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Fulltext Chemopreventive and immunomodulatory effects of Murraya koenigii aqueous extract on 4T1 breast cancer cell-challenged mice

Yeap SK, Abu N, Mohamad NE, Beh BK, Ho WY, Ebrahimi S, et al.

BMC Complement Altern Med, 2015;15:306.
PMID: 26335427 DOI: 10.1186/s12906-015-0832-z

The progression of breast cancer is increasing at an alarming rate, particularly in western countries. Meanwhile, the lower incidence in Asian countries could be attributed to the heavy incorporation of green leaves vegetables or spices in their diets. Murraya koenigii (MK) or often times known as curry leaves are common spice used mostly in tropical countries. Anti-inflammatory and chemopreventive effects of MK aqueous extract on 4T1 breast cancer cell-challenged mice were evaluated.

Matched MeSH terms: Neoplasms, Experimental/pathology
Fulltext A new concept of the formation of hypoxic cells in tumors and its possible implications for radiotherapy and chemotherapy

Ng CE

Med J Malaysia, 1981 Mar;36(1):24-8.
PMID: 7321933

Hypoxic cells in tumors are proposed to consist of at least 2 types, depending on whether they remain hypoxic for long (chronic hypoxia) or short (acute hypoxia) periods. Experimental evidence of the possible presence ofacutely-hypoxic cells in one type of murine tumour is presented. Finally, the possible implications for radiotherapy and chemotherapy of the presence of acutely-hypoxic cells in human tumors is discussed briefly.

Matched MeSH terms: Neoplasms, Experimental/pathology*
The association between phenotype and size of breast tumors induced by 1-methyl-1-nitrosourea (MNU) injection in rats

Jaafar H, Mohamad Idris F, Mohd Nafi SN

Med Sci Monit, 2009 May;15(5):BR129-34.
PMID: 19396029

Administration of 1-methyl-1-nitrosourea (MNU) is considered a simple and rapid method for inducing breast tumors in rats. While most studies focus on the time frame of tumor development, there are little data on the development of breast tumor in relation to tumor size. Thus the current study was carried out to analyze the phenotype of MNU-induced tumors in relation to tumor size.

Matched MeSH terms: Mammary Neoplasms, Experimental/pathology*
The effect of neem (Azadirachta indica) extract and dietary selenium on distribution of selenium in hepatocarcinogenesis induced rat

Hanachi P, Loh LN, Fauziah O, Rafiuz ZH, Tee ST, Lye CW, et al.

Med J Malaysia, 2004 May;59 Suppl B:208-9.
PMID: 15468891

Neem, Azadirachta indica, is a plant from the family Meliaceae, known as "Pokok Semambu" in Malay community. It has been extensively used in India as traditional Ayurvedic and folklore minedicine for the treatment of various diseases. This study aimed to determine the distribution of selenium in the liver of rats during hepatocarcinogenesis when neem aqueous extract and dietary selenium was supplemented.

Matched MeSH terms: Liver Neoplasms, Experimental/pathology*
Fulltext Antitumor and antioxidant effects of Clinacanthus nutans Lindau in 4 T1 tumor-bearing mice

Nik Abd Rahman NMA, Nurliyana MY, Afiqah MNFNN, Osman MA, Hamid M, Lila MAM

BMC Complement Altern Med, 2019 Nov 29;19(1):340.
PMID: 31783838 DOI: 10.1186/s12906-019-2757-4

BACKGROUND: Clinacanthus nutans Lindau (C. nutans) is a species of in Acanthaceae family and primarily used in South East Asian countries. C. nutans is well known as Sabah snake grass in Malaysia, and its leaves have diverse medicinal potential in conventional applications, including cancer treatments. On the basis of literature search, there is less conclusive evidence of the involvement of phytochemical constituents in breast cancer, in particular, animal tumor models. The current study aimed to determine the antitumor and antioxidant activities of C. nutans extract in 4 T1 tumor-bearing mice.
METHODS: C. nutans leaves were subjected to methanol extraction and divided into two different concentrations, 200 mg/kg (low-dose) and 1000 mg/kg (high-dose). The antitumor effects of C. nutans extracts were assessed using bone marrow smearing, clonogenic, and splenocyte immunotype analyses. In addition, hematoxylin and eosin, tumor weight and tumor volume profiles also used to indicate apoptosis appearance. Serum cytokine levels were examined using ELISA assay. In addition, nitric oxide assay reflecting antioxidant activity was performed.
RESULTS: From the results obtained, the methanol extract of C. nutans leaves at 200 mg/kg (P

Matched MeSH terms: Mammary Neoplasms, Experimental/pathology
Antagonistic effects of styrylpyrone derivative (SPD) on 7,12-dimethylbenzanthracene-induced rat mammary tumors

Hawariah A, Stanslas J

In Vivo, 1998 Jul-Aug;12(4):403-10.
PMID: 9706492

Early studies reported that a styrylpyrone derivative (SPD) purified from the Goniothalamus sp. acts as a non-competitive antiestrogen in early pregnant mice (1). In the immature rat uterine wet weight test, we found that SPD markedly reduced uterine weight at doses 1 and 100 mg/kg, thus reflecting negative antiestrogenicity, probably attributed to low binding affinities towards ER. Tamoxifen (Tam) on the other hand exhibited partial antiestrogenicity at all doses (0.01-10 mg/kg BW) and dose-dependent estrogenicity. However, the estrogen antagonism: agonism ratio for SPD is much higher than Tam, which is indicative of the breast cancer antitumor activity as seen in compounds such as MER-25. Pretreatment assessment on 1 mg/kg BW SPD and Tam showed that SPD is not a very good, estrogen antagonist compared to Tam, as it was unable to revert the estrogenicity effect of estradiol benzoate (EB) on immature rat uterine weight. Antitumor activity assessment for SPD exhibited significant tumor growth retardation in 7,12-dimethyl benzanthracene (DMBA) induced rat mammary tumors at all doses employed (2, 10 and 50 mg/kg) compared to the controls (p < 0.01). This compound was found to be more potent than Tam (2 and 10 mg/kg) and displayed greater potency at a dose of 10 mg/kg. It caused complete remission of 33.3% of tumors but failed to prevent onset of new tumors. However, SPD administration at 2 mg/kg caused 16.7% complete remission and partial remission. It also prevented the onset of new tumors throughout the experiment.

Matched MeSH terms: Mammary Neoplasms, Experimental/pathology
Fulltext The differential roles of caspase family members in mediating PF4-induced breast cancer apoptosis

Tengku Din TADAA, Abdul Jalal MI, Seeni A, Shamsuddin S, Jaafar H

Malays J Pathol, 2018 Dec;40(3):303-312.
PMID: 30580361

INTRODUCTION: This study focused on PF4 effects on caspase-3,-6, -7, -8 and -9 which regulate the apopotosis process in breast cancer.

MATERIALS AND METHODS: Breast tumours were induced in forty 21-day-old female Sprague Dawley rats (SDRs) using MNU until tumour size reached 14.5 mm (SD: 0.5 mm). The rats were then divided into two groups: Group 1 (control injected with 0.9% saline; n = 20), and Group 2 (platelet factor 4 (PF4); n = 20). PF4 was administered through focal intralesional injection at 20 μg/lesion dose. Following 5-day treatment, the SDRs were sacrificed. Subsequently, representative sections from the tumour were obtained for haematoxylin and eosin (H&E) staining. The expressions of caspase-3, -6, -7, -8 and -9 were evaluated using immunohistochemistry (IHC) staining.

RESULTS: The majority of breast tumour specimens were of aggressive types [ncontrol = 13 (65%); nPF4 = 12 (60%)]. Invasive ductal carcinoma not otherwise specified (IDC-NOS) was the most commonly observed breast tumour histology for control and PF4 groups (n = 8 (40%) in respective groups). PF4-treated group exhibited significant differences in the caspase-3, -6 and -8 expression levels compared to the control group (all p < 0.001). There were no significant differences in caspase-7 (p = 0.347) and caspase-9 (p = 0.373) expression levels between both groups.

CONCLUSION: This study found that PF4 acts via the caspase-mediated extrinsic apoptosis pathway without the involvement of the intrinsic pathway.

Matched MeSH terms: Mammary Neoplasms, Experimental/pathology
Fulltext Expression of E-cadherin and specific CXCR3 isoforms impact each other in prostate cancer

Ma B, Khazali A, Shao H, Jiang Y, Wells A

Cell Commun Signal, 2019 12 12;17(1):164.
PMID: 31831069 DOI: 10.1186/s12964-019-0489-1

BACKGROUND: Carcinoma cells shift between epithelial and mesenchymal phenotypes during cancer progression, as defined by surface presentation of the cell-cell cohesion molecule E-cadherin, affecting dissemination, progression and therapy responsiveness. Concomitant with the loss of E-cadherin during the mesenchymal transition, the predominant receptor isoform for ELR-negative CXC ligands shifts from CXCR3-B to CXCR3-A which turns this classical G-protein coupled receptor from an inhibitor to an activator of cell migration, thus promoting tumor cell invasiveness. We proposed that CXCR3 was not just a coordinately changed receptor but actually a regulator of the cell phenotype.
METHODS: Immunoblotting, immunofluorescence, quantitative real-time PCR and flow cytometry assays investigated the expression of E-cadherin and CXCR3 isoforms. Intrasplenic inoculation of human prostate cancer (PCa) cells with spontaneous metastasis to the liver analyzed E-cadherin and CXCR3-B expression during cancer progression in vivo.
RESULTS: We found reciprocal regulation of E-cadherin and CXCR3 isoforms. E-cadherin surface expression promoted CXCR3-B presentation on the cell membrane, and to a lesser extent increased its mRNA and total protein levels. In turn, forced expression of CXCR3-A reduced E-cadherin expression level, whereas CXCR3-B increased E-cadherin in PCa. Meanwhile, a positive correlation of E-cadherin and CXCR3-B expression was found both in experimental PCa liver micro-metastases and patients' tissue.
CONCLUSIONS: CXCR3-B and E-cadherin positively correlated in vitro and in vivo in PCa cells and liver metastases, whereas CXCR3-A negatively regulated E-cadherin expression. These results suggest that CXCR3 isoforms may play important roles in cancer progression and dissemination via diametrically regulating tumor's phenotype.

Matched MeSH terms: Neoplasms, Experimental/pathology
Rapid metastasis of breast cancer cells from primary tumour to liver

Kumar SS, Radhakrishnan AK, Cheong SK

Pak J Biol Sci, 2010 Apr 01;13(7):303-15.
PMID: 20836285

The aim of this study was to establish an animal model of mammary carcinoma metastasis to discern the in vivo effects of growth and spread of breast cancer. Six-week-old female BALB/c mice were inoculated with 4T1 murine breast cancer cells. Mice weight and primary tumour mass volume were regularly recorded to study the physical effects of a vigorously growing and spreading of cancer cell line. Gross and histological studies were carried out to determine the approximate day of metastatic onset. Production of IFN-gamma was assessed by ELISA to understand its role in tumour growth and metastasis. Lymphocyte markers such as CD8+, CD25 and CD49b were analysed to elucidate its role in tumour growth and progression. Present study showed that the metastatic onset occurs approximately 11 days after the mice were inoculated with the 4T1 murine breast cancer cells. Gross studies showed hepatosplenomegaly. The breast cancer cells from primary tumour were found to spread rapidly to the liver on day 11. IFN-gamma production was higher in inoculated mice serum compared to control mice serum. Higher numbers of CD8+, CD25 and CD49b cells were observed in the peripheral blood of inoculated mice, compared to control mice. In conclusion, the 4T1 murine breast cancer cells can migrate and metastasise rapidly to the liver, eliciting various immune responses.

Matched MeSH terms: Mammary Neoplasms, Experimental/pathology*
Fulltext Cytotoxic effect of magnetic iron oxide nanoparticles synthesized via seaweed aqueous extract

Namvar F, Rahman HS, Mohamad R, Baharara J, Mahdavi M, Amini E, et al.

Int J Nanomedicine, 2014;9:2479-88.
PMID: 24899805 DOI: 10.2147/IJN.S59661

Magnetic iron oxide nanoparticles (Fe3O4 MNPs) are among the most useful metal nanoparticles for multiple applications across a broad spectrum in the biomedical field, including the diagnosis and treatment of cancer. In previous work, we synthesized and characterized Fe3O4 MNPs using a simple, rapid, safe, efficient, one-step green method involving reduction of ferric chloride solution using brown seaweed (Sargassum muticum) aqueous extract containing hydroxyl, carboxyl, and amino functional groups mainly relevant to polysaccharides, which acts as a potential stabilizer and metal reductant agent. The aim of this study was to evaluate the in vitro cytotoxic activity and cellular effects of these Fe3O4 MNPs. Their in vitro anticancer activity was demonstrated in human cell lines for leukemia (Jurkat cells), breast cancer (MCF-7 cells), cervical cancer (HeLa cells), and liver cancer (HepG2 cells). The cancer cells were treated with different concentrations of Fe3O4 MNPs, and an MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay was used to test for cytotoxicity, resulting in an inhibitory concentration 50 (IC50) value of 23.83±1.1 μg/mL (HepG2), 18.75±2.1 μg/mL (MCF-7), 12.5±1.7 μg/mL (HeLa), and 6.4±2.3 μg/mL (Jurkat) 72 hours after treatment. Therefore, Jurkat cells were selected for further investigation. The representative dot plots from flow cytometric analysis of apoptosis showed that the percentages of cells in early apoptosis and late apoptosis were increased. Cell cycle analysis showed a significant increase in accumulation of Fe3O4 MNP-treated cells at sub-G1 phase, confirming induction of apoptosis by Fe3O4 MNPs. The Fe3O4 MNPs also activated caspase-3 and caspase-9 in a time-response fashion. The nature of the biosynthesis and therapeutic potential of Fe3O4 MNPs could pave the way for further research on the green synthesis of therapeutic agents, particularly in nanomedicine, to assist in the treatment of cancer.

Matched MeSH terms: Neoplasms, Experimental/pathology*
Inhibitory effects of Tualang Honey on experimental breast cancer in rats: a preliminary study

Kadir EA, Sulaiman SA, Yahya NK, Othman NH

Asian Pac J Cancer Prev, 2013;14(4):2249-54.
PMID: 23725121

The study was conducted to determine the effect of Malaysian jungle Tualang Honey (TH) on development of breast cancer induced by the carcinogen 7,12-dimethylbenz(α)anthracene (DMBA) in rats. Forty nulliparous female Sprague-Dawley rats were given 80 mg/kg DMBA then randomly divided into four groups: Group 1 served as a Control while Groups 2, 3 and 4 received 0.2, 1.0 or 2.0 g/kg bodyweight/day of TH, respectively, for 150 days. Results showed that breast cancers in the TH-treated groups had slower size increment and smaller mean tumor size (≤ 2 cm3) compared to Controls (≤ 8 cm3). The number of cancers developing in TH-treated groups was also significantly fewer (P<0.05). Histological grading showed majority of TH-treated group cancers to be of grade 1 and 2 compared to grade 3 in controls. There was an increasing trend of apoptotic index (AI) seen in TH-treated groups with increasing dosage of Tualang Honey, however, the mean AI values of all TH-treated groups were not significantly different from the Control value (p>0.05). In conclusion, Tualang Honey exerted positive modulation effects on DMBA-induced breast cancers in rats in this preliminary study.

Matched MeSH terms: Mammary Neoplasms, Experimental/pathology
Effects of tocotrienols on cell viability and apoptosis in normal murine liver cells (BNL CL.2) and liver cancer cells (BNL 1ME A.7R.1), in vitro

Har CH, Keong CK

Asia Pac J Clin Nutr, 2005;14(4):374-80.
PMID: 16326644

The effects of tocotrienols on murine liver cell viability and their apoptotic events were studied over a dose range of 0-32 microg mL(-1). Normal murine liver cells (BNL CL.2) and murine liver cancer cells (BNL 1ME A.7R.1) were treated with tocotrienols (T(3)), alpha tocopherol (alpha-T) and the chemo drug, Doxorubicin (Doxo, as a positive control). Cell viability assay showed that T(3) significantly (P < or = 0.05) lowered the percentage of BNL 1ME A.7R.1 cell viability in a dose-responsive manner (8-16 microg mL(-1)), whereas T did not show any significant (P>0.05) inhibition in cell viability with increasing treatment doses of 0-16 microg mL(-1). The IC(50) for tocotrienols were 9.8, 8.9, 8.1, 9.7, 8.1 and 9.3 microg mL(-1) at 12, 24, 36, 48, 60 and 72 hours respectively. Early apoptosis was detected 6 hours following T(3) treatment of BNL 1ME A.7R.1 liver cancer cells, using Annexin V-FITC fluorescence microscopy assay for apoptosis, but none were observed for the non-treated liver cancer cells at the average IC(50) of 8.98 microg mL(-1) tocotrienols for liver cancer cells. Several apoptotic bodies were detected in BNL 1ME A.7R.1 liver cancer cells at 6 hours post-treatment with tocotrienols (8.98 microg mL(-1)) using Acridine Orange/Propidium Iodide fluorescence assay. However, only a couple of apoptotic bodies were seen in the non-treated liver cancer cells and the BNL CL.2 normal liver cells. Some mitotic bodies were also observed in the T(3)-treated BNL 1ME A.7R.1 liver cancer cells but were not seen in the untreated BNL 1ME A.7R.1 cells and the BNL CL.2 liver cells. Following T(3)-treatment (8.98 microg mL(-1)) of the BNL 1ME A.7R.1 liver cancer cells, 24.62%, 25.53% and 44.90% of the cells showed elevated active caspase 3 activity at 9, 12 and 24 hours treatment period, respectively. DNA laddering studies indicated DNA fragmentation occurred in the T(3)-treated liver cancer cells, BNL 1ME A.7R.1 but not in non-treated liver cancer cells and the T(3)-treated and non-treated normal liver cells. These results suggest that tocotrienols were able to reduce the cell viability in the murine liver cancer cells at a dose of 8-32 microg mL(-1) and that this decrease in percentage cell viability may be due to apoptosis.

Matched MeSH terms: Liver Neoplasms, Experimental/pathology*
Fulltext Anti-Tumor Action, Clinical Biochemistry Profile and Phytochemical Constituents of a Pharmacologically Active Fraction of S. crispus in NMU-Induced Rat Mammary Tumour Model

Yaacob NS, Yankuzo HM, Devaraj S, Wong JK, Lai CS

PLoS One, 2015;10(5):e0126426.
PMID: 26000968 DOI: 10.1371/journal.pone.0126426

Cancer patients seek alternative remedies such as traditional medicinal plants for safe and effective treatment and help overcome the side effects of conventional therapy. Current knowledge indicates that extracts of Strobilanthes crispus of the Acanthaceae family exhibit potent anticancer properties in vitro and are non-toxic in vivo. S. crispus was also reported to be protective against chemical hepatocarcinogenesis. We previously showed that a bioactive fraction of S. crispus leaves also synergized with tamoxifen to cause apoptosis of human breast cancer cell lines without damaging non-malignant epithelial cells. The present study aimed to evaluate the antitumor effect of S. crispus dichloromethane fraction (F3) using N-methyl-N-Nitrosourea (NMU)-induced rat mammary tumor model. Tumor regression was observed in 75% of the rats following 8-week oral administration of F3 with no secondary tumour formation and no signs of anemia or infection. However, no improvement in the liver and renal function profiles was observed. Major constituents of F3 were identified as lutein, 131-hydroxy-132-oxo-pheophytin a, campesterol, stigmasterol, β-sitosterol, pheophytin a and 132-hydroxy-pheophytin a. These compounds however, may not significantly contribute to the antitumor effect of F3.

Matched MeSH terms: Mammary Neoplasms, Experimental/pathology
Vitamin C and aloe vera supplementation protects from chemical hepatocarcinogenesis in the rat

Shamaan NA, Kadir KA, Rahmat A, Ngah WZ

Nutrition, 1998 12 3;14(11-12):846-52.
PMID: 9834927

The effects of vitamin C and aloe vera gel extract supplementation on induced hepatocarcinogenesis in male Sprague-Dawley rats (120-150 g) by diethylnitrosamine (DEN) and 2-acetylaminofluorene (AAF) was investigated. The severity of the carcinogenesis process was determined by measuring gamma-glutamyl transpeptidase (GGT) and the placental form of glutathione S-transferase (GSTP) histochemically in situ and in plasma and liver fractions. In addition, plasma alkaline phosphatase (ALP) and liver microsomal uridine diphosphate glucuronyl transferase (UDPGT) activity were also determined. Administration of DEN/AAF caused an increase in the surface area and number of enzyme-positive foci (both GGT and GSTP) compared with control. Supplementation of vitamin C or aloe vera gel extract to the cancer-induced rats suppressed this increase significantly (P < 0.05; P < 0.001). Increases in liver UDPGT, GGT, and GSTP activities were also observed with cancer induction that were again suppressed with either vitamin C or aloe vera gel supplementation. Plasma GGT in the DEN/AAF rats were determined monthly for the duration of the experiment and found to be reduced as early as 1 mo with aloe vera gel supplementation and 2 mo with vitamin C supplementation. In conclusion, vitamin C and aloe vera gel extract supplementation were found to be able to reduce the severity of chemical hepatocarcinogenesis.

Matched MeSH terms: Liver Neoplasms, Experimental/pathology
Effect of ovariectomy and sex hormone replacement on glutathione and glutathione-related enzymes in rat hepatocarcinogenesis

Hambali Z, Ngah WZ, Wahid SA, Kadir KA

Pathology, 1995 Jan;27(1):30-5.
PMID: 7603748

The effects of ovariectomy and hormone replacement in control and carcinogen treated female rats were investigated by measuring whole blood and liver glutathione (WGSH, HGSH), glutathione S-transferase (GST), glutathione peroxidase (GPx), and glutathione reductase (GRx) and histological evaluation. Hepatocarcinogenesis was induced by diethylnitrosamine and 2-acetylaminofluorene. In control rats not receiving carcinogen, ovariectomy significantly increased the GST and GRx activities. Replacement with either estrogen or progesterone reduced the GST activities to below intact female values whereas replacement of both hormones together brought the GST activities to that of intact females. GRx activities were brought to intact female values by replacement with estrogen or progesterone, either singly or in combination. Neither ovariectomy nor sex hormone/s replacement influenced the levels of WGSH, HGSH and GPx activities. Carcinogen administration to intact rats increased all the parameters measured. Ovariectomized rats treated with carcinogen showed lower GPx and GRx activities at 2 mths. However, replacement with either progesterone or combined estrogen and progesterone increased GPx and GRx activities to original values. On the other hand GST and GPx activities in ovariectomized rats which had carcinogen treatment were lower than intact rats after 5 mths. Replacement with hormones either singly or both brought GST and GPx activities up to intact rat levels receiving carcinogen. The levels of WGSH, HGSH and GRx activities (5 mths) in carcinogen treated rats were not influenced by ovariectomy and/or hormone/s replacement. The results from this study suggested that ovariectomy reduced the severity of hepatocarcinogenesis which was restored by sex hormone/s replacement.

Matched MeSH terms: Liver Neoplasms, Experimental/pathology
Fulltext Evaluation of NMU-Induced Breast Cancer Treated with Sirolimus and Sunitinib on Breast Cancer Growth

Jaffar NFN, Muhammad Sakri MS, Jaafar H, Wan Abdul Rahman WF, Tengku Din TADA

Asian Pac J Cancer Prev, 2020 Oct 01;21(10):2919-2925.
PMID: 33112549 DOI: 10.31557/APJCP.2020.21.10.2919

OBJECTIVE: To analyze the effect of sirolimus and sunitinib in blocking the tumor growth and to evaluate the expressions of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER2/neu) after treated with sirolimus and sunitinib.
METHODS: Thirty-two female Sprague Dawley rats at age 21-days old were administered intraperitoneally with N-Methyl-N-Nitroso Urea (NMU), dosed at 70mg/kg body weight. The rats were divided into 4 groups; Group 1 (Control, n=8), Group 2 (Sirolimus, n=8), Group 3 (Sunitinib, n=8) and Group 4 (Sirolimus+Sunitinib, n=8), being treated twice when the tumor reached the size of 14.5±0.5 mm and subsequently sacrificed after 5 days. The protein expressions of ER, PgR and HER2/neu of the tumor tissues were evaluated by using immunohistochemistry analysis.
RESULTS: Treatment with sirolimus alone lowered expressions of ER and PgR of breast cancer and reduced tumor size. There was no significant difference of ER and PgR expressions between control and sunitinib treated tumor. Sunitinib treated tumors reduce in diameter after the first treatment, however the diameter increases after the second treatment. Histologically, sunitinib treated tumor did not show any aggressive invasive carcinoma of no special type (NST) histological subtypes. In addition, all NMU-induced tumors are HER2/neu-negative scoring.
CONCLUSION: Sirolimus is neither synergistic nor additive with sunitinib for breast cancer treatment.
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Matched MeSH terms: Mammary Neoplasms, Experimental/pathology
Fulltext Determination of an optimally sensitive and specific chemical exchange saturation transfer MRI quantification metric in relevant biological phantoms

Ray KJ, Larkin JR, Tee YK, Khrapitchev AA, Karunanithy G, Barber M, et al.

NMR Biomed, 2016 11;29(11):1624-1633.
PMID: 27686882 DOI: 10.1002/nbm.3614

The purpose of this study was to develop realistic phantom models of the intracellular environment of metastatic breast tumour and naïve brain, and using these models determine an analysis metric for quantification of CEST MRI data that is sensitive to only labile proton exchange rate and concentration. The ability of the optimal metric to quantify pH differences in the phantoms was also evaluated. Novel phantom models were produced, by adding perchloric acid extracts of either metastatic mouse breast carcinoma cells or healthy mouse brain to bovine serum albumin. The phantom model was validated using 1 H NMR spectroscopy, then utilized to determine the sensitivity of CEST MRI to changes in pH, labile proton concentration, T1 time and T2 time; six different CEST MRI analysis metrics (MTRasym , APT*, MTRRex , AREX and CESTR* with and without T1 /T2 compensation) were compared. The new phantom models were highly representative of the in vivo intracellular environment of both tumour and brain tissue. Of the analysis methods compared, CESTR* with T1 and T2 time compensation was optimally specific to changes in the CEST effect (i.e. minimal contamination from T1 or T2 variation). In phantoms with identical protein concentrations, pH differences between phantoms could be quantified with a mean accuracy of 0.6 pH units. We propose that CESTR* with T1 and T2 time compensation is the optimal analysis method for these phantoms. Analysis of CEST MRI data with T1 /T2 time compensated CESTR* is reproducible between phantoms, and its application in vivo may resolve the intracellular alkalosis associated with breast cancer brain metastases without the need for exogenous contrast agents.

Matched MeSH terms: Neoplasms, Experimental/pathology
In vivo tumor targeting and anti-tumor effects of 5-fluororacil loaded, folic acid targeted quantum dot system

Bwatanglang IB, Mohammad F, Yusof NA, Abdullah J, Alitheen NB, Hussein MZ, et al.

J Colloid Interface Sci, 2016 Oct 15;480:146-58.
PMID: 27428851 DOI: 10.1016/j.jcis.2016.07.011

In this study, we modulated the anti-cancer efficacy of 5-Fluorouracil (5-FU) using a carrier system with enhanced targeting efficacy towards folate receptors (FRs) expressing malignant tissues. The 5-FU drug was loaded onto Mn-ZnS quantum dots (QDs) encapsulated with chitosan (CS) biopolymer and conjugated with folic acid (FA) based on a simple wet chemical method. The formation of 5-FU drug loaded composite was confirmed using Fourier transform infrared spectroscopy (FTIR), thermo gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Furthermore, the in vivo biodistribution and tumor targeting specificity of the 5-FU@FACS-Mn:ZnS in the tumor-bearing mice was conducted based on the Zn(2+) tissue bioaccumulation using inductively coupled plasma (ICP) spectroscopy. In addition to the characterization, the in vitro release profile of 5-FU from the conjugates investigated under diffusion controlled method demonstrated a controlled release behaviour as compared against the release behaviour of free 5-FU drug. The as-synthesized 5-FU@FACS-Mn:ZnS nanoparticle (NP) systemically induced higher level of apoptosis in breast cancer cells in vitro as compared to cells treated with free 5-FU drug following both cell cycle and annexin assays, respectively. Also, the in vivo toxicity assessment of the 5-FU@FACS-Mn:ZnS NPs as compared to the control did not cause any significant increase in the activities of the liver and kidney function biomarkers, malondialdehyde (MDA) and nitric oxide (NO) levels. However, based on the FA-FRs chemistry, the 5-FU@FACS-Mn:ZnS NPs specifically accumulated in the tumor of the tumor-bearing mice and thus contributed to the smaller tumor size and less event of metastasis was observed in the lungs when compared to the tumor-bearing mice groups treated with the free 5-FU drug. In summary, the results demonstrated that the 5-FU@FACS-Mn:ZnS QDs exhibits selective anti-tumor effect in MDA-MB231 breast cancer cells in vitro and 4TI breast cancer cells in vivo, providing a blueprint for improving the 5-FU efficacy and tumor targeting specificity with limited systemic toxicity.

Matched MeSH terms: Mammary Neoplasms, Experimental/pathology
Fulltext Expression of complement C5a receptor and the viability of 4T1 tumor cells following agonist-antagonist treatment

Kosni NN, Ganti N, Noor MH, Razak IS, Ajat MM, Omar AR

J Cancer Res Ther, 2016 Apr-Jun;12(2):590-6.
PMID: 27461615 DOI: 10.4103/0973-1482.146066

BACKGROUND: Complement system is theoretically believed to halt the progression of tumor by the activity of C5a/CD88. Protein C5a is a potent pro.inflammatory mediator that activates the complement system by binding to its receptor.
OBJECTIVES: The purpose of this study is to determine the expression of the anaphylatoxin C5a receptor on 4T1 cell line and to study the viability of the cells after being treated with the C5a peptides.
MATERIALS AND METHODS: The cells 4T1 had undergone immunofluorescence staining, conventional polymerase chain reaction (PCR) and real-time PCR for the expression of determination part. Whereas Alamar Blue and MTT assays were conducted for the viability study of the cells.
RESULTS: The cells showed positive result in expressing the receptor of the C5a through immunostaining and PCR. The CT value recorded at initial dilution was 22.24. In cell viability assay, the cell was treated with C5a peptides, PMX205 and EP54. The purpose of this treatment was to see whether C5a had a direct effect on the cell itself using both assays. The result showed that PMX205, which is an antagonist, gave more effects towards the cell as compared with the treatment of EP54.
CONCLUSION: This experiment shows the presence of C5a receptor on 4T1 cell line. We believe that the antagonist peptide is eligible to be used widely in cancer immunotherapy field; but in vivo studies need to be carried out first in the future, as it will determine how these drugs affect the tumor cell growth.

Matched MeSH terms: Mammary Neoplasms, Experimental/pathology
Eosinophil-Associated Gene Pathways but not Eosinophil Numbers are Differentially Regulated between Synchrotron Microbeam Radiation Treatment and Synchrotron Broad-Beam Treatment by 48 Hours Postirradiation

Ibahim MJ, Yang Y, Crosbie JC, Stevenson A, Cann L, Paiva P, et al.

Radiat Res, 2016 Jan;185(1):60-8.
PMID: 26720800 DOI: 10.1667/RR14115.1

Synchrotron microbeam radiation treatment (MRT) is a preclinical radiotherapy technique with considerable clinical promise, although some of the underlying radiobiology of MRT is still not well understood. In recently reported studies, it has been suggested that MRT elicits a different tumor immune profile compared to broad-beam treatment (BB). The aim of this study was to investigate the effects of synchrotron MRT and BB on eosinophil-associated gene pathways and eosinophil numbers within and around the tumor in the acute stage, 48 h postirradiation. Balb/C mice were inoculated with EMT6.5 mouse mammary tumors and irradiated with microbeam radiation (112 and 560 Gy) and broad-beam radiation (5 and 9 Gy) at equivalent doses determined from a previous in vitro study. After tumors were collected 24 and 48 h postirradiation, RNA was extracted and quantitative PCR performed to assess eosinophil-associated gene expression. Immunohistochemistry was performed to detect two known markers of eosinophils: eosinophil-associated ribonucleases (EARs) and eosinophil major basic protein (MBP). We identified five genes associated with eosinophil function and recruitment (Ear11, Ccl24, Ccl6, Ccl9 and Ccl11) and all of them, except Ccl11, were differentially regulated in synchrotron microbeam-irradiated tumors compared to broad-beam-irradiated tumors. However, immunohistochemical localization demonstrated no significant differences in the number of EAR- and MBP-positive eosinophils infiltrating the primary tumor after MRT compared to BB. In conclusion, our work demonstrates that the effects of MRT on eosinophil-related gene pathways are different from broad-beam radiation treatment at doses previously demonstrated to be equivalent in an in vitro study. However, a comparison of the microenvironments of tumors, which received MRT and BB, 48 h after exposure showed no difference between them with respect to eosinophil accumulation. These findings contribute to our understanding of the role of differential effects of MRT on the tumor immune response.

Matched MeSH terms: Neoplasms, Experimental/pathology*

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