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Fulltext A side-effect free method for identifying cancer drug targets

Ashraf MI, Ong SK, Mujawar S, Pawar S, More P, Paul S, et al.

Sci Rep, 2018 04 27;8(1):6669.
PMID: 29703908 DOI: 10.1038/s41598-018-25042-2

Identifying effective drug targets, with little or no side effects, remains an ever challenging task. A potential pitfall of failing to uncover the correct drug targets, due to side effect of pleiotropic genes, might lead the potential drugs to be illicit and withdrawn. Simplifying disease complexity, for the investigation of the mechanistic aspects and identification of effective drug targets, have been done through several approaches of protein interactome analysis. Of these, centrality measures have always gained importance in identifying candidate drug targets. Here, we put forward an integrated method of analysing a complex network of cancer and depict the importance of k-core, functional connectivity and centrality (KFC) for identifying effective drug targets. Essentially, we have extracted the proteins involved in the pathways leading to cancer from the pathway databases which enlist real experimental datasets. The interactions between these proteins were mapped to build an interactome. Integrative analyses of the interactome enabled us to unearth plausible reasons for drugs being rendered withdrawn, thereby giving future scope to pharmaceutical industries to potentially avoid them (e.g. ESR1, HDAC2, F2, PLG, PPARA, RXRA, etc). Based upon our KFC criteria, we have shortlisted ten proteins (GRB2, FYN, PIK3R1, CBL, JAK2, LCK, LYN, SYK, JAK1 and SOCS3) as effective candidates for drug development.

Matched MeSH terms: Antineoplastic Agents/adverse effects; Antineoplastic Agents/isolation & purification*; Antineoplastic Agents/pharmacology*
Fulltext DK1 Induces Apoptosis via Mitochondria-Dependent Signaling Pathway in Human Colon Carcinoma Cell Lines In Vitro

Hussin Y, Aziz MNM, Che Rahim NF, Yeap SK, Mohamad NE, Masarudin MJ, et al.

Int J Mol Sci, 2018 Apr 11;19(4).
PMID: 29641445 DOI: 10.3390/ijms19041151

Extensive research has been done in the search for innovative treatments against colon adenocarcinomas; however, the incidence rate of patients remains a major cause of cancer-related deaths in Malaysia. Natural bioactive compounds such as curcumin have been substantially studied as an alternative to anticancer drug therapies and have been surmised as a potent agent but, nevertheless, remain deficient due to its poor cellular uptake. Therefore, efforts now have shifted toward mimicking curcumin to synthesize novel compounds sharing similar effects. A synthetic analog, (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2-ene-1-one (DK1), was recently synthesized and reported to confer improved bioavailability and selectivity toward human breast cancer cells. This study, therefore, aims to assess the anticancer mechanism of DK1 in relation to the induction of in vitro cell death in selected human colon cancer cell lines. Using the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay, the cytotoxicity of DK1 towards HT29 and SW620 cell lines were investigated. Acridine orange/propidium iodide (AO/PI) dual-staining assay and flow cytometry analyses (cell cycle analysis, Annexin/V-FITC and JC-1 assays) were incorporated to determine the mode of cell death. To further determine the mechanism of cell death, quantitative real-time polymerase chain reaction (qRT-PCR) and proteome profiling were conducted. Results from this study suggest that DK1 induced changes in cell morphology, leading to a decrease in cell viability and subsequent induction of apoptosis. DK1 treatment inhibited cell viability and proliferation 48 h post treatment with IC50 values of 7.5 ± 1.6 µM for HT29 cells and 14.5 ± 4.3 µM for SW620 cells, causing cell cycle arrest with increased accumulation of cell populations at the sub-G₀/G₁phaseof 74% and 23%, respectively. Flow cytometry analyses showed that DK1 treatment in cancer cells induced apoptosis, as indicated by DNA fragmentation and depolarization of the mitochondrial membrane. qRT-PCR results show significant upregulation in the expression of caspase-9 in both HT29 and SW620 cell lines, further supporting that cell death induction by DK1 is via an intrinsic pathway. These outcomes, therefore, demonstrate DK1 as a potential anticancer agent for colon adenocarcinoma due to its anti-apoptotic attributes.

Matched MeSH terms: Antineoplastic Agents/chemical synthesis; Antineoplastic Agents/pharmacology*; Antineoplastic Agents/chemistry
Transferrin receptors-targeting nanocarriers for efficient targeted delivery and transcytosis of drugs into the brain tumors: a review of recent advancements and emerging trends

Choudhury H, Pandey M, Chin PX, Phang YL, Cheah JY, Ooi SC, et al.

Drug Deliv Transl Res, 2018 10;8(5):1545-1563.
PMID: 29916012 DOI: 10.1007/s13346-018-0552-2

Treatment of glioblastoma multiforme (GBM) is a predominant challenge in chemotherapy due to the existence of blood-brain barrier (BBB) which restricts delivery of chemotherapeutic agents to the brain together with the problem of drug penetration through hard parenchyma of the GBM. With the structural and mechanistic elucidation of the BBB under both physiological and pathological conditions, it is now viable to target central nervous system (CNS) disorders utilizing the presence of transferrin (Tf) receptors (TfRs). However, overexpression of these TfRs on the GBM cell surface can also help to avoid restrictions of GBM cells to deliver chemotherapeutic agents within the tumor. Therefore, targeting of TfR-mediated delivery could counteract drug delivery issues in GBM and create a delivery system that could cross the BBB effectively to utilize ligand-conjugated drug complexes through receptor-mediated transcytosis. Hence, approach towards successful delivery of antitumor agents to the gliomas has been making possible through targeting these overexpressed TfRs within the CNS and glioma cells. This review article presents a thorough analysis of current understanding on Tf-conjugated nanocarriers as efficient drug delivery system.

Matched MeSH terms: Antineoplastic Agents/administration & dosage*; Antineoplastic Agents/pharmacology; Antineoplastic Agents/chemistry
Fulltext Bioactive Compounds: Natural Defense Against Cancer?

Subramaniam S, Selvaduray KR, Radhakrishnan AK

Biomolecules, 2019 11 21;9(12).
PMID: 31766399 DOI: 10.3390/biom9120758

Cancer is a devastating disease that has claimed many lives. Natural bioactive agents from plants are gaining wide attention for their anticancer activities. Several studies have found that natural plant-based bioactive compounds can enhance the efficacy of chemotherapy, and in some cases ameliorate some of the side-effects of drugs used as chemotherapeutic agents. In this paper, we have reviewed the literature on the anticancer effects of four plant-based bioactive compounds namely, curcumin, myricetin, geraniin and tocotrienols (T3) to provide an overview on some of the key findings that are related to this effect. The molecular mechanisms through which the active compounds may exert their anticancer properties in cell and animal-based studies also discussed.

Matched MeSH terms: Antineoplastic Agents
Recent developments on (-)-colchicine derivatives: Synthesis and structure-activity relationship

Ghawanmeh AA, Al-Bajalan HM, Mackeen MM, Alali FQ, Chong KF

Eur J Med Chem, 2020 Jan 01;185:111788.
PMID: 31655432 DOI: 10.1016/j.ejmech.2019.111788

(-)-Colchicine, an anti-microtubulin polymerization agent, is a valuable medication and the drug of choice for gout, Behçet's disease and familial Mediterranean fever. It has a narrow therapeutic index due to its high toxicity towards normal cells. Nonetheless, numerous (-)-colchicine derivatives have been synthesized and studied for their structure-activity relationship and preferential toxicity. Different functional groups such as amides, thioamides, N-arylurea and 8,12-diene cyclic have been incorporated into (-)-colchicine, resulting in derivatives (with moieties) that include electron-withdrawing and electron-donating groups. This review article focuses on recent developments in the chemical synthesis of (-)-colchicine derivatives, the substituents used, the functional groups linked to the substituents, the moieties and biological studies. Moreover, the current classification of derivatives based on the (-)-colchicine rings, namely ring A, B, and C (-)-colchicine derivatives, is discussed. This work demonstrates and summarizes the significance of (-)-colchicine derivatives in the biological field, and discusses their promising therapeutics for the future.

Matched MeSH terms: Antineoplastic Agents, Phytogenic/chemical synthesis; Antineoplastic Agents, Phytogenic/pharmacology*; Antineoplastic Agents, Phytogenic/chemistry
Fulltext Assessment of cytotoxicity potency of paclitaxel in combination with clinacanthus nutans extracts on human MDA-MB-231 breast cancer cells

Nor Fadilah Rajab, Chan Kok Meng, Nur Hasnieza Mohd Rosli, Fariza Juliana Nordin, Leong Lek Mun, Nur Syazwani Abdul Aziz

Jurnal Sains Kesihatan Malaysia, 2018;16(101):95-103.
MyJurnal

ABSTRACT
Clinacanthus nutans (C. nutans) leaf extracts have been widely used by cancer patients in Malaysia and local practice claims a cure to cancer. There were several studies done to determine the cytotoxicity potency of C. nutans extracts on various types of cells. However, there is still lacking on the knowledge regarding the combination effect of C. nutans with anticancer drugs. Thus, the study was carried out to determine the cytotoxicity potency of C. nutans extracts and paclitaxel (PTX) alone and, in combination on MDA-MB-231 cells. The cells were treated with 100% ethanol extract of C. nutans (CNE) and water extract of C. nutans (CNA), PTX and combination of both extracts and PTX for 72 hours and the cytotoxic activity was determined using SRB assay. Result showed that CNE had little cytotoxic activity, whereas CNA showed no cytotoxic activity on MDA-MB-231 cells. For combination treatment of C. nutans extracts and PTX, only CNE showed significant enhanced PTX-induced cytotoxicity (p < 0.05), meanwhile CNA inhibited PTX-induced cytotoxicity significantly (p < 0.05). As a conclusion, CNE was able to increase PTX potency to inhibit the viability of MDA-MB-231 cells.

Matched MeSH terms: Antineoplastic Agents
Enantiomeric pairs of ternary copper(ii) complexes and their aldol-type condensation products: synthesis, characterization, and anticancer and epigenetic properties

Lee KY, Ng YL, Wang WS, Ng PY, Chan CW, Lai JW, et al.

Dalton Trans, 2019 Apr 09;48(15):4987-4999.
PMID: 30916098 DOI: 10.1039/c9dt00506d

Chiral enantiomers [Cu(phen)(l-ser)(H2O)]NO31 and [Cu(phen)(d-ser)(H2O)]NO32 (ser = serinato) underwent aldol-type condensation with formaldehyde, with retention of chirality, to yield their respective enantiomeric ternary copper(ii) complexes, viz. l- and d-[Cu(phen)(OCA)(H2O)]NO3·xH2O (3 and 4; phen = 1,10-phenanthroline; OCA = oxazolidine-4-carboxylate; x = 1/2, 0-2) respectively. These chiral complexes were characterized by FTIR, elemental analysis, circular dichroism, UV-visible spectroscopy, fluorescence spectroscopy (FL), molar conductivity measurement, ESI-MS and X-ray crystallography. The crystal structures of 1 and 3 showed both the cationic complexes to have a square pyramidal geometry. These complexes were about nine fold more potent than cisplatin against metastatic MDA-MB-231 breast cancer cells, inducing apoptotic cell death via ROS generation and a massive drop in mitochondrial membrane potential. The results of monitoring EZH1, EZH2 and H3K27me3 revealed that the mode of action of 1-4 also involved the downregulation of EZH2 and it seemed to be independent of the H3K27me3 status.

Matched MeSH terms: Antineoplastic Agents/chemical synthesis; Antineoplastic Agents/pharmacology*; Antineoplastic Agents/chemistry
Anticancer activities of dietary benzyl isothiocyanate: A comprehensive review

Dinh TN, Parat MO, Ong YS, Khaw KY

Pharmacol Res, 2021 07;169:105666.
PMID: 33989764 DOI: 10.1016/j.phrs.2021.105666

Benzyl isothiocyanate (BITC) is one of the common isothiocyanates found in cruciferous vegetables such as broccoli, cabbage or watercress. Preclinical studies report of its effectiveness in the prevention and treatment against several cancers. This review aims to report and discuss findings on anticancer activities of BITC and its modes of action against 14 types of cancer. A literature search was conducted using the keywords "BITC" and "anticancer" from PubMed, Google Scholar and CINAHL Plus to obtain relevant research articles. This review highlights the anticancer efficacy of BITC through modulation of various signaling pathways involved in apoptosis, cell proliferation, cell cycle arrest, metastasis, angiogenesis, autophagy and the effects of BITC in combination with other drugs. With the available pharmacology evidence, we conclude that further studies are needed to validate its effectiveness in humans for further development and translation into prophylaxis or therapy by promoting optimal therapeutic effects and minimizing toxicity in cancer treatment.

Matched MeSH terms: Antineoplastic Agents/administration & dosage; Antineoplastic Agents/pharmacology; Antineoplastic Agents/therapeutic use*
Synthesis, Molecular Docking and Biological Activity Evaluation of Alkoxy Substituted Chalcone Derivatives: Potential Apoptosis Inducing Agent on MCF-7 Cells

Khairul WM, Hashim F, Mohammed M, Shah NSMN, Johari SATT, Rahamathullah R, et al.

Anticancer Agents Med Chem, 2021;21(13):1738-1750.
PMID: 33176667 DOI: 10.2174/1871520620999201110190709

INTRODUCTION: In this contribution, a series of alkoxy substituted chalcones were successfully designed, synthesized, spectroscopically characterized and evaluated for their cytotoxicity potential in inhibiting the growth of MCF-7 cells.
OBJECTIVE: In order to investigate the influence between electron density in conjugated π-systems and biological activities, different withdrawing substituents, namely Nitro (NO2), Cyano (C≡N) and trifluoromethyl (CF3) were introduced in the chalcone-based molecular system.
METHODS: All the derivatives were then tested on MCF-7 cell line using the fluorescence microscopy-based cytotoxicity analyses.
RESULTS: The preliminary findings showed that both -NO2 and -CF3 substituents revealed their potential to inhibit the growth of MCF-7 with IC;50 values of 14.75 and 13.75 μg/ml, respectively. In addition, the morphological changes of MCF-7 cells were observed in response to alkoxy substituted chalcone treatment through an induction of apoptosis pathway with cell blebbing, phosphatidylserine exposure and autophagic activity with acidification of lysosomal structure. Intermolecular interaction based on in silico investigation on nitro, trifluoromethyl and cyano based chalcones exhibited several types of interactions with tumor necrosis factor receptor (PDB: 1EXT) protein and high hydrogen bond in the molecule-receptor interaction have given significant impact towards their toxicity on MCF-7 cells.
CONCLUSION: Significantly, these types of chalcones exhibited ideal and high potential to be further developed as anti-cancer agents.

Matched MeSH terms: Antineoplastic Agents/chemical synthesis; Antineoplastic Agents/pharmacology*; Antineoplastic Agents/chemistry
Isolation and Characterization of Lectin from the Artist's Conk Medicinal Mushroom, Ganoderma applanatum (Agaricomycetes), and Evaluation of Its Antiproliferative Activity in HT-29 Colon Cancer Cells

Kumaran S, Pandurangan AK, Shenbhagaraman R, Esa NM

Int J Med Mushrooms, 2017;19(8):675-684.
PMID: 29199567 DOI: 10.1615/IntJMedMushrooms.2017021274

The growth and lectin production of Ganoderma applanatum, a white rot fungus, was optimized in broth cultures. The fungus was found to have a higher growth rate and higher lectin activity when grown in a medium adjusted to pH 6.5 at 26°C under stationary conditions. Expression of lectin activity started in 5-day-old mycelial culture; maximum activity was expressed after the 15th day of incubation. Among the various carbon and nitrogen sources tested, the carbon source sucrose and the nitrogen source yeast extract support maximum growth and lectin production. Lectin from G. applanatum was purified by ammonium sulfate precipitation and ion exchange chromatography. The purified fraction revealed a single band with a molecular weight of 35.0 kDa. Moreover, carbohydrates such as mannitol, glucose, sucrose, maltose, mannose, galactose, sorbose, and fructose were found to inhibit the hemagglutinating activity of the lectin. The purified lectins from G. applanatum contain cytotoxic and proapoptotic activities against HT-29 colon adenocarcinoma cells.

Matched MeSH terms: Antineoplastic Agents/isolation & purification*; Antineoplastic Agents/pharmacology; Antineoplastic Agents/chemistry
Fulltext Targeting Membrane Lipid a Potential Cancer Cure?

Tan LT, Chan KG, Pusparajah P, Lee WL, Chuah LH, Khan TM, et al.

Front Pharmacol, 2017;8:12.
PMID: 28167913 DOI: 10.3389/fphar.2017.00012

Cancer mortality and morbidity is projected to increase significantly over the next few decades. Current chemotherapeutic strategies have significant limitations, and there is great interest in seeking novel therapies which are capable of specifically targeting cancer cells. Given that fundamental differences exist between the cellular membranes of healthy cells and tumor cells, novel therapies based on targeting membrane lipids in cancer cells is a promising approach that deserves attention in the field of anticancer drug development. Phosphatidylethanolamine (PE), a lipid membrane component which exists only in the inner leaflet of cell membrane under normal circumstances, has increased surface representation on the outer membrane of tumor cells with disrupted membrane asymmetry. PE thus represents a potential chemotherapeutic target as the higher exposure of PE on the membrane surface of cancer cells. This feature as well as a high degree of expression of PE on endothelial cells in tumor vasculature, makes PE an attractive molecular target for future cancer interventions. There have already been several small molecules and membrane-active peptides identified which bind specifically to the PE molecules on the cancer cell membrane, subsequently inducing membrane disruption leading to cell lysis. This approach opens up a new front in the battle against cancer, and is of particular interest as it may be a strategy that may be prove effective against tumors that respond poorly to current chemotherapeutic agents. We aim to highlight the evidence suggesting that PE is a strong candidate to be explored as a potential molecular target for membrane targeted novel anticancer therapy.

Matched MeSH terms: Antineoplastic Agents
Fulltext Leflunomide an immunomodulator with antineoplastic and antiviral potentials but drug-induced liver injury: A comprehensive review

Alamri RD, Elmeligy MA, Albalawi GA, Alquayr SM, Alsubhi SS, El-Ghaiesh SH

Int Immunopharmacol, 2021 Apr;93:107398.
PMID: 33571819 DOI: 10.1016/j.intimp.2021.107398

Leflunomide (LF) represents the prototype member of dihydroorotate dehydrogenase (DHODH) enzyme inhibitors. DHODH is a mitochondrial inner membrane enzyme responsible for catalytic conversion of dihydroorotate into orotate, a rate-limiting step in the de novo synthesis of the pyrimidine nucleotides. LF produces cellular depletion of pyrimidine nucleotides required for cell growth and proliferation. Based on the affected cells the outcome can be attainable as immunosuppression, antiproliferative, and/or the recently gained attention of the antiviral potentials of LF and its new congeners. Also, protein tyrosine kinase inhibition is an additional mechanistic benefit of LF, which inhibits immunological events such as cellular expansion and immunoglobulin production with an enhanced release of immunosuppressant cytokines. LF is approved for the treatment of autoimmune arthritis of rheumatoid and psoriatic pathogenesis. Also, LF has been used off-label for the treatment of relapsing-remitting multiple sclerosis. However, LF antiviral activity is repurposed and under investigation with related compounds under a phase-I trial as a SARS CoV-2 antiviral in cases with COVID-19. Despite success in improving patients' mobility and reducing joint destruction, reported events of LF-induced liver injury necessitated regulatory precautions. LF should not be used in patients with hepatic impairment or in combination with drugs elaborating a burden on the liver without regular monitoring of liver enzymes and serum bilirubin as safety biomarkers. This study aims to review the pharmacological and safety profile of LF with a focus on the LF-induced hepatic injury from the perspective of pathophysiology and possible protective agents.

Matched MeSH terms: Antineoplastic Agents/adverse effects; Antineoplastic Agents/pharmacology; Antineoplastic Agents/therapeutic use
Fulltext RSK1 vs. RSK2 Inhibitory Activity of the Marine β-Carboline Alkaloid Manzamine A: A Biochemical, Cervical Cancer Protein Expression, and Computational Study

Mayer AMS, Hall ML, Lach J, Clifford J, Chandrasena K, Canton C, et al.

Mar Drugs, 2021 Sep 07;19(9).
PMID: 34564169 DOI: 10.3390/md19090506

Manzamines are complex polycyclic marine-derived β-carboline alkaloids with reported anticancer, immunostimulatory, anti-inflammatory, antibacterial, antiviral, antimalarial, neuritogenic, hyperlipidemia, and atherosclerosis suppression bioactivities, putatively associated with inhibition of glycogen synthase kinase-3, cyclin-dependent kinase 5, SIX1, and vacuolar ATPases. We hypothesized that additional, yet undiscovered molecular targets might be associated with Manzamine A's (MZA) reported pharmacological properties. We report here, for the first time, that MZA selectively inhibited a 90 kDa ribosomal protein kinase S6 (RSK1) when screened against a panel of 30 protein kinases, while in vitro RSK kinase assays demonstrated a 10-fold selectivity in the potency of MZA against RSK1 versus RSK2. The effect of MZA on inhibiting cellular RSK1 and RSK2 protein expression was validated in SiHa and CaSki human cervical carcinoma cell lines. MZA's differential binding and selectivity toward the two isoforms was also supported by computational docking experiments. Specifically, the RSK1-MZA (N- and C-termini) complexes appear to have stronger interactions and preferable energetics contrary to the RSK2-MZA ones. In addition, our computational strategy suggests that MZA binds to the N-terminal kinase domain of RSK1 rather than the C-terminal domain. RSK is a vertebrate family of cytosolic serine-threonine kinases that act downstream of the ras-ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, which phosphorylates substrates shown to regulate several cellular processes, including growth, survival, and proliferation. Consequently, our findings have led us to hypothesize that MZA and the currently known manzamine-type alkaloids isolated from several sponge genera may have novel pharmacological properties with unique molecular targets, and MZA provides a new tool for chemical-biology studies involving RSK1.

Matched MeSH terms: Antineoplastic Agents/pharmacology; Antineoplastic Agents/therapeutic use*; Antineoplastic Agents/chemistry
Fulltext Mycomedicine: A Unique Class of Natural Products with Potent Anti-tumour Bioactivities

Dai R, Liu M, Nik Nabil WN, Xi Z, Xu H

Molecules, 2021 Feb 19;26(4).
PMID: 33669877 DOI: 10.3390/molecules26041113

Mycomedicine is a unique class of natural medicine that has been widely used in Asian countries for thousands of years. Modern mycomedicine consists of fruiting bodies, spores, or other tissues of medicinal fungi, as well as bioactive components extracted from them, including polysaccharides and, triterpenoids, etc. Since the discovery of the famous fungal extract, penicillin, by Alexander Fleming in the late 19th century, researchers have realised the significant antibiotic and other medicinal values of fungal extracts. As medicinal fungi and fungal metabolites can induce apoptosis or autophagy, enhance the immune response, and reduce metastatic potential, several types of mushrooms, such as Ganoderma lucidum and Grifola frondosa, have been extensively investigated, and anti-cancer drugs have been developed from their extracts. Although some studies have highlighted the anti-cancer properties of a single, specific mushroom, only limited reviews have summarised diverse medicinal fungi as mycomedicine. In this review, we not only list the structures and functions of pharmaceutically active components isolated from mycomedicine, but also summarise the mechanisms underlying the potent bioactivities of several representative mushrooms in the Kingdom Fungi against various types of tumour.

Matched MeSH terms: Antineoplastic Agents/pharmacology; Antineoplastic Agents/therapeutic use*; Antineoplastic Agents/chemistry
Fulltext Anticancer and antitumor potential of fucoidan and fucoxanthin, two main metabolites isolated from brown algae

Zorofchian Moghadamtousi S, Karimian H, Khanabdali R, Razavi M, Firoozinia M, Zandi K, et al.

ScientificWorldJournal, 2014;2014:768323.
PMID: 24526922 DOI: 10.1155/2014/768323

Seaweed is one of the largest producers of biomass in marine environment and is a rich arsenal of active metabolites and functional ingredients with valuable beneficial health effects. Being a staple part of Asian cuisine, investigations on the crude extracts of Phaeophyceae or brown algae revealed marked antitumor activity, eliciting a variety of research to determine the active ingredients involved in this potential. The sulfated polysaccharide of fucoidan and carotenoid of fucoxanthin were found to be the most important active metabolites of brown algae as potential chemotherapeutic or chemopreventive agents. This review strives to provide detailed account of all current knowledge on the anticancer and antitumor activity of fucoidan and fucoxanthin as the two major metabolites isolated from brown algae.

Matched MeSH terms: Antineoplastic Agents/isolation & purification; Antineoplastic Agents/metabolism*; Antineoplastic Agents/therapeutic use
Fulltext Anticancer nanodelivery system with controlled release property based on protocatechuate-zinc layered hydroxide nanohybrid

Barahuie F, Hussein MZ, Abd Gani S, Fakurazi S, Zainal Z

Int J Nanomedicine, 2014;9:3137-49.
PMID: 25061291 DOI: 10.2147/IJN.S59541

BACKGROUND: We characterize a novel nanocomposite that acts as an efficient anticancer agent.
METHODS: This nanocomposite consists of zinc layered hydroxide intercalated with protocatechuate (an anionic form of protocatechuic acid), that has been synthesized using a direct method with zinc oxide and protocatechuic acid as precursors.
RESULTS: The resulting protocatechuic acid nanocomposite (PAN) showed a basal spacing of 12.7 Å, indicating that protocatechuate was intercalated in a monolayer arrangement, with an angle of 54° from the Z-axis between the interlayers of the zinc layered hydroxide, and an estimated drug loading of about 35.7%. PAN exhibited the properties of a mesoporous type material, with greatly enhanced thermal stability of protocatechuate as compared to its free counterpart. The presence of protocatechuate in the interlayers of the zinc layered hydroxide was further supported by Fourier transform infrared spectroscopy. Protocatechuate was released from PAN in a slow and sustained manner. This mechanism of release was well represented by a pseudo-second order kinetics model. PAN has shown increased cytotoxicity compared to the free form of protocatechuic acid in all cancer cell lines tested. Tumor growth suppression was extensive, particularly in HepG2 and HT29 cell lines.
CONCLUSION: PAN is suitable for use as a controlled release formulation, and our in vitro evidence indicates that PAN is an effective anticancer agent. PAN may have potential as a chemotherapeutic drug for human cancer.

Matched MeSH terms: Antineoplastic Agents/pharmacokinetics*; Antineoplastic Agents/toxicity; Antineoplastic Agents/chemistry
A new chromanone acid from the stem bark of Calophyllum teysmannii

Lim CK, Subramaniam H, Say YH, Jong VY, Khaledi H, Chee CF

Nat Prod Res, 2015;29(21):1970-7.
PMID: 25716662 DOI: 10.1080/14786419.2015.1015020

A new chromanone acid, namely caloteysmannic acid (1), along with three known compounds, calolongic acid (2), isocalolongic acid (3) and stigmasterol (4) were isolated from the stem bark of Calophyllum teysmannii. All these compounds were evaluated for their cytotoxic and antioxidant activities in the MTT and DPPH assays, respectively. The structure of compound 1 was determined by means of spectroscopic methods including 1D and 2D NMR experiments as well as HR-EIMS spectrometry. The stereochemical assignment of compound 1 was done based on the NMR results and X-ray crystallographic analysis. The preliminary assay results revealed that all the test compounds displayed potent inhibitory activity against HeLa cancer cell line, in particular with compound 1 which exhibited the highest cytotoxic activity comparable to the positive control used, cisplatin. However, no significant antioxidant activity was observed for all the test compounds in the DPPH radical scavenging capacity assay.

Matched MeSH terms: Antineoplastic Agents, Phytogenic/isolation & purification; Antineoplastic Agents, Phytogenic/chemistry*
Fulltext Evaluation of selected honey and one of its phenolic constituent eugenol against L1210 lymphoid leukemia

Jaganathan SK, Mondhe D, Wani ZA, Supriyanto E

ScientificWorldJournal, 2014;2014:912051.
PMID: 25506620 DOI: 10.1155/2014/912051

People affected with leukemia are on the rise and several strategies were employed to thwart this deadly disease. Recent decade of research focuses on phenolic constituents as a tool for combating various inflammatory, cancer, and cardiac diseases. Our research showed honey and its phenolic constituents as crusaders against cancer. In this work, we explored the antileukemic activity of selected honey and one of its phenolic constituent eugenol against L1210 leukemia animal model. Results of this experiment showed that the selected honey samples as well as eugenol after intraperitoneal injection could not increase the median survival time (MST) of animals. Further, there was only slight marginal increase in the %T/C values of honey and eugenol treated groups. The number of phenolics present in the honey may not be a prime factor to promote antileukemic effect since there was no difference in the MST of two different honeys tested. This study limits the use of selected honey and eugenol against leukemia animal model.

Matched MeSH terms: Antineoplastic Agents/pharmacology; Antineoplastic Agents/therapeutic use
Fulltext Facile, regio- and diastereoselective synthesis of spiro-pyrrolidine and pyrrolizine derivatives and evaluation of their antiproliferative activities

Almansour AI, Kumar RS, Beevi F, Shirazi AN, Osman H, Ismail R, et al.

Molecules, 2014 Jul 10;19(7):10033-55.
PMID: 25014532 DOI: 10.3390/molecules190710033

A number of novel spiro-pyrrolidines/pyrrolizines derivatives were synthesized through [3+2]-cycloaddition of azomethine ylides with 3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones 2a-n. Azomethine ylides were generated in situ from the reaction of 1H-indole-2,3-dione (isatin, 3) with N-methylglycine (sarcosine), phenylglycine, or proline. All compounds (50 μM) were evaluated for their antiproliferative activity against human breast carcinoma (MDA-MB-231), leukemia lymphoblastic (CCRF-CEM), and ovarian carcinoma (SK-OV-3) cells. N-α-Phenyl substituted spiro-pyrrolidine derivatives (5a-n) showed higher antiproliferative activity in MDA-MB-231 than other cancer cell lines. Among spiro-pyrrolizines 6a-n, a number of derivatives including 6a-c and 6i-m showed a comparable activity with doxorubicin in all three cell lines. Among all compounds in three classes, 6a, 6b, and 6m, were found to be the most potent derivatives showing 64%, 87%, and 74% antiproliferative activity in MDA-MB-231, SK-OV-3, and CCRF-CEM cells, respectively. Compound 6b showed an IC50 value of 3.6 mM in CCRF-CEM cells. These data suggest the potential antiproliferative activity of spiro-pyrrolidines/pyrrolizines.

Matched MeSH terms: Antineoplastic Agents/chemical synthesis; Antineoplastic Agents/pharmacology
A review on antiproliferative and apoptotic activities of natural honey

Jaganathan SK, Balaji A, Vellayappan MV, Asokan MK, Subramanian AP, John AA, et al.

Anticancer Agents Med Chem, 2015;15(1):48-56.
PMID: 25052987

Recent statistics revealed that cancer is one among the main reasons for death throughout the world. Several treatments are available but still there is no cure when it is detected at late stages. One of the treatment modes for cancer is chemotherapy which utilizes anticancer drugs in order to eradicate the cancer cells by apoptosis. Apoptosis is a programmed cell death through which body maintains homeostasis or kills cancer cells by utilizing its cell machinery. Recent researches have concluded that dietary agents have a putative role in instituting apoptosis of cancer cells. Honey, one of the victuals rich in antioxidants, has a long-standing exposure to humans and its role in cancer prevention and treatment is a topic of current interest. Various researchers have been experimenting honey against different cancers and provided valuable insights about the apoptosis induced by the honey. This review will highlight the recent findings of apoptotic mechanism involved in different cancer cells. Further it also reports antitumor activity of honey in some animal models. Hence it is high-time to initiate more preclinical trials as well as clinical experiments which would further add to the knowledge of anticancer nature of honey and also endorse honey as a potential candidate in the war against cancer.

Matched MeSH terms: Antineoplastic Agents/pharmacology*; Antineoplastic Agents/therapeutic use*

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