlorophenylphosphine) (2) have been synthesized and characterized by different analytical techniques. These complexes are square planar with picoplatin or phenanthriplatin type steric hindrance from aromatic C–H groups of the phosphine ligand as shown by single-crystal analysis. In 1, the Pt square plane is hindered by two axially oriented hydrogens, whereas by only one in 2 and 3. DNA-binding studies by UV/visible spectroscopy revealed a stronger electrostatic interaction of 1 compared to 2 and 3, and the results are further supported by viscometry and cyclic voltammetric measurements. Their in vitro anticancer activity against five different cancer cell lines using a MTT assay revealed high potency of the complexes. The higher activity of 1 than both 2 and 3 is consistent with DNA binding strength and we speculate that it may be due to the relatively inert nature of platinum towards off-target biomolecules ensured by the hindrance caused by the two axially oriented hydrogens.

Endophytic fungi associated with Taxus fuana (West Himalayan Yew) of Pakistan: potential bio-resources for cancer chemopreventive agents.

Abstract: Context: Endophytic fungi, being a prolific source of bioactive secondary metabolites, are of great interest for natural product discovery.Objective: Isolation and partial characterization of endophytic fungi inhabiting the leaves and woody parts of Taxus fuana Nan Li & R.R. Mill. (Taxaceae) and evaluation of biological activity.Materials and methods: Endophytic fungal isolates were identified by molecular analysis of internal transcribed spacer (ITS) regions of 18S rDNA. Extracts of the endophytic fungi cultured on potato dextrose agar and modified medium were evaluated using cancer chemoprevention bioassays [inhibition of TNF-α-induced NFκB, aromatase and inducible nitric oxide synthase (iNOS); induction of quinone reductase 1 (QR1)] and growth inhibition with MCF-7 cells.Results: Nine of 15 fungal isolates were identified as belonging to Epicoccum, Mucor, Penicillium, Chaetomium, Paraconiothriym, Plectania or Trichoderma. Five of the 15 extracts inhibited NFκB activity (IC50 values ranging betw...

Bruceantin inhibits multiple myeloma cancer stem cell proliferation.

Abstract: Multiple myeloma (MM) continues to claim the lives of a majority of patients. MM cancer stem cells (CSCs) have been demonstrated to sustain tumor growth. Due to their ability to self-renew and to express detoxifying enzymes and efflux transporters, MM-CSCs are rendered highly resistant to conventional therapies. Therefore, managing MM-CSCs characteristics could have profound clinical implications. Bruceantin (BCT) is a natural product previously demonstrated to inhibit the growth of MM in RPMI 8226 cells-inoculated mouse xenograft models, and to cause regression in already established tumors. The objectives of the present study were to test the inhibitory effects of BCT on MM-CSCs growth derived from a human primary tumor, and to explore a mechanism of action underlying these effects. BCT exhibited potent antiproliferative activity in MM-CSCs starting at 25 nM. BCT induced cell cycle arrest, cell death and apoptosis in MM-CSCs as well as inhibited cell migration and angiogenesis in vitro. Using a qPCR screen, it was found that the gene expression of a number of Notch pathway members was altered. Pretreatment of MM-CSCs with the γ-secretase inhibitor RO4929097, a Notch pathway inhibitor, reversed BCT-induced effects on MM-CSCs proliferation. In this study, BCT was shown to be an effective agent in controlling the proliferation, viability and migration of MM-CSCs as well as angiogenesis in vitro. The effect on MM-CSCs proliferation may be mediated by the Notch pathway. These results warrant further investigation of BCT in a broader set of human-derived MM-CSCs and with in vivo models representative of MM.

Induction of cell cycle arrest and apoptosis with downregulation of Hsp90 client proteins and histone modification by 4β-hydroxywithanolide E isolated from Physalis peruviana.

Abstract: Scope Physalis peruviana (Solanaceae) is used for culinary and medicinal purposes. We currently report withanolides, isolated from P. peruviana, inhibit the growth of colon cancer monolayer and spheroid cultures. A detailed mechanistic evaluation was performed with 4β-hydroxywithanolide E (4HWE). Methods and results Treatment of HT-29 cells with low concentrations of 4HWE inhibited growth while enhancing levels of p21(Waf1/Cip1) and reducing levels of several cell cycle-related proteins. Apoptosis was induced at higher concentrations. In addition, 4HWE treatment downregulated the levels of Hsp90 client proteins. Nuclear sirtuin 1 (SIRT1) was increased and histone H3 acetylated at lysine 9 was decreased. An additional consequence of SIRT1 elevation in the nucleus may be inhibition of c-Jun activity. The expression of 21 genes was altered, including downregulation of PTGS2, and this correlated with reduced protein levels of cyclooxygenase-2 (COX-2). Overall, efficacious induction of G0/G1 cell cycle arrest at low concentrations, and induction of apoptosis at higher concentrations are interesting 4HWE-mediated phenomena that are accompanied by a complex array of molecular events. Conclusion Considering the worldwide prevalence of colon cancer, and the unique mode of action mediated by 4HWE, it is reasonable to investigate additional mechanistic details and the potential utility of this compound.

Anti-inflammatory and Quinone Reductase Inducing Compounds from Fermented Noni (Morinda citrifolia) Juice Exudates

Abstract: A new fatty acid ester disaccharide, 2-O-(β-d-glucopyranosyl)-1-O-(2E,4Z,7Z)-deca-2,4,7-trienoyl-β-d-glucopyranose (1), a new ascorbic acid derivative, 2-caffeoyl-3-ketohexulofuranosonic acid γ-lactone (2), and a new iridoid glycoside, 10-dimethoxyfermiloside (3), were isolated along with 13 known compounds (4–16) from fermented noni fruit juice (Morinda citrifolia). The structures of the new compounds, together with 4 and 5, were determined by 1D and 2D NMR experiments, as well as comparison with published values. Compounds 2 and 7 showed moderate inhibitory activities in a TNF-α-induced NF-κB assay, and compounds 4 and 6 exhibited considerable quinone reductase-1 (QR1) inducing effects.

Hedera nepalensis K. Koch: A Novel Source of Natural Cancer Chemopreventive and Anticancerous Compounds.

Abstract: Traditional medicinal plants are often used for both the prevention and the treatment of local diseases. Taking into consideration the medicinal importance of Hedera nepalensis within local Pakistani traditions, the present study was undertaken to analyze the in vitro cancer chemopreventive and cytotoxic properties of the plant. The in vitro cancer chemopreventive testing was performed using nitrite assay, NFκB assay, aromatase assay, and quinone reductase 1 (QR1) assay. The cytotoxic potential was evaluated on three cancer-cell lines: MCF-7, MDA-MB-231, and HeLa using sulforhodamine B (SRB) assay. The results of cancer chemopreventive assays show that n-hexane and ethyl acetate fractions of tested plant have promising cancer chemopreventive potential. Lupeol isolated from n-hexane as well as ethyl acetate fraction showed lowest IC50 (0.20 ± 1.9 μM) in NFκB assay. Crude extract and its fractions inhibited the growth of three cancer cell lines by more than 60%, IC50 value of lupeol varied from 2.32 to 10.2 μM. HPLC-DAD-based quantification of lupeol in different plant tissues demonstrated that leaves of H. nepalensis are a rich source of lupeol (0.196 mg/100 mg dry weight). Our data have shown that H. nepalensis harbors cancer chemopreventive and cytotoxic agents.

Litsea Species as Potential Antiviral Plant Sources.

Abstract: Litsea verticillata Hance (Lauraceae), a Chinese medicine used to treat swelling caused by injury or by snake bites, was the first plant identified by our National Institutes of Health (NIH)-funded International Cooperative Biodiversity Group (ICBG) project to exhibit anti-HIV activities. From this plant, we discovered a class of 8 novel litseane compounds, prototypic sesquiterpenes, all of which demonstrated anti-HIV activities. In subsequent studies, 26 additional compounds of different structural types were identified. During our continuing investigation of this plant species, we identified two new litseanes, litseaverticillols L and M, and a new sesquiterpene butenolide, litseasesquibutenolide. Litseaverticillols L and M were found to inhibit HIV-1 replication, with an IC[Formula: see text] value of 49.6[Formula: see text][Formula: see text]M. To further determine the antiviral properties of this plant, several relatively abundant isolates, including a litseane compound, two eudesmane sesquiterpenes and three lignans, were evaluated against an additional 21 viral targets. Lignans 8 and 9 were shown to be active against the Epstein-Barr Virus (EBV), with EC[Formula: see text] values of 22.0[Formula: see text][Formula: see text]M ([Formula: see text]) and 16.2[Formula: see text][Formula: see text]M ([Formula: see text]), respectively. Since many antiviral compounds have been discovered in L. verticillata, we further prepared 38 plant extracts made from the different plant parts of 9 additional Litsea species. These extracts were evaluated for their anti-HIV and cytotoxic activities, and four of the extracts, which ranged across three different species, displayed 97-100% inhibitory effects against HIV replication without showing cytotoxicity to a panel of human cell lines at a concentration of 20 μg/mL.

The Daniel K. Inouye College of Pharmacy Scripts: Poha Berry (Physalis peruviana) with Potential Anti-inflammatory and Cancer Prevention Activities.

Abstract: The Daniel K. Inouye College of Pharmacy, during a historic event in Spring 2016, graduated the first two students in the Pacific region to earn a PhD in pharmaceutical sciences at the University of Hawai'i at Hilo. The college offers PhD programs in these five disciplines: Cancer Biology, Medicinal Chemistry, Pharmaceutics, Pharmacognosy, and Pharmacology. One of the Pharmacognosy dissertations focused on plant-derived natural products with potential anti-inflammatory and cancer chemopreventive activities. Physalis peruviana (Pp) L. originated in tropical South America. It has become naturalized and is found readily on the Island of Hawai'i. The edible fruits are commonly known as cape gooseberry or poha in Hawai'i. In part of our study, three new withanolides, physaperuvin G (1), physaperuvins I-J (2-3), along with four known withanolides, namely, 4β-hydroxywithanolide E (4), withaperuvin C (5), and physalactone (6), coagulin (7) were isolated from the aerial parts of P. peruviana. In addition, two known compounds, phyperunolide F (8), and withanolide S (9), were isolated and identified from the poha berry fruits. The structures and absolute stereochemistry of new compounds from poha were elucidated by several spectroscopy methods: Nuclear Magnetic Resonance (NMR) spectroscopy, X-ray diffraction, and mass spectrometry analyses. All isolated poha compounds (aerial parts and fruits) were evaluated for their anti-inflammatory activity with lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells, and tumor necrosis factor alpha (TNF-α)-activated nuclear factor-kappa B (NF-κB) with transfected human embryonic kidney cells 293. Most of the isolated natural compounds showed activity with these assays. Additional studies were performed with models of colon cancer. Specifically, 4β-hydroxywithanolide E (4HWE) inhibited the growth of colon cancer monolayer and spheroid cultures. The compound induced cell cycle arrest at low concentrations and apoptosis at higher concentrations. These data suggest the ingestion of poha berries may have some effect on the prevalence of colon cancer. Additionally, poha isolates compounds were evaluated for their growth inhibitory effects with U251MG glioblastoma and MDA-MB-231 breast cancer cells that harbor aberrantly-active signal transducer and activation of transcription 3 (STAT3), compared to normal NIH-3T3 mouse fibroblasts. This work has led to the filing of three provisional patents with the University of Hawai'i Office of Technology Transfer and Economic Development.

Grapes and Health

Abstract: Grapes are vines that are cultivated in temperate climates around the world. There are an estimated 8000 grape varieties grown for consumption. The latest data showed table grape production of about 20 million tons. Vine growth and floral initiation result in the berry formation of the subsequent year. The growth and maturation of the grape berry and/or seeds affect changes in sugars, acids, and phenolic compounds. Pests and diseases are numerous as are the continuous searches for better chemical control. Natural resistance such as the grape plants’ L.L. Creasy (*) • M.T. Creasy Department of Horticulture, Cornell University, Ithaca, NY 14850, USA e-mail: llc10@cornell.edu © Springer International Publishing Switzerland 2016 J.M. Pezzuto (ed.), Grapes and Health, DOI 10.1007/978-3-319-28995-3_1 1 ability to escape infection through anatomical attributes and the production of phytoalexins such as resveratrol also play important roles in control of diseases. Grapes are a multiuse crop with nutritional and pharmaceutical applications.

Evidence supporting the conceptual framework of cancer chemoprevention in canines

Abstract: As with human beings, dogs suffer from the consequences of cancer. We investigated the potential of a formulation comprised of resveratrol, ellagic acid, genistein, curcumin and quercetin to modulate biomarkers indicative of disease prevention. Dog biscuits were evaluated for palatability and ability to deliver the chemopreventive agents. The extent of endogenous DNA damage in peripheral blood lymphocytes from dogs given the dietary supplement or placebo showed no change. However, H2O2-inducible DNA damage was significantly decreased after consumption of the supplement. The expression of 11 of 84 genes related to oxidative stress was altered. Hematological parameters remained in the reference range. The concept of chemoprevention for the explicit benefit of the canine is compelling since dogs are an important part of our culture. Our results establish a proof-of-principle and provide a framework for improving the health and well-being of “man’s best friend”.