scholarly journals Attenuation of Tumor Development in Mammary Carcinoma Rats by Theacrine, an Antagonist of Adenosine 2A Receptor

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7455
Author(s):  
Cian-Fen Jhuo ◽  
Yu-Yu Hsu ◽  
Wen-Ying Chen ◽  
Jason T. C. Tzen

Caffeine has been reported to induce anti-tumor immunity for attenuating breast cancer by blocking the adenosine 2A receptor. Molecular modeling showed that theacrine, a purine alkaloid structurally similar to caffeine, might be an antagonist of the adenosine 2A receptor equivalent to or more effective than caffeine. Theacrine was further demonstrated to be an effective antagonist of the adenosine 2A receptor as its concurrent supplementation significantly reduced the elevation of AMPK phosphorylation level in MCF-7 human breast cells induced by CGS21680, an agonist of adenosine 2A receptors. In an animal model, the development of mammary carcinoma induced by 7,12-Dimethylbenz[a]anthracene in Sprague–Dawley rats could be attenuated by daily supplement of theacrine of 50 or 100 mg/kg body weight. Both expression levels of cleaved-caspase-3/pro-caspase-3 and granzyme B in tumor tissues were significantly elevated when theacrine was supplemented, indicating the induction of programmed cell death in tumor cells might be involved in the attenuation of mammary carcinoma. Similar to the caffeine, significant elevation of interferon-γ and tumor necrosis factor-α was observed in the serum and tumor tissues of rats after the theacrine supplement of 50 mg/kg body weight. Taken together, theacrine is an effective antagonist of adenosine 2A receptors and possesses great potential to be used to attenuate breast cancer.

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Deena Priscilla Henry ◽  
Jasmine Ranjan ◽  
Rajesh Kumar Murugan ◽  
Annapoorani Sivanantham ◽  
Manikandan Alagumuthu

Abstract Background Plant extracts are effectively acting as the natural medicinal cocktail, non-side effective, efficacious, and freely available. The present study aimed to unveil the pharmacological and medicinal effects of Terminalia chebula plant extract in 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinoma in Sprague Dawley rats. The plant extract obtained was subjected to in vivo antioxidant and anticancer studies in various concentrations after an analytical technique such as FTIR, GCMS, and HPLC-based chemo-profiling in Sprague Dawley rats. Results Apart from the antiproliferative effect on breast cancer cell line (MCF-7) and normal breast epithelial cells (MCF-10a), we have measured the changes in body weight, along with other tumor parameters such as tumor volume, tumor incidence, tumor weight, tumor burden, serum biochemical parameters, and histopathological findings of breast tissue. As the oxidative stress further enhances the development of cancer, the antioxidant property of the plant extract demonstrates its use against cancer treatment. One hundred fifty milligrams per milliliter (IC50 250 μg/mL) concentration of the ethanolic extract was vital for the proliferation of MCF-7 cell lines (Fig. 7a). Meanwhile, 300 μg/mL (IC50 150 μg/mL) was an effective dose to attain a maximum HDAC inhibition of 78%. Also, the normal liver and kidney functioning revealed the non-toxicity nature of the plant. Conclusion Terminalia chebula could be one of the effective naturally obtained anti-breast cancer medications. Isolation and characterization of individual bioactive compounds of T. chebula would be the future perspective.


2004 ◽  
Vol 3 (2) ◽  
pp. 24-29
Author(s):  
Ye. Yu. Sherstoboyev ◽  
O. A. Kaplya ◽  
Ye. P. Zuyeva ◽  
T. G. Razina ◽  
O. I. Epstein

Cytokine production by cell-effectors of natural cytotoxicity system under Lewis lung carcinoma development in F1(CBAxC57B1/6) line mice has been studied. It has been revealed the increase of interleukin-1β (IL-1β) production and tumor necrosis factor-α (TNF-α) by peritoneal macrophages. At this the balance of cytokines produced by T-helpers (Th)  has  been displaced to Th2 side, IL-4 production has increased and interferon-γ (IFN-γ) and IL-2 production has decreased. The rise of IL-10 production by lymphocytes has been observed in the later terms of tumor development.


2015 ◽  
Vol 20 (4) ◽  
pp. 259-268 ◽  
Author(s):  
Ayyakkannu Purushothaman ◽  
Elumalai Nandhakumar ◽  
Palanivelu Shanthi ◽  
Thiruvaiyaru Panchanatham Sachidanandam

A herbal preparation, Shemamruthaa (SM), was formulated to investigate the molecular mechanism by which it exhibits anticancer effects in mammary carcinoma bearing rats. Female Sprague-Dawley rats were used for the study, and mammary carcinoma was induced by administration of 7,12-dimethylbenz( a)anthracene, intragastrically. After 3 months of induction period, the rats were treated with SM (400 mg/kg body weight) for 14 days. Our study shows that SM-treated mammary carcinoma rats showed regression in tumor volume with concomitant increase in p53, Bax, caspase-3, and caspase-9 mRNA and protein levels compared with mammary carcinoma–induced rats. Proliferating cell nuclear antigen and anti-apoptotic Bcl-2 were markedly increased in mammary carcinoma–induced rats, whereas the SM treatment significantly decreased the expression of these proteins. The expression pattern of apoptotic signaling molecules analyzed in the present study signifies the therapeutic efficacy of SM against breast cancer.


2020 ◽  
Vol 19 ◽  
pp. 153473542093562
Author(s):  
Nursyamirah Abd Razak ◽  
Swee Keong Yeap ◽  
Noorjahan Banu Alitheen ◽  
Wan Yong Ho ◽  
Chean Yeah Yong ◽  
...  

Eupatorin is a polymethoxy flavone extracted from Orthosiphon stamineus and was reported to exhibit cytotoxic effects on several cancer cell lines. However, its effect as an anti–breast cancer agent in vivo has yet to be determined. This study aims to elucidate the potential of eupatorin as an anti–breast cancer agent in vivo using 4T1 challenged BALB/c mice model. In this article, BALB/c mice (20-22 g) challenged with 4T1 cells were treated with 5 mg/kg or 20 mg/kg eupatorin, while the untreated and healthy mice were fed with olive oil (vehicle) via oral gavage. After 28 days of experiment, the mice were sacrificed and blood was collected for serum cytokine assay, while tumors were harvested to extract RNA and protein for gene expression assay and hematoxylin-eosin staining. Organs such as spleen and lung were harvested for immune suppression and clonogenic assay, respectively. Eupatorin (20 mg/kg) was effective in delaying the tumor development and reducing metastasis to the lung compared with the untreated mice. Eupatorin (20 mg/kg) also enhanced the immunity as the population of NK1.1+ and CD8+ in the splenocytes and the serum interferon-γ were increased. Concurrently, eupatorin treatment also has downregulated the expression of pro-inflammatory and metastatic related genes (IL-1β. MMP9, TNF-α, and NF-κB). Thus, this study demonstrated that eupatorin at the highest dosage of 20 mg/kg body weight was effective in delaying the 4T1-induced breast tumor growth in the animal model.


2007 ◽  
Vol 204 (5) ◽  
pp. 1037-1047 ◽  
Author(s):  
Caroline Aspord ◽  
Alexander Pedroza-Gonzalez ◽  
Mike Gallegos ◽  
Sasha Tindle ◽  
Elizabeth C. Burton ◽  
...  

We previously reported (Bell, D., P. Chomarat, D. Broyles, G. Netto, G.M. Harb, S. Lebecque, J. Valladeau, J. Davoust, K.A. Palucka, and J. Banchereau. 1999. J. Exp. Med. 190: 1417–1426) that breast cancer tumors are infiltrated with mature dendritic cells (DCs), which cluster with CD4+ T cells. We now show that CD4+ T cells infiltrating breast cancer tumors secrete type 1 (interferon γ) as well as high levels of type 2 (interleukin [IL] 4 and IL-13) cytokines. Immunofluorescence staining of tissue sections revealed intense IL-13 staining on breast cancer cells. The expression of phosphorylated signal transducer and activator of transcription 6 in breast cancer cells suggests that IL-13 actually delivers signals to cancer cells. To determine the link between breast cancer, DCs, and CD4+ T cells, we implanted human breast cancer cell lines in nonobese diabetic/LtSz-scid/scid β2 microglobulin–deficient mice engrafted with human CD34+ hematopoietic progenitor cells and autologous T cells. There, CD4+ T cells promote early tumor development. This is dependent on DCs and can be partially prevented by administration of IL-13 antagonists. Thus, breast cancer targets DCs to facilitate its development.


2018 ◽  
Vol 47 (5) ◽  
pp. 2147-2158 ◽  
Author(s):  
Feiyu Chen ◽  
Na Luo ◽  
Yu Hu ◽  
Xin Li ◽  
Kejing  Zhang

Background/Aims: Triple negative breast cancer (TNBC) is resistant to conventional chemotherapy due to high proportions of cancer stem cells (CSCs). The aim of this study is to unravel the miR-137-mediated regulatory mechanism of B-cell lymphoma/leukemia 11A (BCL11A) in TNBC. Methods: A corhort of 34 TNBC tumor tissues and paired adjacent normal tissues, as well as 25 non-TNBC tumor tissues and paired adjacent normal tissues were collected post-operatively from patients with breast cancer. Q-PCR was performed to determine the mRNA levels of miR-137 and BCL11A in breast tissues and cell lines. Bioinformatics analysis and dual luciferase reporter assay were used to verify the direct interaction between miR-137 and BCL11A. After up-/down-regulation of BCL11A, miR-137, or DNMT1 via lentiviral transduction in TNBC cell lines SUM149 and MDA-MB-231 cells, Q-PCR and Western blot assays were used to detect the expression levels of BCL11A, DNA methyltransferases 1 (DNMT1), and Islet-1 (ISL1). Mammosphere assay was conducted to assess tumorosphere formation ability of cells, coupled with flow cytometry to determine the percentage of breast cancer stem cells. Co-immunoprecipitation assay was used to determine the interaction between BCL11A and DNMT1. Xenograft tumorigenesis assay was performed to monitor tumor formation in vivo. Results: BCL11A was highly expressed in TNBC, whereas miR-137 was significantly lower in both TNBC tissues and cell lines. miR-137 suppressed BCL11A expression at both mRNA and protein levels by directly targeting its 3’UTR. In both SUM149 and MDA-MB-231 cells, overexpression of miR-137 or knockdown of BCL11A reduced the number of tumoroshperes and the percentage of cancer stem cells in vitro, and inhibited tumor development in vivo. Furthermore, BCL11A interacted with DNMT1 in TNBC cells. Silencing of either BCL11A or DNMT1 impaired cancer stemness and tumorigenesis of TNBC via suppressing ISL1 expression both in vitro, and in vivo. Conclusions: By perturbing BCL11A-DNMT1 interaction, miR-137 impairs cancer stemness and suppresses tumor development in TNBC.


Biomedicine ◽  
2020 ◽  
Vol 39 (2) ◽  
pp. 380-386
Author(s):  
Maninder Kour ◽  
Kumar Megur Ramakrishna Bhat ◽  
Vinodini Nithyanandamadom Anatharaya ◽  
Shrijeet Chakraborty ◽  
Reshma Kumara Chandra

Introduction and Aim: Breast cancer accounts for about 30% of all cancers in women. The present study aims to see the role of prolactin and Vitex agnus fruit extract in breast cancer progression in mammary tumor induced Sprague Dawley (SD) rats. Materials and Methods: Thirty-day old inbred SD female rats of body weight 70-80 grams were taken for this study. The rats were induced with N- Methyl-Nitroso-Urea for mammary tumor development. After the development of palpable and visible tumor the rats were treated with anti-prolactin drug (Cabergoline) and a prolactin lowering herb Vitex agnus Castus (VAC) for two months. After the treatment the rats were sacrificed for antioxidants estimation and histopathological section examination. Results: The rats treated with anti-prolactin drug showed benign tumors with hyperplasia and lactational change proving the presence of prolactin in the tumor tissue, whereas the plant extract showed mammary tumor regression by the presence of foamy macrophages in the histopathological sections. Results also showed treatment with cabergoline increased the GSH level and decreased the MDA level compared to tumor induced group. Conclusion: Prolactin may have a potential role in progression of breast cancer and Vitex agnus extract showed a prolactin lowering effect and facilitated in regression of the tumor.  


2019 ◽  
Vol 29 (2) ◽  
pp. 135-142
Author(s):  
Zauhani Kusnul ◽  
Suryono Suryono ◽  
Anas Tamsuri

Abstract Body weight is a general indicator for assessing health status. Various diseases cause drastic weight loss, including cancer. Propolis is a bee product that has various therapeutic effects such as; anti-bacterial, antitumor, antioxidant and immunomodulatory. Propolis is also reported to be able to reduce digestive organ disorders, increase appetite and improve metabolic processes. Chemicals such as 7.12-dymethyilbenz (a) antracene (DMBA) are widely reported to have strong carcinogenic effects, especially in Sprague–Dawley rat. This study aims to assess the effect of propolis extract on the weight of Sprague–Dawley female rat induced with DMBA (7,12-dymethylbenz (a) antracene). Twenty-four female Sprague–Dawley rats 45-50 days old were induced by DMBA with a combination of injection and oral methods, as negative controls 6 Sprague–Dawley rats without DMBA induction. At the 11th week randomized negative control rats and DMBA treated rats were taken for histopathological examination of breast tissue. After it was found that rat with DMBA treatment were positive for breast cancer, in the 12th week the rat that had received DMBA treatment were divided into 4 groups, 3 groups received oral propolis extract through a gastric sonde with doses 50, 100 and 200 mg in 1 ml of corn oil, 1 group as a positive control did not get the treatment of propolis extract. Body weight is weighed before starting treatment and monitored every two weeks to 15 weeks. The results of weighing showed that the group of rat that received DMBA increased their body weight lower than the group without DMBA, and then the treatment group of propolis extract increased their body weight higher than the group without the treatment of propolis extract. The results showed that the treatment of propolis extract had a potency to improve the body weight profile of rat breast cancer model induced by DMBA. Abstrak Berat badan merupakan indikator umum untuk menilai status kesehatan. Berbagai penyakit menyebabkan penurunan berat badan yang drastis, diantaranya adalah kanker. Propolis merupakan produk lebah yang memiliki berbagai efek terapi seperti; anti bakteri, anti tumor, antioksidan dan imunomodulator. Propolis juga dilaporkan mampu menurunkan gangguan organ pencernaan, peningkatan nafsu makan, dan perbaikan proses metabolisme. Bahan kimia seperti 7,12-dymethyilbenz(a)antracene (DMBA) banyak dilaporkan memiliki efek karsinogenik yang kuat khususnya terhadap tikus Sprague–Dawley. Penelitian ini bertujuan untuk menilai pengaruh pemberian ekstrak propolis terhadap berat badan tikus Sprague–Dawley betina yang diinduksi untuk mengalami kanker payudara dengan DMBA. Sebanyak 24 ekor tikus Sprague– Dawley betina berumur 45-50 hari diinduksi dengan DMBA dengan kombinasi metode injeksi dan oral, sebagai kontrol negatif 6 ekor tikus Sprague–Dawley tanpa induksi DMBA. Pada minggu ke-11 diambil secara acak tikus kontrol negatif dan tikus perlakuan DMBA untuk dilakukan pemeriksaan histolopatogi jaringan payudara. Setelah didapatkan bahwa tikus dengan perlakuan DMBA positif mengalami kanker payudara, pada minggu ke-12 tikus yang telah mendapat perlakuan DMBA dibagi menjadi 4 kelompok, 3 kelompok mendapat ekstrak propolis oral melalui sonde dengan dosis masing-masing 50, 100, dan 200 mg dalam 1 ml minyak jagung, 1 kelompok sebagai kontrol positif tidak mendapat perlakuan ekstrak propolis. Berat badan ditimbang sebelum mulai perlakuan dan dipantau tiap dua minggu sampai 15 minggu. Hasil penimbangan berat badan menunjukkan bahwa kelompok tikus yang mendapat DMBA peningkatan berat badannya lebih rendah dibanding kelompok tanpa DMBA, dan selanjutnya kelompok perlakuan ekstrak propolis kenaikan berat badannya lebih tinggi dibanding kelompok tanpa perlakuan ekstrak propolis. Hasil penelitian menunjukkan bahwa perlakuan ekstrak propolis memiliki potensi memperbaiki profil berat badan tikus model kanker payudara yang diinduksi dengan DMBA.


2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Jun-Ho Lee ◽  
Soo-Bong Choi ◽  
Mingli Jin ◽  
Ju-Han Lee ◽  
Sang-Don Han ◽  
...  

Euglycemia is the ultimate goal in diabetes care to prevent complications. However, the benefits of euglycemia in type 2 diabetes are controversial because near-euglycemic subjects show higher mortality than moderately hyperglycemic subjects. We previously reported that euglycemic-diabetic rats on calorie-control lose a critical liver weight (LW) compared with hyperglycemic rats. Here, we elucidated the molecular mechanisms underlying the loss of LW in euglycemic-diabetic rats and identified a potential risk in achieving euglycemia by calorie-control. Sprague-Dawley diabetic rats generated by subtotal-pancreatectomy were fed a calorie-controlled diet for 7 weeks to achieve euglycemia using 19 kcal% (19R) or 6 kcal% (6R) protein-containing chow or fedad libitum(19AL). The diet in both R groups was isocaloric/kg body weight to the sham-operated group (19S). Compared with 19S and hyperglycemic 19AL, both euglycemic R groups showed lower LWs, increased autophagy, and increased AMPK and caspase-3 and decreased mTOR activities. Though degree of insulin deficiency was similar among the diabetic rats, Akt activity was lower, and PTEN activity was higher in both R groups than in 19AL whose signaling patterns were similar to 19S. In conclusion, euglycemia achieved by calorie-control is deleterious in insulin deficiency due to increased autophagy and apoptosis in the liver via AMPK and caspase-3 activation.


Author(s):  
Karthick Dharmalingam ◽  
Stalin Ramakrishnan ◽  
Sachidanandam Panchanatham ◽  
Shanthi Palanivelu*

ABSTRACTObjective: To study the restorative effect of Tridham (TD) and 1,2,3,4,6-penta-o-galloyl-β-D-glucose (PGG) on 7,12-dimethyl benz(a)anthracene(DMBA)-induced mammary carcinoma in female Sprague-Dawley rats.Methods: Rats were divided into seven groups of six animals each. Group I rats served as control. Group II - mammary carcinoma was inducedby DMBA. Group III and Group IV were induced with DMBA and subsequently treated with TD and PGG, respectively, for 48 days. Group V wastreated with DMBA and subsequently with a standard drug, cyclophosphamide (CYC). Group VI and Group VII were given TD and PGG alone,respectively, for 48 days. After the experimental period, the levels of lipid peroxides (LPO), activities of enzymic and non-enzymic antioxidantssuch as superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, reduced glutathione, vitamin C, and vitamin E wereevaluated in the breast tissue of control and experimental rats. Levels of LPO, marker enzymes such as 5’-nucleotidase and lactate dehydrogenase,were also evaluated.Results: The levels of enzymic and non-enzymic antioxidants were decreased in DMBA-induced rats when compared to control rats. The levels oftumor markers were increased in DMBA-induced rats when compared to control rats. These parameters were restored to near normal levels ontreatment with TD and PGG.Conclusions: The results suggest that TD and PGG have a cytoprotective role in DMBA-induced breast cancer-bearing rats. The effect of TD and PGGwas found to be more pronounced than CYC, a standard drug.Keywords: Breast cancer, Tridham, Penta galloyl glucose, Antioxidants, Tumor markers, Sprague-Dawley rats.


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