Enhancing the anticancer efficacy of a LL-37 peptide fragment analog using peptide-linked PLGA conjugate micelles in tumor cells

Various epidemiological and preclinical studies have already established the cancer chemopreventive potential of vanadium-based compounds. In addition to its preventive efficacy, studies have also indicated the abilities of vanadium-based compounds to induce cell death selectively toward malignant cells. Therefore, the objective of the present investigation is to improve the therapeutic efficacy and toxicity profile of an alkylating agent, cyclophosphamide, by the concurrent use of an organovanadium complex, vanadium(III)-l-cysteine. In this study, vanadium(III)-l-cysteine (1 mg/kg body weight, per os) was administered alone as well as in combination with cyclophosphamide (25 mg/kg body weight, intraperitoneal) in concomitant and pretreatment schedule in mice bearing breast adenocarcinoma cells. The results showed that the combination treatment significantly decreased the tumor burden and enhanced survivability of tumor-bearing mice through generation of reactive oxygen species in tumor cells. These ultimately led to DNA damage, depolarization of mitochondrial membrane potential, and apoptosis in tumor cells. Further insight into the molecular pathway disclosed that the combination treatment caused upregulation of p53 and Bax and suppression of Bcl-2 followed by the activation of caspase cascade and poly (ADP-ribose) polymerase cleavage. Administration of vanadium(III)-l-cysteine also resulted in significant attenuation of peritoneal vasculature and sprouting of the blood vessels by decreasing the levels of vascular endothelial growth factor A and matrix metalloproteinase 9 in the ascites fluid of tumor-bearing mice. Furthermore, vanadium(III)-l-cysteine significantly attenuated cyclophosphamide-induced hematopoietic, hepatic, and genetic damages and provided additional survival advantages. Hence, this study suggested that vanadium(III)-l-cysteine may offer potential therapeutic benefit in combination with cyclophosphamide by augmenting anticancer efficacy and diminishing toxicity to the host.

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THE APPLICATION OF NANOMATERIALS IN DIAGNOSIS AND TREATMENT FOR MALIGNANT PRIMARY BRAIN TUMORS

NANO ◽

10.1142/s1793292014300011 ◽

2014 ◽

Vol 09 (01) ◽

pp. 1430001 ◽

Cited By ~ 4

Author(s):

RUICHAO LIANG ◽

FANG FANG

Keyword(s):

Brain Tumor ◽

Brain Tumors ◽

Tumor Cells ◽

Primary Brain Tumor ◽

High Morbidity ◽

Convection Enhanced Delivery ◽

Anticancer Efficacy ◽

Agent Based ◽

Diagnostic Strategies ◽

Primary Brain Tumors

Malignant primary brain tumors have a very high morbidity and mortality. Even though enormous advances have been made in primary brain tumor management, in the case of malignant primary brain tumors, current diagnostic strategies cannot identify exact infiltrating margins, surgery alone cannot achieve total mass resection, and adjuvant therapies cannot improve survivals. Therefore, there is an urgent need to explore novel strategies to diagnose and treat such infiltrating brain tumors. Nanomaterials, particularly zero-dimensional and one-dimensional platforms, can carry various compounds such as contrast agents, anticancer drugs and genes into brain tumor cells specifically. Thus, contrast agent-based nanomaterials can selectively present infiltrating tumor outlines, while anticancer agent-based nanomaterials can specifically kill malignant tumor cells. In addition, dual-targeting nanomaterials, multifunctional nanocarriers, theranostic nanovehicles as well as convection-enhanced delivery technology hold promise to increase drug accumulation in tumor tissues, which could largely improve anticancer efficacy. In this review, we will mainly focus on the application of nanomaterials in preoperative diagnosis, intraoperative diagnosis and adjuvant treatment for malignant primary brain tumors.

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Membranous alterations in the cytoplasm and nucleus in a primitive neuroectodermal tumor of the brain

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100084016 ◽

1978 ◽

Vol 36 (2) ◽

pp. 628-629

Author(s):

C. N. Sun ◽

C. Araoz ◽

H. J. White

Keyword(s):

Nuclear Envelope ◽

Tumor Cells ◽

Osmium Tetroxide ◽

Primitive Neuroectodermal Tumor ◽

Uranyl Acetate ◽

Neuroectodermal Tumor ◽

Annulate Lamellae ◽

Lead Citrate ◽

Thin Sections ◽

The Brain

The ultrastructure of a cerebral primitive neuroectodermal tumor has been reported previously. In the present case, we will present some unusual previously unreported membranous structures and alterations in the cytoplasm and nucleus of the tumor cells.Specimens were cut into small pieces about 1 mm3 and immediately fixed in 4% glutaraldehyde in phosphate buffer for two hours, then post-fixed in 1% buffered osmium tetroxide for one hour. After dehydration, tissues were embedded in Epon 812. Thin sections were stained with uranyl acetate and lead citrate.In the cytoplasm of the tumor cells, we found paired cisternae (Fig. 1) and annulate lamellae (Fig. 2) noting that the annulate lamellae were sometimes associated with the outer nuclear envelope (Fig. 3). These membranous structures have been reported in other tumor cells. In our case, mitochondrial to nuclear envelope fusions were often noted (Fig. 4). Although this phenomenon was reported in an oncocytoma, their frequency in the present study is quite striking.

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Ulcerogenic Tumors of the Pancreas

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100100676 ◽

1968 ◽

Vol 26 ◽

pp. 186-187

Author(s):

J. C. Garancis ◽

J. F. Kuzma ◽

S. D. Wilson ◽

E. H. Ellison

Keyword(s):

Endoplasmic Reticulum ◽

Tumor Cells ◽

Islet Cell ◽

Disease Process ◽

Central Core ◽

Islet Cell Tumors ◽

Opaque Zone ◽

Granular Form ◽

Zollinger Ellison Syndrome

It has been proposed that a gastrin-like hormone elaborated by non-beta islet tumors of the pancreas may be responsible for a fulminating ulcer diathesis. Subsequently, a potent gastric secretagogue was isolated from ulcerogenic tumors of the pancreas. This disease process is known now as “Zollinger-Ellison syndrome”.In our studies of two cases of Zollinger-Ellison syndrome, pancreatic lesions were identified as alpha islet cell tumors (Fig. 1). Tumor cells were fairly uniform. The sizes of the alpha granules were not significantly different, but their number and distribution varied greatly from one cell to another. Each granule consisted of a round, highly dense central core, separated from the limiting membrane by an opaque zone. The granular form of the endoplasmic reticulum was particularly prominent. Numerous mitochondria, round or elongated, were dispersed throughout the cytoplasm. Individual or clusters of lysosomes were observed in the majority of cells.

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Glucose metabolism in cancer cells: immunogold localization of hexokinase to the outer mitochondrial membrane

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100141597 ◽

1995 ◽

Vol 53 ◽

pp. 1044-1045

Author(s):

Krishan K. Arora ◽

Glenn L. Decker ◽

Peter L. Pedersen

Keyword(s):

Tumor Cells ◽

Mitochondrial Membrane ◽

Present Report ◽

Large Fraction ◽

Mitochondrial Fraction ◽

Immunogold Labeling ◽

Outer Mitochondrial Membrane ◽

Immunogold Localization ◽

Hexokinase Activity ◽

Normal Tissues

Hexokinase (ATP: D-hexose 6-phophotransferase EC 2.7.1.1) is the first enzyme of the glycolytic pathway which commits glucose to catabolism by catalyzing the phosphorylation of glucose with ATP. Previous studies have shown diat hexokinase activity is markedly elevated in rapidly growing tumor cells exhibiting high glucose catabolic rates. A large fraction (50-80%) of this enzyme activity is bound to the mitochondrial fraction (1,2) where it has preferred access to ATP (3). In contrast,the hexokinase activity of normal tissues is quite low, with one exception being brain which is a glucose-utilizing tissue (4). Biochemical evidence involving rigorous subfractionation studies have revealed striking differences between the subcellular distribution of hexokinase in normal and tumor cells [See review by Arora et al (4)].In the present report, we have utilized immunogold labeling techniques to evaluate die subcellular localization of hexokinase in highly glycolytic AS-30D hepatoma cells and in the tissue of its origin, i.e., rat liver.

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Sequential detection of mRNA for the chemokine IL-8 and macrophages (F4/80) in human melanoma

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010014141x ◽

1995 ◽

Vol 53 ◽

pp. 1008-1009

Author(s):

C.D. Bucana ◽

R. Sanchez ◽

R. Singh ◽

I.J. Fidler

Keyword(s):

Tumor Cells ◽

Nude Mice ◽

Constitutive Expression ◽

Metastatic Potential ◽

Melanoma Cells ◽

Human Melanoma ◽

Angiogenic Factor ◽

Infiltrating Cells ◽

Immunoperoxidase Assay ◽

Multifunctional Cytokine

The purpose of this study was to demonstrate by ISH the presence of IL-8 mRNA, and by immunohistochemistry (IHC) the presence of the chemokine IL-8 and the distribution of infiltrating macrophages in subcutaneous melanomas in the same tumor. IL-8 is a multifunctional cytokine produced by melanoma cells, activated macrophages and monocytes and it has been shown to be a growth and angiogenic factor for tumor cells. More recently it was shown that constitutive expression of IL-8 correlated directly with metastatic potential of human melanoma cells in nude mice. IL-8 content of a solid tumor as determined by Western blot analysis does not take into account the contribution of macrophages. Previous studies showed that murine tumors contain many infiltrating cells interspersed among tumor cells whereas human tumors growing in nude mice exhibit macrophages at the periphery or between tumor islands. In this study we demonstrate the expression of IL-8 and the distribution of macrophages by immunoperoxidase assay and IL-8 mRNA by ISH.

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Temporal and spatial interrelationships of confronting cisternae to nuclear envelope

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100125051 ◽

1992 ◽

Vol 50 (1) ◽

pp. 930-931

Author(s):

John R. Palisano

Keyword(s):

Endoplasmic Reticulum ◽

Nuclear Envelope ◽

Tumor Cells ◽

Hela Cells ◽

Microscopic Investigation ◽

Electron Microscopic Investigation ◽

Serial Sections ◽

Electron Microscopic ◽

Fetal Rat ◽

Temporal And Spatial

Although confronting cistemae (CC) have been observed in a variety of tumor cells and normal fetal rat, mouse, and human epithelial tissues, little is known about their origin or role in mitotic cells. While several investigators have suggested that CC arise from nuclear envelope (NE) folding back on itself during prophase, others have suggested that CC arise when fragments of NE pair with endoplasmic reticulum. An electron microscopic investigation of 0.25 um thick serial sections was undertaken to examine the origin of CC in HeLa cells.

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Effect of pH and inhibitors on beta-amyloid fibril assembly

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100166221 ◽

1996 ◽

Vol 54 ◽

pp. 752-753

Author(s):

Beverly E. Maleeff ◽

Timothy K. Hart ◽

Stephen J. Wood ◽

Ronald Wetzel

Keyword(s):

Amyloid Fibril ◽

Peptide Fragment ◽

Hydrophobic Peptides ◽

Amyloid Fibril Formation ◽

Effects Of Ph ◽

Severity Of The Disease ◽

Kinetics Of ◽

The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

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