Anticancer Agents

1.
Biomed Pharmacother. 2017 Feb 17;89:146-151. doi: 10.1016/j.biopha.2017.02.003. [Epub ahead of print]
Technetium-99m radiolabeled paclitaxel as an imaging probe for breast cancer in vivo.
Monteiro LO1, Fernandes RS1, Castro LC1, Cardoso VN2, Oliveira MC1, Townsend DM3, Ferretti A4, Rubello D5, Leite EA1, de Barros AL6.
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Abstract
The high incidence and mortality of breast cancer supports efforts to develop innovative imaging probes to effectively diagnose, evaluate the extent of the tumor, and predict the efficacy of tumor treatments while concurrently and selectively delivering anticancer agents to the cancer tissue. In the present study we described the preparation of technetium-99m (99mTc)-labeled paclitaxel (PTX) and evaluated its feasibility as a radiotracer for breast tumors (4T1) in BALB/c mice. Thin Layer Chromatography (TLC) was used to determine the radiochemical purity and in vitro stability of 99mTc-PTX. PTX micelles showed a unimodal distribution with mean diameter of 13.46±0.06nm. High radiochemical purity (95.8±0.3%) and in vitro stability (over than 95%), up to 24h, were observed. Blood circulation time of 99mTc-PTX was determined in healthy BALB/c mice. 99mTc-PTX decays in a one-phase manner with a half-life of 464.3 minutes. Scintigraphic images and biodistribution were evaluated at 4, 8 and 24h after administration of 99mTc-PTX in 4T1 tumor-bearing mice. The data showed a significant uptake in the liver, spleen and kidneys, due to the importance of these routes for excretion. Moreover, high tumor uptake was achieved, indicated by high tumor-to-muscle ratios. These findings indicate the usefulness of 99mTc-PTX as a radiotracer to identify 4T1 tumor in animal models. In addition, 99mTc-PTX might be used to follow-up treatment protocols in research, being able to provide information about tumor progression after therapy.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.

KEYWORDS:
4T1 tumor; Biodistribution profile; Breast cancer; Paclitaxel; Scintigraphic images
PMID: 28222395 DOI: 10.1016/j.biopha.2017.02.003
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Select item 28222318
2.
Eur J Med Chem. 2017 Feb 10;129:186-208. doi: 10.1016/j.ejmech.2017.02.021. [Epub ahead of print]
Design, synthesis, biological evaluation and molecular modeling study of novel macrocyclic bisbibenzyl analogues as antitubulin agents.
Sun B1, Li L2, Hu QW2, Zheng HB2, Tang H2, Niu HM3, Yuan HQ3, Lou HX4.
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Abstract
A series of macrocyclic bisbibenzyls with novel skeletons was designed, synthesized, and evaluated for antiproliferative activity against five anthropic cancer cell lines. Among these novel molecules, compound 47 displayed excellent anticancer activity against HeLa, k562, HCC1428, HT29 and PC-3/Doc cell lines, with IC50 values ranging from of 1.51 μM-5.51 μM, which were more potent than the parent compound, marchantin C. Compounds 44 and 55 with novel bisbibenzyl skeletons also exhibited significantly improved antiproliferative potency. Structure-activity relationship (SAR) analyses of these synthesized compounds were also performed. In addition, compound 47 effectively inhibited tubulin polymerization in HCC1482 cells and induced HCC1482 cell cycle arrest at the G2/M phase in a concentration-dependent manner. The binding mode of compound 47 to tubulin was also investigated utilizing a molecular docking study. In conclusion, the present study discovered several potent antitubulin compounds with novel bisbibenzyl skeletons, and our systematic studies revealed new scaffolds that target tubulin and mitosis and provide progress towards the discovery of novel antitumor drugs discovery.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.

KEYWORDS:
Anticancer; Bisbibenzyls; Molecular modeling; Tubulin polymerization inhibitors
PMID: 28222318 DOI: 10.1016/j.ejmech.2017.02.021
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Select item 28221346
3.
Nat Chem. 2017 Mar;9(3):264-272. doi: 10.1038/nchem.2657. Epub 2016 Nov 21.
Synthesis of ent-BE-43547A1 reveals a potent hypoxia-selective anticancer agent and uncovers the biosynthetic origin of the APD-CLD natural products.
Villadsen NL1, Jacobsen KM1, Keiding UB1,2, Weibel ET1, Christiansen B1, Vosegaard T1,3, Bjerring M1,3, Jensen F1, Johannsen M2, Tørring T1,3, Poulsen TB1.
Author information
Abstract
Tumour hypoxia is speculated to be a key driver of therapeutic resistance and metastatic dissemination. Consequently, the discovery of new potent agents that selectively target the hypoxic cell population may reveal new and untapped antitumour mechanisms. Here we demonstrate that the BE-43547 subclass of the APD-CLD (amidopentadienoate-containing cyclolipodepsipeptides) natural products possesses highly hypoxia-selective growth-inhibitory activity against pancreatic cancer cells. To enable this discovery, we have developed the first synthesis of the BE-43547-macrocyclic scaffold in 16 steps (longest linear sequence), which also allowed access to the full panel of relative stereoisomers and ultimately to the assignment of stereochemical configuration. Discrepancies between the spectroscopic signatures of the synthetic compounds with that originally reported for the BE-43547 members stimulated us to re-isolate the natural product from a BE-43547-producing microorganism during which we elucidated the biosynthetic gene clusters for the BE-43547 family as well as for all other known APD-CLDs. Our studies underline the exciting possibilities for the further development of the anticancer activities of these natural products.
PMID: 28221346 DOI: 10.1038/nchem.2657
[PubMed - in process]
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Select item 28218686
4.
Molecules. 2017 Feb 17;22(2). pii: E308. doi: 10.3390/molecules22020308.
Natural Products as Chemopreventive Agents by Potential Inhibition of the Kinase Domain in ErbB Receptors.
Olivero-Acosta M1, Maldonado-Rojas W2, Olivero-Verbel J3.
Author information
Abstract
Small molecules found in natural products provide therapeutic benefits due to their pharmacological or biological activity, which may increase or decrease the expression of human epidermal growth factor receptor (HER), a promising target in the modification of signaling cascades involved in excessive cellular growth. In this study, in silico molecular protein-ligand docking protocols were performed with AutoDock Vina in order to evaluate the interaction of 800 natural compounds (NPs) from the NatProd Collection (http://ift.tt/2kwY8SJ), with four human HER family members: HER1 (PDB: 2ITW), HER2 (PDB: 3PP0), HER3 (PDB: 3LMG) and HER4 (PDB: 2R4B). The best binding affinity values (kcal/mol) for docking pairs were obtained for HER1-podototarin (-10.7), HER2-hecogenin acetate (-11.2), HER3-hesperidin (-11.5) and HER4-theaflavin (-10.7). The reliability of the theoretical calculations was evaluated employing published data on HER inhibition correlated with in silico binding calculations. IC50 values followed a significant linear relationship with the theoretical binding Affinity data for HER1 (R = 0.656, p < 0.0001) and HER2 (R = 0.543, p < 0.0001), but not for HER4 (R = 0.364, p > 0.05). In short, this methodology allowed the identification of several NPs as HER inhibitors, being useful in the discovery and design of more potent and selective anticancer drugs.
KEYWORDS:
AutoDock Vina; HER receptors; molecular docking; natural compounds
PMID: 28218686 DOI: 10.3390/molecules22020308
[PubMed - in process] Free full text
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Select item 28218257
5.
Nat Rev Clin Oncol. 2017 Feb 20;14(3):133-134. doi: 10.1038/nrclinonc.2017.12.
Approvals in 2016: cost-benefit challenges of new anticancer agents.
Savage P1.
Author information
PMID: 28218257 DOI: 10.1038/nrclinonc.2017.12
[PubMed - in process]
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Select item 28217550
6.
J Adv Pharm Technol Res. 2017 Jan-Mar;8(1):19-24. doi: 10.4103/2231-4040.197371.
Antidiabetic and anticancer activities of Mangifera indica cv. Okrong leaves.
Ganogpichayagrai A1, Palanuvej C1, Ruangrungsi N2.
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Abstract
Diabetes and cancer are a major global public health problem. Plant-derived agents with undesirable side-effects were required. This study aimed to evaluate antidiabetic and anticancer activities of the ethanolic leaf extract of Mangifera indica cv. Okrong and its active phytochemical compound, mangiferin. Antidiabetic activities against yeast α-glucosidase and rat intestinal α-glucosidase were determined using 1 mM of p-nitro phenyl-α-D-glucopyranoside as substrate. Inhibitory activity against porcine pancreatic α-amylase was performed using 1 mM of 2-chloro-4 nitrophenol-α-D-maltotroside-3 as substrate. Nitrophenol product was spectrophotometrically measured at 405 nm. Anticancer activity was evaluated against five human cancer cell lines compared to two human normal cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Mango leaf extract and mangiferin exhibited dose-dependent inhibition against yeast α-glucosidase with the IC50 of 0.0503 and 0.5813 mg/ml, respectively, against rat α-glucosidase with the IC50 of 1.4528 and 0.4333 mg/ml, respectively, compared to acarbose with the IC50 of 11.9285 and 0.4493 mg/ml, respectively. For anticancer activity, mango leaf extract, at ≥200 μg/ml showed cytotoxic potential against all tested cancer cell lines. In conclusion, mango leaf possessed antidiabetic and anticancer potential in vitro.
KEYWORDS:
Anticancer; Mangifera indica L.; antidiabetic; mangiferin
PMID: 28217550 PMCID: PMC5288965 DOI: 10.4103/2231-4040.197371
[PubMed - in process] Free PMC Article
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Select item 28217315
7.
ESC Heart Fail. 2017 Feb;4(1):71-74. doi: 10.1002/ehf2.12113. Epub 2016 Sep 21.
Gemcitabine induced cardiomyopathy: a case of multiple hit cardiotoxicity.
Mohebali D1, Matos J2, Chang JD3.
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Abstract
Gemcitabine is a commonly used antineoplastic agent used to treat a variety of cancers with rarely reported cardiac side effects. We describe a case of a 67-year-old woman with follicular lymphoma who experienced a rarely reported side effect of gemcitabine: cardiomyopathy. This case highlights a multiple hit mechanism of myocyte damage that may occur following the use of multiple cardio-toxic agents despite their administration in doses not associated with cardiotoxicity.
KEYWORDS:
Cardiomyopathy; Cardio‐oncology; Chemotherapy
PMID: 28217315 PMCID: PMC5292629 DOI: 10.1002/ehf2.12113
[PubMed] Free PMC Article
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Select item 28217276
8.
Medchemcomm. 2016 Dec 1;7(12):2418-2427. doi: 10.1039/C6MD00459H. Epub 2016 Sep 22.
Synthesis and Biological Evaluation of Benzocyclooctene-based and Indene-based Anticancer Agents that Function as Inhibitors of Tubulin Polymerization.
Herdman CA1, Strecker TE1, Tanpure RP1, Chen Z1, Winters A2, Gerberich J2, Liu L2, Hamel E3, Mason RP2, Chaplin DJ4, Trawick ML1, Pinney KG1.
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Abstract
The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs). Combination of salient structural features associated with colchicine and CA4 led to the design and synthesis of a variety of fused aryl-cycloalkyl and aryl-heterocyclic compounds that function as inhibitors of tubulin polymerization. Prominent among these compounds is a benzosuberene analogue (referred to as KGP18), which demonstrates sub-nM cytotoxicity against human cancer cell lines and functions (when administered as a water-soluble prodrug salt) as a VDA in mouse models. Structure activity relationship considerations led to the evaluation of benzocyclooctyl [6,8 fused] and indene [6,5 fused] ring systems. Four benzocyclooctene and four indene analogues were prepared and evaluated biologically. Three of the benzocyclooctene analogues were active as inhibitors of tubulin polymerization (IC50 < 5 μM), and benzocyclooctene phenol 23 was comparable to KGP18 in terms of potency. The analogous indene-based compound 31 also functioned as an inhibitor of tubulin polymerization (IC50 = 11 μM) with reduced potency. The most potent inhibitor of tubulin polymerization from this group was benzocyclooctene analogue 23, and it was converted to its water-soluble prodrug salt 24 to assess its potential as a VDA. Preliminary in vivo studies, which utilized the MCF7-luc-GFP-mCherry breast tumor in a SCID mouse model, demonstrated that treatment with 24 (120 mg/kg) resulted in significant vascular shutdown, as evidenced by bioluminescence imaging at 4 h post administration, and that the effect continued at both 24 and 48 h. Contemporaneous studies with CA4P, a clinically relevant VDA, were carried out as a positive control.
KEYWORDS:
benzocyclooctene analogues; bioluminescence imaging (BLI); indene analogues; inhibitors of tubulin polymerization; small-molecule synthesis; vascular disrupting agents (VDAs)
PMID: 28217276 PMCID: PMC5308454 [Available on 2017-12-01] DOI: 10.1039/C6MD00459H
[PubMed]
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Select item 28216624
9.
Acta Pharmacol Sin. 2017 Feb 20. doi: 10.1038/aps.2016.166. [Epub ahead of print]
Dual-targeted hybrid nanoparticles of synergistic drugs for treating lung metastases of triple negative breast cancer in mice.
Zhang T1, Prasad P1, Cai P1, He C1, Shan D1, Rauth AM2, Wu XY1.
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Abstract
Lung metastasis is the major cause of death in patients with triple negative breast cancer (TNBC), an aggressive subtype of breast cancer with no effective therapy at present. It has been proposed that dual-targeted therapy, ie, targeting chemotherapeutic agents to both tumor vasculature and cancer cells, may offer some advantages. The present work was aimed to develop a dual-targeted synergistic drug combination nanomedicine for the treatment of lung metastases of TNBC. Thus, Arg-Gly-Asp peptide (RGD)-conjugated, doxorubicin (DOX) and mitomycin C (MMC) co-loaded polymer-lipid hybrid nanoparticles (RGD-DMPLN) were prepared and characterized. The synergism between DOX and MMC and the effect of RGD-DMPLN on cell morphology and cell viability were evaluated in human MDA-MB-231 cells in vitro. The optimal RGD density on nanoparticles (NPs) was identified based on the biodistribution and tumor accumulation of the NPs in a murine lung metastatic model of MDA-MB-231 cells. The microscopic distribution of RGD-conjugated NPs in lung metastases was examined using confocal microscopy. The anticancer efficacy of RGD-DMPLN was investigated in the lung metastatic model. A synergistic ratio of DOX and MMC was found in the MDA-MB-231 human TNBC cells. RGD-DMPLN induced morphological changes and enhanced cytotoxicity in vitro. NPs with a median RGD density showed the highest accumulation in lung metastases by targeting both tumor vasculature and cancer cells. Compared to free drugs, RGD-DMPLN exhibited significantly low toxicity to the host, liver and heart. Compared to non-targeted DMPLN or free drugs, administration of RGD-DMPLN (10 mg/kg, iv) resulted in a 4.7-fold and 31-fold reduction in the burden of lung metastases measured by bioluminescence imaging, a 2.4-fold and 4.0-fold reduction in the lung metastasis area index, and a 35% and 57% longer median survival time, respectively. Dual-targeted RGD-DMPLN, with optimal RGD density, significantly inhibited the progression of lung metastasis and extended host survival.
PMID: 28216624 DOI: 10.1038/aps.2016.166
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Select item 28216402
10.
Bioorg Med Chem Lett. 2017 Feb 1. pii: S0960-894X(17)30110-5. doi: 10.1016/j.bmcl.2017.01.088. [Epub ahead of print]
Synthesis of novel spiro[pyrazolo[4,3-d]pyrimidinones and spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,3'-indoline]-2',4(3H)-diones and their evaluation for anticancer activity.
Ismail1, Kuthati B1, Thalari G1, Bommarapu V2, Mulakayala C3, Chitta SK3, Mulakayala N4.
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Abstract
An efficient and novel method for the preparation of spiro[pyrazolo[4,3-d]pyrimidin]-7'(1'H)-ones by the condensation of 4-amino-1-methyl-3-propylpyrazole-5-carboxamide with ketones under mild conditions using catalytic InCl3 was reported. This method has been extended for the synthesis of novel spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,3'-indoline]-2',4(3H)-dione which are having potential applications in medicinal chemistry. All the synthesized compounds were evaluated for their anti-proliferative properties in vitro against cancer cell lines and several compounds were found to be active. Further in vitro studies revealed that inhibition of sirtuins could be the possible mechanism of action of these molecules.
Copyright © 2017 Elsevier Ltd. All rights reserved.

KEYWORDS:
4-Amino-1-methyl-3-propylpyrazole-5-carboxamide; Anticancer agents; InCl(3); Spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,3′-indoline]-2′,4(3H)-dione; Spiro[pyrazolo[4,3-d]pyrimidin]-7′(1′H)-ones
PMID: 28216402 DOI: 10.1016/j.bmcl.2017.01.088
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Select item 28216371
11.
Cancer Lett. 2017 Feb 16. pii: S0304-3835(17)30106-4. doi: 10.1016/j.canlet.2017.02.006. [Epub ahead of print]
ATP-binding cassette transporters in tumor endothelial cells and resistance to metronomic chemotherapy.
Hida K1, Kikuchi H2, Maishi N3, Hida Y4.
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Abstract
Drug resistance is a major problem in anticancer therapy. ATP-binding cassette (ABC) transporters have a role in the multidrug resistance. A new regimen of chemotherapy has been proposed, called "metronomic chemotherapy". Metronomic chemotherapy is the frequent, regular administration of drug doses designed to maintain low, but active, concentrations of chemotherapeutic drugs over prolonged periods of time, without causing serious toxicities. Metronomic chemotherapy regimens were developed to optimize the antitumour efficacy of agents that target the tumour vasculature instead of tumour cells, and to reduce toxicity of antineoplastic drugs" [1]. Nevertheless, recent studies revealed that ABC transporters are expressed at a higher level in the endothelium in the tumor. To avoid resistance to metronomic anti-angiogenic chemotherapy, ABC transporter inhibition of tumor endothelial cells may be a promising strategy. In this mini-review, we discuss the possible mechanism of resistance to metronomic chemotherapy from the viewpoint of tumor endothelial cell biology, focusing on ABC transporters.
Copyright © 2017. Published by Elsevier B.V.

KEYWORDS:
ABC transporters; anti-angiogenic therapy; drug resistance; metronomic chemotherapy; tumors endothelial cells
PMID: 28216371 DOI: 10.1016/j.canlet.2017.02.006
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Select item 28215600
12.
Bioorg Chem. 2017 Feb 1. pii: S0045-2068(16)30350-9. doi: 10.1016/j.bioorg.2017.01.020. [Epub ahead of print]
Synthesis of dual-action parthenolide prodrugs as potent anticancer agents.
Taleghani A1, Nasseri MA1, Iranshahi M2.
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Abstract
Cancer stem cells are responsible for the failure of a large number of cancer treatments and the re-emergence of cancer in patients. Parthenolide is a potent anticancer sesquiterpene lactone that is also able to kill cancer stem cells. The main problem with this compound is its poor solubility in water. To solve this problem, medicinal chemists have tried to prepare amino-derivatives of parthenolide, however, most amino-derivatives have less potency than that of parthenolide. In this paper, we proposed a new approach to synthesize parthenolide derivatives with better solubility and higher potency. We prepared novel parthenolide derivatives through the aza-Michael addition of nitrogen-containing anticancer drug molecules (cytarabine and melphalan) to the α-methylene-γ-lactone group of parthenolide. Different types of catalysts were used to catalyze the aza-Michael addition. Among all the used catalysts, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) was found to have the highest catalytic activity. In addition, we examined the effects of parthenolide-anticancer drug hybrids on the growth and proliferation of three cancer cell lines (MCF-7, LNcaP, Hep G2) and CHO. The parthenolide prodrugs showed potent cytotoxic property with IC50 values ranging from 0.2 to 5.2μM, higher than those of parthenolide and anticancer drugs (cytarabine and melphalan).
Copyright © 2017 Elsevier Inc. All rights reserved.

KEYWORDS:
Cytarabine; Cytotoxic activity; Melphalan; Parthenolide; aza-Michael addition
PMID: 28215600 DOI: 10.1016/j.bioorg.2017.01.020
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Select item 28215530
13.
Int Rev Cell Mol Biol. 2017;330:115-156. doi: 10.1016/bs.ircmb.2016.09.003. Epub 2016 Nov 29.
Rationale for the Combination of Dendritic Cell-Based Vaccination Approaches With Chemotherapy Agents.
Truxova I1, Hensler M2, Skapa P3, Halaska MJ4, Laco J5, Ryska A5, Spisek R1, Fucikova J6.
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Abstract
Owing to their central role in the initiation and regulation of antitumor immunity, dendritic cells (DCs) have been widely tested for use in cancer immunotherapy. Despite several encouraging clinical applications, existing DC-based immunotherapy efforts have yielded inconsistent results. Recent work has identified strategies that may allow for more potent DC-based vaccines, such as the combination with antitumor agents that have the potential to synergistically enhance DC functions. Selected cytotoxic agents may stimulate DCs either by directly promoting their maturation or through the induction of immunogenic tumor cell death. Moreover, they may support DC-induced adaptive immune responses by disrupting tumor-induced immunosuppressive mechanisms via selective depletion or inhibition of regulatory subsets, such as myeloid-derived suppressor cells and/or regulatory T cells (Tregs). Here, we summarize our current knowledge on the capacity of anticancer chemotherapeutics to modulate DC phenotype and functions and the results of ongoing clinical trials evaluating the use of DC-based immunotherapy in combination with chemotherapy in cancer patients.
© 2017 Elsevier Inc. All rights reserved.

KEYWORDS:
Chemotherapy; Damage-associated molecular patterns; Dendritic cell; Immunogenic cell death; Immunotherapy
PMID: 28215530 DOI: 10.1016/bs.ircmb.2016.09.003
[PubMed - in process]
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Select item 28215320
14.
Adv Food Nutr Res. 2017;80:1-14. doi: 10.1016/bs.afnr.2016.10.001. Epub 2016 Nov 29.
Marine Enzymes in Cancer: A New Paradigm.
Prabhu RH1, Bhise KS1, Patravale VB2.
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Abstract
Over the last decades, the vast chemical and biodiversity of marine environment has been identified as an important source of new anticancer drugs. The evolution of marine life is a result of competition among microorganisms for space and nutrients in the marine environment, which drives marine microorganisms to generate diverse enzyme systems with unique properties to adapt to harsh conditions of ocean. Therefore, marine-derived sources offer novel enzymes endowed with extraordinary properties. Recent advances in cancer therapy have facilitated enzyme therapy as a promising tool. But, the available information on the use of enzymes derived from marine sources as therapeutic agents for cancer therapy is scanty. The potential utility of marine enzymes in cancer therapy will be discussed in this chapter.
© 2017 Elsevier Inc. All rights reserved.

KEYWORDS:
Antiangiogenesis; Anticancer; Apoptosis; Enzyme therapy; Marine enzymes; Nutrient depletion
PMID: 28215320 DOI: 10.1016/bs.afnr.2016.10.001
[PubMed - in process]
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Select item 28215163
15.
Curr Med Chem. 2017 Feb 16. doi: 10.2174/0929867324666170216114248. [Epub ahead of print]
Targeting heparan sulfate proteoglycans and their modifying enzymes to enhance anticancer chemotherapy efficacy and overcome drug resistance.
Lanzi C1, Zaffaroni N, Cassinelli G.
Author information
Abstract
Targeting heparan sulfate proteoglycans (HSPGs) and enzymes involved in heparan sulfate (HS) chain editing is emerging as a new anticancer strategy. The involvement of HSPGs in tumor cell signaling, inflammation, angiogenesis and metastasis indicates that agents able to inhibit aberrant HSPG functions can potentially act as multitarget drugs affecting both tumor cell growth and the supportive boost provided by the microenvironment. Moreover, accumulating evidence supports that an altered expression or function of HSPGs, or of the complex enzyme system regulating their activities, can also depress the tumor response to anticancer treatments in several tumor types. Thereby, targeting HSPGs or HSPG modifying enzymes appears an appealing approach to enhance chemotherapy efficacy. A great deal of effort from academia and industry has led to the development of agents mimicking HS, and/or inhibiting HSPG modifying enzymes. Inhibitors of Sulf-2, an endosulfatase that edits the HS sulfation pattern, and inhibitors of heparanase, the endoglycosidase that produces functional HS fragments, appear particularly promising. In fact, a Sulf-2 inhibitor (OKN-007), and three heparanase inhibitors/HS mimics (roneparstat, necuparanib, PG545) are currently under early clinical investigation. In this review, we summarize preclinical studies in experimental tumor models of the main chemical classes of Sulf-2 and heparanase inhibitors. We describe examples of different mechanisms through which heparanase and HSPGs, often in cooperation, may impact tumor sensitivity to various antitumor agents. Finally, we report a few preclinical studies showing increased antitumor efficacy obtained with the use of candidate clinical HS mimics in combination regimens.
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

KEYWORDS:
Heparan sulfate proteoglycan; anticancer chemotherapy; anticancer drug resistance; heparan sulfate mimic; heparanase; heparanase inhibitor; sulfatase inhibitor
PMID: 28215163 DOI: 10.2174/0929867324666170216114248
[PubMed - as supplied by publisher]
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Select item 28215160
16.
Curr Cancer Drug Targets. 2016 Dec 29. doi: 10.2174/1568009616666161229145115. [Epub ahead of print]
Cathepsin D as a promising target for the discovery of novel anticancer agents.
Dubey V, Luqman S1.
Author information
Abstract
BACKGROUND:
Cathepsin D (CATD), one of the aspartyl endoproteinase involved in different physiological processes and signaling pathways, is accountable for metabolic breakdown of intracellular proteins, activation of growth factors, hormones, and precursors of enzyme, processing of antigens, enzyme inhibitors and activators and regulation of apoptosis. Implication as a Target: Studies have confirmed the role and significance of CATD in an assortment of pathological conditions like Atherosclerosis, Alzheimer, Cancer, Cardiovascular, Huntington and Parkinson diseases. Amalgamated and veiled as inactive proCATD, it undergoes diverse cleavages to attain a desired conformation in an acidic milieu to act as a functionally active protein. In search of new candidate target (s) for cancer, CATD has attracted a wide group of investigators across the globe and is being recognized as a well defined marker in cancer especially for breast and hormone-dependent cancer.
METHODS:
In this review, Pubmed, Sci-finder and other search engines were used to gather information on Catehpsin D. The necessary and relevant information was exploited to make the article an appropriate piece to highlight all the aspects related to Cathepsin D and its role in cancer. Findings & Conclusion: The present review illustrates structural, functional and regulatory aspects of CATD in cancer, its significant role in angiogenesis, metastasis, invasion, apoptosis, cell proliferation, and the therapeutic potential besides benefits of targeting CATD by natural products in cancer chemoprevention.
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

KEYWORDS:
Cathepsin D; aspartic protease; cancer; chemoprevention; natural products
PMID: 28215160 DOI: 10.2174/1568009616666161229145115
[PubMed - as supplied by publisher]
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Select item 28182816
17.
Ann Acad Med Singapore. 2017 Jan;46(1):32-36.
A 13-Year Single Institutional Experience with Definitive Radiotherapy in Hypopharyngeal Cancer.
Sommat K1, Yong SK, Fong KW, Tan TW, Wee JT, Soong YL.
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PMID: 28182816
[PubMed - indexed for MEDLINE] Free full text
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Select item 28182813
18.
Ann Acad Med Singapore. 2017 Jan;46(1):11-19.
Second Malignant Neoplasms in Childhood Cancer Survivors Treated in a Tertiary Paediatric Oncology Centre.
Lim JW1, Yeap FS, Chan YH, Yeoh AE, Quah TC, Tan PL.
Author information
Abstract
Introduction: One of the most feared complications of childhood cancer treatment is second malignant neoplasms (SMNs). This study evaluates the incidence, risk factors and outcomes of SMNs in a tertiary paediatric oncology centre in Singapore. Materials and Methods: A retrospective review was conducted on patients diagnosed with childhood cancer under age 21 and treated at the National University Hospital, Singapore, from January 1990 to 15 April 2012. Case records of patients with SMNs were reviewed. Results: We identified 1124 cases of childhood cancers with a median follow-up of 3.49 (0 to 24.06) years. The most common primary malignancies were leukaemia (47.1%), central nervous system tumours (11.7%) and lymphoma (9.8%). Fifteen cases developed SMNs, most commonly acute myeloid leukaemia/myelodysplastic syndrome (n = 7). Median interval between the first and second malignancy was 3.41 (0.24 to 18.30) years. Overall 20-year cumulative incidence of SMNs was 5.3% (95% CI, 0.2% to 10.4%). The 15-year cumulative incidence of SMNs following acute lymphoblastic leukaemia was 4.4% (95% CI, 0% to 8.9%), significantly lower than the risk after osteosarcoma of 14.2% (95% CI, 0.7% to 27.7%) within 5 years (P <0.0005). Overall 5-year survival for SMNs was lower than that of primary malignancies. Conclusion: This study identified factors explaining the epidemiology of SMNs described, and found topoisomerase II inhibitor use to be a likely risk factor in our cohort. Modifications have already been made to our existing therapeutic protocols in osteosarcoma treatment. We also recognised the importance of other risk management strategies, including regular long-term surveillance and early intervention for detected SMNs, to improve outcomes of high risk patients.
PMID: 28182813
[PubMed - indexed for MEDLINE] Free full text
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MeSH Terms, Substances
Select item 28178720
19.
Cancer Control. 2017 Jan;24(1):89-95.
ERBB4 Expression in Ovarian Serous Carcinoma Resistant to Platinum-Based Therapy.
Saglam O1, Xiong Y2, Marchion DC2, Strosberg C2, Wenham RM3, Johnson JJ4, Saeed-Vafa D2, Cubitt C5, Hakam A2, Magliocco AM6.
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Abstract
Few data exist on the prognostic and predictive impact of erb-b2 receptor tyrosine kinase 4 (ERBB4) in ovarian cancer. Thus, we evaluated ERBB4 expression by immunohistochemistry in a tumor microarray consisting of 100 ovarian serous carcinoma specimens (50 complete responses [CRs] and 50 incomplete responses [IRs] to platinum-based therapy), 51 normal tissue controls, and 16 ovarian cancer cell lines. H scores were used to evaluate expression and were semiquantitatively classified into low, intermediate, and high categories. Category frequencies were compared between tumor specimens vs controls using an unpaired t test. Among tumors, category frequencies were compared between CR and IR to chemotherapy. Overall survival (OS) was stratified by category. In total, 74 ovarian serous carcinoma samples (32 CRs and 42 IRs), 28 normal controls, and 16 ovarian cancer cell lines were evaluable. High-level ERBB4 expression was observed at a significantly higher frequency in ovarian serous carcinoma compared with normal control tissue. Among tumor specimens, ERBB4 expression was significantly higher for those with an IR to chemotherapy compared with CR (P = .033). OS was inversely correlated with ERBB4 expression levels. Median rates of OS were 18, 22, and 58 months among high-, intermediate-, and low-expression tumors, respectively. Our results indicate that ERBB4 expression by immunohistochemistry may correlate with chemotherapy-resistant ovarian serous carcinoma and shortened OS.
PMID: 28178720
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20.
Cancer Control. 2017 Jan;24(1):54-56.
Thrombotic Microangiopathy in a Patient Treated With Gemcitabine.
Nanjappa S1, Singh V2, Uttamchandani S3, Pabbathi S4.
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Abstract
Thrombotic microangiopathy syndromes consist of a collection of disorders with a varied etiology that share common clinical and pathological features. Although thrombotic microangiopathy is rare, it is associated with significant morbidity and mortality. Without early recognition and intervention, the prognosis of the disease is poor. This report illustrates the case of a 56-year-old man with advanced-stage metastatic pancreatic cancer who presented with hemolytic uremic syndrome associated with gemcitabine use. His condition was managed with eculizumab, a monoclonal antibody, although he was dependent on dialysis. This report reflects the importance of considering thrombotic microangiopathy syndromes in the differential diagnosis, because many malignancies and use of chemotherapeutic agents can trigger hemolytic uremic syndrome.
PMID: 28178713
[PubMed - indexed for MEDLINE] Free full text
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