Anti-inflammatory therapies in TRAMP mice: delay in PCa progression

Kido, Larissa Akemi; Montico, Fábio; Sauce, Rafael; Macedo, Aline Barbosa; Minatel, Elaine; Vendramini–Costa, Débora Barbosa; Carvalho, João Ernesto de; Pilli, Ronaldo Aloise; Cagnon, Valéria Helena Alves

doi:10.1530/erc-15-0540

Cited by 30 publications

(69 citation statements)

References 54 publications

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“…Regarding the mitogenic process, studies showed higher IGFR1 in the prostatic stroma close to tumor epithelial cells and also an increased expression in the prostate ventral lobe in older TRAMP mice (Ryan et al, 2007;Kido et al, 2016). In addition, other studies indicated that increased IGFR1, around tumoral areas, is related to increased genic transcription level, due to IGF1 signaling, which promotes prostate epithelial proliferation (Hellawell et al, 2002;Yu et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…In each quadrant, the prostate tissue was classified in: healthy epithelium (HE); low-grade prostatic intraepithelial neoplasia (LGPIN); high-grade prostatic intraepithelial (HGPIN), and well-differentiated adenocarcinoma (WDA) (modified from Berman-Booty et al, 2012;Kido et al, 2016;Silva et al, 2017). Thus, the morphological analyses were made based on the observation of eight random and non-overlapping microscopic fields under 400 magnification per animal.…”

Section: Light Microscopymentioning

confidence: 99%

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Nintedanib treatment delays prostate dorsolateral lobe cancer progression in the TRAMP model: contribution to the epithelial‐stromal interaction balance

Pangrazi

Silva

Kido

et al. 2017

Cell Biology International

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Prostate cancer (PCa) progression mechanism has been linked to epithelial proliferation, tumor invasion ability, and growth factors. Nintedanib (BIBF 1120) has been reported as being FGF and VEGF pathway inhibitors, exhibiting antitumor activity. Thus, the objective herein was to characterize the early Nintedanib treatment effects on the structure and molecules involved in the basal membrane, the extracellular matrix (ECM) maintenance, in addition to the angiogenesis and mitogenic processes at different grades of prostatic tumor development in TRAMP mice. Therefore, 45 male TRAMP mice were divided into control groups: 8-week-old mice (TC8), 12-week-old mice (TC12), and 16-week-old mice (TC16); and treated groups with 10 mg/kg/day Nintedanib dose for 4 weeks. The treated groups were euthanized at 12 (TN12) and 16 (TN16) weeks of age. Samples from the dorsolateral lobe were collected and processed for light microscopy, immunohistochemistry, Western blotting, and microvessel density analysis. The results showed that early Nintedanib treatment led to an increase of healthy epithelium frequency and a reduction of LGPIN and a maximum vascularization density in the TN12 group. Also, treatment led to a well-differentiated adenocarcinoma decrease and an α and β dystroglycan and also laminin 1 increase in the TN16 group. IGFR1 decreased in the TN16 group. To conclude, early Nintedanib treatment led to a reduction in cancer severity, interfering in both ECM compounds and angiogenesis process to then contribute to a balance, not only in the prostatic epithelium and stroma, but also in the epithelial-stromal interaction during PCa progression.

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Section: Discussionmentioning

confidence: 99%

Section: Light Microscopymentioning

confidence: 99%

Nintedanib treatment delays prostate dorsolateral lobe cancer progression in the TRAMP model: contribution to the epithelial‐stromal interaction balance

Pangrazi

Silva

Kido

et al. 2017

Cell Biology International

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“…Racemic GTN, a styryl lactone found in its R configuration in plants of the genus Goniothalamus, Annonaceae, has in vitro antiproliferative activity in human tumor cell lines via activation of apoptosis (18)(19)(20)23,38). GTN also presents general anti-inflammatory effects, without side effects (as seen with aspirin, for example) in the therapeutic doses (20,22,39). Although the intake of aspirin can prevent CRC development, it can cause serious health problems, such as stomach bleeding, due to inhibition of cyclooxygenases (COX) 1 and 2 (40).…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory natural product goniothalamin reduces colitis-associated and sporadic colorectal tumorigenesis

Vendramini–Costa

Francescone

Posocco

et al. 2016

CARCIN

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The tumor microenvironment offers multiple targets for cancer therapy, including pro-tumorigenic inflammation. Natural compounds represent an enormous source of new anti-inflammatory and anticancer agents. We previously showed that the styryl lactone goniothalamin (GTN) has promising antiproliferative and anti-inflammatory activities. Because inflammation is a major driver of colorectal cancer (CRC), we therefore evaluated the therapeutic and preventive potentials of GTN in colitis, colitis-associated cancer (CAC) and spontaneous CRC. First, in a simplistic model of inflammation in vitro, GTN was able to inhibit cytokine production in bone marrow-derived macrophages induced by lipopolysaccharide. Next, in dextran sulfate sodium (DSS) induced-colitis model, mice treated with GTN displayed restored tissue architecture, increased cell proliferation in the colonic crypts and reduced epithelial damage. Moreover, colon tissue from GTN-treated mice had significantly less expression of the inflammatory genes interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), S100A9, interleukin 23A (IL-23A), IL-22 and IL-17A. In the azoxymethane/DSS model of CAC, GTN reduced tumor multiplicity, load and size. Additionally, GTN suppressed production of IL-6, IL-17 and TNF-α in tumor tissue, as well as abrogated stromal immune cell activation and nuclear translocation of NF-κB. Finally, in a tamoxifen inducible model of sporadic CRC, GTN-treated mice had significantly fewer tumors and decreased levels of IL-17A, IL-6, S100A9 and TNF-α protein within the tumors. These results suggest that GTN possesses anti-inflammatory and antitumor activities and represents a preventive and therapeutic agent modulating the inflammatory environment in the colon during colitis as well as CAC and CRC development.

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“…In order to assess the effects of short and long‐term treatment, the animals were treated from 8 to 12 weeks of age, and euthanized at different times: the immediate‐response groups at 12‐week‐old (CEL1 or GTN1) and the late‐response groups at 22 weeks‐old (CEL2 or GTN2). Celecoxib Treatment: CEL1 (n = 10) and CEL2 (n = 10) groups received a 10 mg/kg Celecoxib dose orally five times a week for 30 days only (from 8 to 12‐week old mice [Kido et al, ]). Goniothalamin Treatment: GTN1 (n = 10) and GTN2 (n = 10) groups received a 150 mg/kg GTN dose orally, three times a week for 30 days only (from 8 to 12‐weeks old mice) (Kido et al, ).…”

Section: Methodsmentioning

confidence: 99%

Steroidal hormone and morphological responses in the prostate anterior lobe in different cancer grades after Celecoxib and Goniothalamin treatments in TRAMP mice

Silva

Kido

Montico

et al. 2018

Cell Biology International

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Prostate cancer is the second most diagnosed cancer in the world, and alternative methods to prevent and treat different lesion grades need to be evaluated. The objective was to evaluate the morphological, hormonal, and inflammatory responses in the prostate anterior lobe in transgenic adenocarcinoma of the mouse prostate (TRAMP), following Celecoxib and Goniothalamin (GTN) treatments. All animals were treated for 4 weeks, from 8 weeks of age and euthanized either immediately after treatment (12-week-old mice: immediate response) or later (22-week-old mice: late response). The results showed a significant increase of high-grade prostatic intraepithelial neoplasia (HGPIN) and well-differentiated adenocarcinoma (WDA), according to the age in the control groups. Celecoxib treatment decreased the WDA incidence in the late response group. GTN led to a significant healthy tissue increase, and an LGPIN and HGPIN decrease in the immediate response group. In the late response group, GTN led to healthy area increase and there was no occurrence of WDA. AR and ERα immunoexpressions were reduced by both treatments in the immediate response groups. However, only GTN was able to decrease the ERα level in the late response group. Regarding COX-2 immunoreactivity, both treatments reduced the frequency of this enzyme. We can conclude that the prostate anterior lobe is a good model to study prostate cancer, considering its slow progression. Both treatments led to cancer delay in the prostate anterior lobe. However, GTN pointed towards a better treatment spectrum in the signaling pathways in the prostate microenvironment, particularly in ERα.

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Anti-inflammatory therapies in TRAMP mice: delay in PCa progression

Cited by 30 publications

References 54 publications

Nintedanib treatment delays prostate dorsolateral lobe cancer progression in the TRAMP model: contribution to the epithelial‐stromal interaction balance

Nintedanib treatment delays prostate dorsolateral lobe cancer progression in the TRAMP model: contribution to the epithelial‐stromal interaction balance

Anti-inflammatory natural product goniothalamin reduces colitis-associated and sporadic colorectal tumorigenesis

Steroidal hormone and morphological responses in the prostate anterior lobe in different cancer grades after Celecoxib and Goniothalamin treatments in TRAMP mice

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