Begell House Inc.
Journal of Environmental Pathology, Toxicology and Oncology
JEP(T)
0731-8898
34
3
2015
Anticancer Property of Iron Oxide Nanoparticle-Drug Complexes: An In Vitro Study
183-189
10.1615/JEnvironPatholToxicolOncol.2015013482
S.
Sreeja
MACFAST, Tiruvalla, Kerala, India
Cherupally Krishnan Krishnan
Nair
Mar Athanasious College for Advanced Studies, Tiruvalla, Tiruvalla, Kerala, India; St.Gregorios Dental College & Research Centre, Kothamangalam, Kerala, India
berberine
sanazole
iron oxide nanoparticles
apoptosis
gene expression
Tumor-specific targeting of chemotherapeutic drugs can increase the therapeutic efficacy of most anticancer drugs. On surface-modified iron oxide nanoparticles (NPs), we complexed a hypoxic cell-targeting agent, sanazole (SAN), and a cytotoxic isoquinoline alkaloid, berberine (BBN). The major objective of this study was to elucidate the molecular mechanism of cytotoxicity in murine tumor cells (DLA) induced by NP−BBN-SAN complexes. The cytotoxicity of these complexes was determined using the dye exclusion method. The induction of apoptosis and cellular DNA damage in these cells was analyzed using dual staining and comet assay, respectively. The expression of genes in the treated cells elucidated the molecular mechanism underlying cytotoxicity. Cells treated with NP−BBN-SAN complexes showed significant increases in cytotoxicity and apoptosis, as well as extensive damage to cellular DNA compared to control cells. The cells treated with NP−BBN-SAN complexes showed greater DNA damage compared with other treatments. The increase in the expression of a pro-apoptotic gene suggested that apoptosis was the mechanism underlying cytotoxicity induced by NP−BBN-SAN complexes. Complexing with SAN increased the cytotoxic potential of NP−BBN complexes. Further in vivo studies are needed to evaluate the potential application of this method in controlling tumors.
Generation of Reactive Oxygen Species and Endoplasmic Reticulum Stress by Dictyopteris undulata Extract Leads to Apoptosis in Human Melanoma Cells
191-200
10.1615/JEnvironPatholToxicolOncol.2015013074
Joon Ki
Kim
Department of Bio and Nanochemistry, Kookmin University, Seoul, Korea
Kyoung Ah
Kang
School of Medicine, Jeju National University, Jeju, Republic of Korea
Mei Jing
Piao
School of Medicine, Jeju National University, Jeju, Republic of Korea
Madduma Hewage Susara Ruwan
Kumara
School of Medicine, Jeju National University, Jeju, Korea
Yong Joo
Jeong
Department of Bio and Nanochemistry, Kookmin University, Seoul, Korea
Mi Hee
Ko
Jeju Biodiversity Research Institute, Jeju Technopark, Jeju, Republic of Korea
Jin Won
Hyuna
School of Medicine, Jeju National University, Jeju, Republic of Korea
Dictyopteris undulata extract
melanoma
mitochondrial Ca2+ levels
In this study, we evaluated the hypothesis that a marine brown algae, Dictyopteris undulata ethanol extract (DUE), provokes apoptosis in a human melanoma cell line, A2058, via reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. DUE inhibited A2058 cell proliferation and increased apoptotic body formation, as indicated by the presence of fragmented nuclei and the activation of caspase-3. Moreover, DUE-treated cells showed elevated ER staining, mitochondrial calcium cation (Ca2+) overloading, augmented levels of ER stress-related and cell death modulatory proteins, including RNA-dependent protein kinase-related ER kinase, phospho-inositol-requiring enzyme 1α, phospho-eukaryotic translation initiation factor 2α, and CCAAT/enhancer-binding protein-homologous protein, as well as increased intracellular ROS levels. However, the antioxidant N-acetyl cysteine reversed the elevated ROS levels, decreased apoptosis, and mitigated ER stress in A2058 cells following DUE treatment. These findings suggest that DUE treatment triggers apoptosis in human melanoma cells through a mechanism involving ER stress and ROS.
Cytoskeletal Focal Adhesion Proteins Fascin-1 and Paxillin Are Predictors of Malignant Progression and Poor Prognosis in Human Breast Cancer
201-212
10.1615/JEnvironPatholToxicolOncol.2015013663
Ola M.
Omran
Departments of Pathology, Faculty of Medicine, Assiut and Qassim Universities, Egypt and Kingdom of Saudi Arabia
Muneera
Al Sheeha
Department of Obstetrics and Gynecology, College of Medicine, Qassim University, Qassim, Saudi Arabia
immunohistochemistry
breast carcinoma
fascin-1
paxillin
Breast cancer is a major health problem in both developing and developed countries. The incremental
motility of malignant cells is a critical step in their migration, invasion, and metastasis and is regulated by the reorganization of the actin cytoskeleton and regulation of focal adhesion. Fascin-1 and paxillin are essential components of these cellular structures. In cancer, the expression level of fascin-1 and paxillin can vary depending on cell type. However, its precise role in breast cancer of Saudi women has not been evaluated in any published study. We investigated fascin-1 and paxillin expression in breast carcinoma, and we have related these results to the established prognostic factors. We studied 100 breast carcinoma specimens. Immunohistochemical analyses for fascin-1 and paxillin were conducted on paraffin sections of breast tissues using the avidin-biotin peroxidase method. Fascin-1 and paxillin were expressed in 58% and 43% of infiltrating duct carcinoma (IDC) cases. There was a statistically
significant correlation between fascin-1 and paxillin expression with each of the following: tumor grade, clinical stage, lymph-node metastasis grade, and HER2 expression. Furthermore, there was a significant correlation between fascin-1 expression with paxillin immunostaining but no such association with PR or ER status. Increased fascin-1 and paxillin expression in IDC cells and their correlation with poor prognostic factors support their strong correlation with tumor progression, invasion, and metastasis in human breast cancer, indicating that these markers can be used as a target for the development of novel therapies.
Role of GLI1 and NDRG1 in Increased Resistance to Apoptosis Induction
213-225
10.1615/JEnvironPatholToxicolOncol.2015013472
Feng
Wu
Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York
William N.
Rom
Division of Pulmonary and Critical Care Medicine, and Department of Environmental Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
Minori
Koshiji
Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York; Clinical Oncology, Merck & Co., Inc., Whitehouse Station, New Jersey
Yiqun
Mo
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, New York University School of Medicine, New York; Department of Environmental and Occupational Health Sciences, University of Louisville, Louisville, Kentucky
Yukio
Hosomi
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, New York University School of Medicine, New York; Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
Kam-Meng
Tchou-Wong
Division of Pulmonary and Critical Care Medicine, and Department of Environmental Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
GLI1
NDRG1
apoptosis
lung cancer
We examined the effects of GLI1 expression in PW mouse embryo fibroblasts and H441 lung carcinoma cells. Ectopic expression of GLI1 in PW cells induced anchorage-independent growth and increased resistance to staurosporine-induced apoptosis, and overexpression of GLI1 in H441 cells caused resistance to apoptosis induced by staurosporine and etoposide. GLI1 expression in both H441 and PW cells was associated with increased expression
of NDRG1, a gene known to be downregulated by the MYC family of proteins, indicating that upregulation of NDRG1 by GLI1 is not cell-type specific. Consistent with suppression of NDRG1 by c-MYC and N-MYC, increased NDRG1 expression correlated with decreased expression of c-MYC and N-MYC in GLI1-expressing H441 and GLI1-expressing PW cells, respectively. Downregulation of GLI1 expression in A549 cells by siRNA transfection increased sensitivity to etoposide-induced apoptosis, and downregulation of NDRG1 expression in H441 cells by siRNA transfection increased sensitivity to etoposide-induced apoptosis. Of clinical significance, inhibition of GLI1 and NDRG1 expression may increase sensitivity of cancer cells to chemotherapeutic drugs. Strategies that aim to inhibit GLI1 function and NDRG1 expression may be useful for targeted therapy of cancers induced by the SHH-GLI signaling pathway.
Fourier Transform Infrared Spectroscopic Studies on Modulation of N-Nitrosodiethylamine-Induced Hepatocarcinogenesis by Azadirachta indica
227-236
10.1615/JEnvironPatholToxicolOncol.2015012145
Sanjay
Bharati
Department of Biophysics, Basic Medical Sciences Block, Panjab University, Chandigarh, India
Parveen
Rishi
Department of Microbiology, Basic Medical Sciences Block, Panjab University, Chandigarh, India
Ashwani
Koul
Department of Biophysics, Basic Medical Sciences Block, Panjab University, Chandigarh, India
chemoprevention
carcinogen metabolism
hepatic tumors
hepatocellular carcinoma
Fourier transform infrared spectroscopy was employed in the present study to obtain information about the molecular composition of hepatic tumor versus hepatic tissue. A hepatic cancer model was developed by administering N-nitrosodiethylamine (NDEA) to male Balb/c mice. The results revealed that NDEA-induced hepatic cancer tumor tissue had altered molecular composition compared with normal liver tissue. Compared with the normal
tissue, the saturation level of membrane phospholipids was observed to be decreased in tumors along with an abnormal distribution of protein secondary structures. A significant decrease in glycogen and a significant increase in total nucleic acid content were also observed in tumor cells. The administration of aqueous Azadirachta indica leaf extract (AAILE) prior to NDEA treatment resulted in the normalization of saturation levels in phospholipids and total nucleic acid content and in the distribution of protein secondary structures in tumors. A significant increase in the amount of stored glycogen was observed in AAILE cotreated tumors compared with NDEA-induced tumors, which might indicate that AAILE cotreatment impeded the ability of tumor cells to consume glucose at a faster rate. The normalization of molecular composition upon AAILE cotreatment in hepatic tumors might indicate that AAILE hampered the process of evolution of tumors, which could be responsible for its observed chemopreventive action.
Development of an Anti-Atherosclerotic Polyherbal Formulation: GSTC3
237-248
10.1615/JEnvironPatholToxicolOncol.2015012673
Jeksy J.
Manalil
Amala Cancer Research Centre (Recognized by University of Calicut, Kerala), Amala Nagar, Kerala, India
Merin
Baby
Amala Cancer Research Centre (Recognized by University of Calicut, Kerala), Amala Nagar, Kerala, India
Smitha K.
Ramavarma
Amala Cancer Research Centre (Recognized by University of Calicut, Kerala), Amala Nagar, Kerala, India
Indu M.
Suseela
Amala Cancer Research Centre (Recognized by University of Calicut, Kerala), Amala Nagar, Kerala, India
Jose
Padikkala
Department of Biochemistry, Amala Cancer Research Centre, Thrissur
Achuthan C.
Raghavamenon
Department of Biochemistry, Amala Cancer Research Centre, Thrissur
hypolipidemic
atherosclerosis
herbal formulation
lipid peroxidation
A polyherbal formulation consisting of different proportions of Commiphora mukul (Hook ex Stocks) Eng., Salacia reticulata Wight, Terminalia arjuna (Roxb.) Wight & Arn, and Curcuma longa Linn extracts was tested for free-radical scavenging and anti-lipid peroxidative effects on serum and platelets in vitro. The most active formulation (GSTC3) was evaluated for its hypolipidemic potential on a high-fat, high-cholesterol diet (HFD) fed to male Wistar rats for a period of 45 days. At a dose of 100 mg/kg body weight, GSTC3 decreased serum total cholesterol, low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), triglycerides, and phospholipids similar to standard atorvastatin while maintaining high-density lipoprotein (HDL) at normal levels. Significantly lower levels of thiobarbituric acid−reactive substances (TBARS) were observed in both the liver and sera of rats treated with GSTC3. Although the phospholipid levels in liver remained unchanged, lower values of LDL, VLDL, and atherogenic index of plasma as well as higher HMG-CoA/ mevalonate ratios suggested a significant hypolipidemic effect for GSTC3, possibly by partial inhibition of HMG-CoA reductase activity. The histopathological analysis of liver tissue did not reveal lipid accumulation or indicate tissue damage. Overall, the results of this study suggest the hypolipidemic and anti-atherogenic efficacy of a nontoxic herbal formulation.
Protective Effect of Solanum muricatum on Tumor Metastasis by Regulating Inflammatory Mediators and Nuclear Factor-Kappa B Subunits
249-262
10.1615/JEnvironPatholToxicolOncol.2015010308
Kittappa
Shathish
Department of Biotechnology, Karunya University, Karunya Nagar, Tamil Nadu, India
Kunnathur Murugesan
Sakthivel
Karunya University, Department of Biotechnology, Karunya Nagar, Coimbatore−641114, Tamil Nadu, India; Laboratory of Cytogenetics and Molecular Diagnostics, Regional Cancer Centre, Medical College Post, Trivandrum 695011, Kerala, India
Chandrasekaran
Guruvayoorappan
Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram - 695011, Kerala, India
metastasis; Solanum muricatum; TNF-α
iNOS
NF-κB
Metastasis is one of the hallmarks of malignant neoplasm or cancer, which is the leading cause of death in many cancer patients. A major challenge in cancer treatment is to find better ways to specifically target tumor metastases. In this study, the anti-metastatic potential of the methanol extract of Solanum muricatum (S. muricatum)
was evaluated using B16F-10 melanoma cell−induced lung metastasis in C57BL/6 mice. Treatment with
S. muricatum significantly inhibited the lung tumor nodule formation and reduced the lung collagen hydroxyproline, hexosamine, and uronic acid levels (p<0.01). Similarly, serum sialic acid and γ-glutamyl transpeptidase levels were also significantly inhibited after S. muricatum treatment. The levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, granulocyte monocyte colony-stimulating factor (GM-CSF), and IL-2 in serum were significantly regulated after treatment with S. muricatum. The serum nitric oxide level was also decreased significantly and was accompanied by a decrease in inducible nitric oxide synthase (iNOS) and cyclo-
oxygenase (COX)-2 expressions after S. muricatum treatment. The present study reveals that S. muricatum treatment was able to alter the proinflammatory cytokine production as well as inhibit the activation and nuclear translocation of nuclear factor-κB (p65 and p50) subunits.
Radioprotective Effect of Carvacrol Against X-Radiation−Induced Cellular Damage in Cultured Human Peripheral Blood Lymphocytes
263-275
10.1615/JEnvironPatholToxicolOncol.2015013548
Sivaranjani
Arivalagan
Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Tamil Nadu, India
Nisha Susan
Thomas
Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Tamil Nadu, India
Thayalan
Kuppusamy
Medical Physics Division, Dr. Kamakshi Memorial Hospital, Pallikaranai, Chennai, Tamil Nadu, India
Nalini
Namashivayam
Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalai Nagar, Tamil Nadu, India
carvacrol
X-radiation
lymphocytes
micronuclei
oxidative stress
In the present study, we evaluated the radioprotective effect of carvacrol (CVC) against X-radiation−induced cellular damage in cultured human blood lymphocytes. By MTT assay, the LD50 doses of CVC and X-radiation to lymphocytes were determined to be 100 μ;g/ml and 4 Gy, respectively. To explore the radioprotective effect of CVC, the cultured lymphocytes were treated with 100 μ;g/mL of CVC 30 min prior to 4 Gy irradiation. Subsequently, the radiation-induced damage was screened by micronuclei (MN) and dicentric chromosome (DC) frequencies and comet assay. The percentage of cell death was evaluated by acridine orange/ethidium bromide (AO/EB) staining. The radiation-induced oxidative stress was estimated by assessing the changes in the levels of enzymatic antioxidants and lipid peroxidation markers. Compared with the sham control, we observed increases in MN and DC frequencies, comet attributes, % cell death, and lipid peroxidation with a concomitant decrease in the antioxidant status of the lymphocytes treated with radiation alone. Pre-treatment of lymphocytes with CVC (100 μ;g/mL) altered those changes mediated by radiation. These results clearly indicate that CVC may be an effective radioprotector against X-radiation. It has the ability to scavenge the free radicals produced and to protect cells from radiation-induced cell damage.