Anticancer Activities of Plant Secondary Metabolites: Rice Callus Suspension Culture as a New Paradigm

Plant natural products including alkaloids, polyphenols, terpenoids and flavonoids have been reported to exert anticancer activity by targeting various metabolic pathways. The biological pathways regulated by plant products can serve as novel drug targets. Plant natural compounds or their derivatives used for cancer treatment and some novel plant-based compounds which are used in clinical trials were discussed. Callus suspension culture with secondary metabolites can provide a continuous source of plant pharmaceuticals without time and space limitations. Previous research has shown that rice callus suspension culture can kill \u3e95% cancer cells with no significant effect on the growth of normal cells. The role of candidate genes and metabolites which are likely to be involved in the process and their potential to serve as anticancer and anti-inflammatory agents were discussed. Large scale production of plant callus suspension culture and its constituents can be achieved using elicitors which enhance specific secondary metabolites combined with bioprocess technology

PHYTIC ACID (MYO-INOSITOL HEXAPHOSPHATE)- A PROMISING PHARMACEUTICAL AGENT: A REVIEW

Phytic acid (myo-inositol hexaphosphate) has gained much attention among researchers for its therapeutic value. This review focuses on pharmacological activities of phytic acid, which have been demonstrated by pre-clinical studies. Anti-carcinogenic, antioxidant, antidiabetic, hypolipidemic, anti-angiogenic, and immunomodulation are the most extensively studied pharmacological activities of phytic acid. In addition to these, phytic acid and its derivatives also possess enzyme inhibitory activities against few key enzymes such as 5-alpha reductase, aldose reductase, cyclooxygenase, lipase, matrix metalloproteinase-2 & 9, pepsin, polyphenol oxidase, protease, β-secretase, tyrosinase, and xanthine oxidase were emphasized. The profound pharmacological activities of phytic acid have proven to be a good therapeutic agent and could be employed in preventing as well as treating such diseases

Structural and biochemical studies of proteins implicated in Kaposi’s Sarcoma-associated Herpesvirus pathobiology

The Kaposi’s sarcoma-associated Herpes virus (KSHV) infects hundreds of millions of people world-wide contributing to the development of Kaposi’s sarcoma (the most common HIV-related cancer), Multicentric Castleman’s disease and Primary effusion lymphoma. The project focused on two key proteins: KSHV SOX and KSHV-vFLIP that operate during the lytic and latent phases of the KSHV life-cycle respectively. KSHV SOX is a virally encoded highly conserved alkaline exonuclease which plays a key role in the global and rapid degradation of host mRNA in a process termed host shutoff as well as the packaging of viral genomes into capsids following replication. Although published (Bagneries et al., 2011) and unpublished (Lee, 2015, Master’s thesis, UCL) crystal structures of SOX bound to DNA has given key insights into the mechanism of DNA recognition and cleavage, it was unclear how RNA could be recognised owing to the lack of canonical RNA binding motifs and therefore uncertain whether the mechanism of cleavage proposed for the exonucleolytic cleavage of DNA substrates would apply. A combination of structural and biochemical approaches were therefore used to address these key outstanding questions which are presented in this thesis. They include the first crystal structure of SOX-E244S mutant bound to the KSHV pre-miRNA K2-31 which was determined at 3.3 Å by molecular replacement. Analysis of this structure has revealed a distinct binding mode for RNA binding relative to DNA in which the “bridge” motif, spanning the C- and N-terminal lobes of the SOX molecule, has an essential role in substrate recognition. Despite these differences, endonucleolytic processing of RNA transcripts could still be achieved by the SN2 (biomolecular nucleophilic substitution) mechanism originally proposed for the exonucleolytic cleavage of DNA. The results of biochemical and biophysical assays performed on wild-type and mutant proteins defective in host shut off further revealed that the degradation of RNA is largely sequence non-specific, but requires structured elements such as stem loop or bulge motifs. They also revealed that impaired host shut off activity could be explained by impaired RNase activity against structured substrates for a subset of the mutants. The ability of compare SOX-DNA and SOX-RNA structures afforded by these studies lead to the identification of phytic acid as a potential inhibitor of both its DNase and RNase activities confirmed by the crystal structure of SOX-phytic acid complex refined to 2.3 Å. Here it is shown that phytic acid not only has the potential to physically block the association of DNA/RNA substrates but also inhibit nucleolytic cleavage by directly co-ordinating to a catalytically important magnesium ion. During latency, KSHV produces a limited number of proteins essential for its survival. One of these is the viral FLICE inhibitory proteins (vFLIPs) that directly activates the canonical and alternative NF-κB pathways resulting in increased cell proliferation, transformation, cytokine secretion, and protection against growth factor withdrawal-induced apoptosis. Previous studies have shown that KSHV-vFLIP forms a ternary complex with the transcription factor p100 and the kinase IKKα for persistent activation of the alternative pathway shown to have an important role in cellular transformation. Although the mechanism underlying this process is unclear, a physical interaction between KSHV-vFLIP and p100 has been implicated. Having successfully produced all three proteins in E. Coli and baculovirus expression systems, the nature of this complex was investigated using pull down assays and site-directed mutagenesis. From these results, it has been possible to deduce that KSHV-vFLIP interacts with residues 860-900 located at the C-terminal end of p100 and does not interact with the death domain of p100

In Silico Identification of Protein Targets for Drug-like Compounds from Epicarp Extract of Cola rostrata K. Shum

Fruit epicarp has been found to contain several bioactive compounds which are useful for herbal treatment of several ailments and diseases. The phytochemicals present in C. rostrata epicarp as well as their potential to bind to human proteins and modify their function have not been investigated. This study, therefore, identified the top protein targets of drug-like components of C. rostrata epicarp extract in humans as well as the disease conditions associated with the targets. The identities of constituents of methanol and n-hexane fractions of absolute ethanol extract of C. rostrata epicarp were determined via GCMS analysis. Druglikeness (adherence to Lipinski, Ghose, Veber, Egan, and Muegge filters) and the protein targets of drug-like constituents were determined using SwissADME and SwissTargetPrediction web tools. GCMS analyses revealed the presence of 49 compounds in the n-hexane and methanol fractions. Corynan-16-carboxylic acid, 16,17-didehydro-9,17-dimethoxy-, methyl ester, (16E)-, a yohimbine derivative, was abundant (13.33%) in the methanol fraction. The n-hexane fraction was rich in odd-chain fatty acids and phytosterols. Four drug-like compounds were identified in the fractions: (1) Azelaic acid, monoethyl ester; (2) 3-(2-Methoxymethoxyethylidene)-2,2 dimethylbicyclo[2.2.1]heptane; (3) Cyclododecanol, 1-aminomethyl-, and (4) Corynan-16-carboxylic acid, 16,17-didehydro-9,17-dimethoxy-, methyl ester, (16E)-. The predicted top protein targets of the drug-like compounds include carbonic anhydrase II, protein-tyrosine phosphatase 1B, sphingosine kinase 1, maltase-glucoamylase, adenosine A2b receptor, P2X purinoceptor 7, MAP kinase p38 alpha, δ-opioid receptor, and alpha-2 adrenergic receptors. Findings show that C. rostrata epicarp contains drug-like phytochemicals with potential against cancer, diabetes, pain and inflammatory diseases, and the extract could have aphrodisiac potential

Drug vectoring systems to target drug delivery using nanotechnologies

Background: The development of nanostructures (nanoparticles and nanocapsules) is one of the most important pipelines of research of pharmaceutical technology. Methods: These nanotechnology pharmaceuticals allow the vectorization of drugs to tissues or cells target, allowing thus actions more specific and therapeutically active directed by molecules. Results: The use of molecules with an affinity for membrane receptors expressed in specific excess in tumor cells, monoclonal antibodies, or proteins, among others, is common for this purpose. In addition, these nanosystems allow to deliver drugs that could be the basis of the pharmacological treatment of many disorders of genetic origin in the future: biomolecules. Conclusion: The future scope of drug vectoring systems to target drug delivery using nanotechnologies can increase the control of pharmacokinetic parameters of chemotherapeutic agents

Gold as a possible alternative to platinum-based chemotherapy for colon cancer treatment

Due to the increasing incidence and high mortality associated with colorectal cancer (CRC), novel therapeutic strategies are urgently needed. Classic chemotherapy against CRC is based on oxaliplatin and other cisplatin analogues; however, platinum-based therapy lacks selectivity to cancer cells and leads to deleterious side effects. In addition, tumor resistance to oxaliplatin is related to chemotherapy failure. Gold(I) derivatives are a promising alternative to platinum complexes, since instead of interacting with DNA, they target proteins overexpressed on tumor cells, thus leading to less side effects than, but a comparable antitumor effect to, platinum derivatives. Moreover, given the huge potential of gold nanoparticles, the role of gold in CRC chemotherapy is not limited to gold(I) complexes. Gold nanoparticles have been found to be able to overcome multidrug resistance along with reduced side effects due to a more efficient uptake of classic drugs. Moreover, the use of gold nanoparticles has enhanced the effect of traditional therapies such as radiotherapy, photothermal therapy, or photodynamic therapy, and has displayed a potential role in diagnosis as a consequence of their optic properties. Herein, we have reviewed the most recent advances in the use of gold(I) derivatives and gold nanoparticles in CRC therapy

Investigation of Rice Bran Derived Anti-cancer Pentapeptide for Mechanistic Potency in Breast Cancer Cell Models

Bioactive peptides derived from food sources with anti-proliferative properties against cancer have drawn more attention in recent years. A pentapeptide derived from rice bran has shown anti-proliferative propertiesagainst human breast cancer cells. The objective of this study was to investigate the mechanistic action of the pentapeptide-induced apoptosis in breast cancer cell models (MCF-7 and MDA-MB-231). The growth inhibition activity of the pentapeptide was evaluated by MTS[3-(4,5-dimethylthiazol-2-yl)-5-(3- arboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] assayand trypan blue assay in a dose- and time-dependent manner. The apoptotic properties of pentapeptide-induced apoptosis on cancerous breast cells were evaluated by morphological changes, DNA fragmentation, and caspases-3/7, -8,and -9 activities. The levels of molecular targets (p53, COX-2, TNF-α, Fas, Bax, Bcl-2, and ErbB-2) were evaluated by enzyme-linked immunosorbent assay (ELISA) kits. Pentapeptide showed growth inhibition activities on MCF-7 and MDA-MB-231 cells. Apoptotic features including morphological changes,DNA fragmentation, and caspases activation were observed in both cells lines after pentapeptide treatment. Decreased levels of COX-2, Bcl-2, and ErbB-2 and increased levels of p53, TNF-α, Fas, and Bax expression were detected after cells exposed to pentapeptide from 72 to 96 hr. The results suggest that the pentapeptide inhibits growth of human breast cancer cells by introducing apoptosis through a caspase-dependent pathway. The pentapeptide amplifies the death signal by down-regulating the expression of ErbB-2 in both cell lines and COX-2 in ER (Estrogen Receptor)-positive MCF-7 cells. This study provides insight on the molecular mechanism of action of the pentapeptide against breast cancer cells. After further animal and human clinic trial, the pentapeptide has the potentiality to be analternative strategy to current anti-cancer drugs

Iron Biofortification of Rice: Progress and Prospects

Biofortification is the process of improving the bioavailability of essential nutrients in food crops either through conventional breeding or modern biotechnology techniques. Rice is one of the most demanding staple foods worldwide. Most global population live on a diet based on rice as the main carbohydrate source that serve as suitable target for biofortification. In general, polished grain or white rice contains nutritionally insufficient concentration of iron (Fe) to meet the daily requirements in diets. Therefore, iron biofortification in rice offers an inexpensive and sustainable solution to mitigate iron deficiency. However, understanding on the mechanism and genes involved in iron uptake in rice is a prerequisite for successful iron biofortification. In this chapter, the overview of iron uptake strategies in plants and as well as different iron-biofortified approaches used in rice will be outlined. Then, the challenges and future prospects of rice iron biofortification to improve global human health will also be discussed