Use of hormones in doping and cancer risk

Hormones with anabolic properties such as growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are commonly abused among professional and recreational athletes to enhance physical ability. Despite their adverse effects are well-documented, the use of GH and IGF-1 has recently grown. This article highlights the anabolic activity related to mechanisms of cancer development and progression. GH/IGF-1 axis is able to activate cellular mechanisms that modulate every key stage of cancer formation and progression, such as inhibition of apoptosis, resistance to treatments, and induction of angiogenesis, metastatic process and cell proliferation. Results from pre-clinical studies and epidemiological observations in patients with an excess of GH and IGF-1 production or treated with these hormones showed a positive association with the risk to develop several types of cancer. In conclusion, athletes should be made aware that long-term treatment with doping agents might increase the risk of developing cancer, especially if associated with other licit or illicit drugs and/or high-protein diet

The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient mice

Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. The plant polyphenol Curcumin has been proposed for dietary prevention of cancer. We therefore examined its effects on the human breast cancer cell line MDA-MB-231 in vitro and in a mouse metastasis model. Curcumin strongly induces apoptosis in MDA- MB- 231 cells in correlation with reduced activation of the survival pathway NF kappa B, as a consequence of diminished I kappa B and p65 phosphorylation. Curcumin also reduces the expression of major matrix metalloproteinases (MMPs) due to reduced NF kappa B activity and transcriptional downregulation of AP-1. NF kappa B/p65 silencing is sufficient to downregulate c-jun and MMP expression. Reduced NF kappa B/AP-1 activity and MMP expression lead to diminished invasion through a reconstituted basement membrane and to a significantly lower number of lung metastases in immunodeficient mice after intercardiac injection of 231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases, most likely as a consequence of down-regulation of NF kappa B/AP-1 dependent MMP expression and direct apoptotic effects on circulating tumor cells but not on established metastases. Dietary chemoprevention of metastases appears therefore feasible. Copyright (c) 2007 S. Karger AG, Basel

The prevention of doping and the improper use of drugs and food supplements in sports and physical activities: a survey on the activity of the prevention departments of Italian local health authorities

Doping is an important public health problem widespread not only among elite athletes, but also among amateur and recreational athletes and the general population. In Italy the introduction of doping prevention within the Essential Levels of Care (LEA) with the DPCM 12/1/2017 represents a crucial step towards the implementation of education and health promotion interventions. In this context, the Departments of Prevention (DP) of the Local Health Authorities (LHA) have to play a fundamental role, becoming the cultural and operational reference on this issue. As part of the "Doping prevention: development of a permanent educational tool coordinated by the National Health Service Prevention Departments" project, funded by the Italian Ministry of Health, a survey was conducted on the activities carried out by the DP regarding doping prevention and improper use and abuse of drugs and food supplements in sports and physical activities, as a basis for the harmonization of organizational structures and prevention programs and the creation of a collaboration network at a regional and national level

Artesunate induces necrotic cell death in schwannoma cells

Established as a potent anti-malaria medicine, artemisinin-based drugs have been suggested to have anti-tumour activity in some cancers. Although the mechanism is poorly understood, it has been suggested that artemisinin induces apoptotic cell death. Here, we show that the artemisinin analogue artesunate (ART) effectively induces cell death in RT4 schwannoma cells and human primary schwannoma cells. Interestingly, our data indicate for first time that the cell death induced by ART is largely dependent on necroptosis. ART appears to inhibit autophagy, which may also contribute to the cell death. Our data in human schwannoma cells show that ART can be combined with the autophagy inhibitor chloroquine (CQ) to potentiate the cell death. Thus, this study suggests that artemisinin-based drugs may be used in certain tumours where cells are necroptosis competent, and the drugs may act in synergy with apoptosis inducers or autophagy inhibitors to enhance their anti-tumour activity

Development of Resistance towards Artesunate in MDA-MB-231 Human Breast Cancer Cells

Breast cancer is the most common cancer and the second leading cause of cancer death in industrialized countries. Systemic treatment of breast cancer is effective at the beginning of therapy. However, after a variable period of time, progression occurs due to therapy resistance. Artesunate, clinically used as anti-malarial agent, has recently revealed remarkable anti-tumor activity offering a role as novel candidate for cancer chemotherapy. We analyzed the anti-tumor effects of artesunate in metastasizing breast carcinoma in vitro and in vivo. Unlike as expected, artesunate induced resistance in highly metastatic human breast cancer cells MDA-MB-231. Likewise acquired resistance led to abolishment of apoptosis and cytotoxicity in pre-treated MDA-MB-231 cells. In contrast, artesunate was more cytotoxic towards the less tumorigenic MDA-MB-468 cells without showing resistance. Unraveling the underlying molecular mechanisms, we found that resistance was induced due to activation of the tumor progression related transcription factors NFκB and AP-1. Thereby transcription, expression and activity of the matrix-degrading enzyme MMP-1, whose function is correlated with increased invasion and metastasis, was up-regulated upon acquisition of resistance. Additionally, activation of the apoptosis-related factor NFκB lead to increased expression of ant-apoptotic bcl2 and reduced expression of pro-apoptotic bax. Application of artesunate in vivo in a model of xenografted breast cancer showed, that tumors growth was not efficiently abolished as compared to the control drug doxorubicin. Taken together our in vitro and in vivo results correlate well showing for the first time that artesunate induces resistance in highly metastatic breast tumors

Inhibition of a vascular ocular tumor growth by IL-12 gene transfer.

Ocular tumors such as retinoblastoma and uveal melanoma have devastating effects on vision. Patients with uveal melanoma also have low 5-year survival rates, thus new therapeutic modalities are necessary. As both retinoblastoma and uveal melanoma are highly vascular, we tested application of a gene transduction approach with a potent TH1 cytokine also endowed with strong anti-angiogenic activity, Interleukin-12 (IL-12). Gene transfer into murine 99E1 uveal melanoma-like cells, while having no effects on growth in vitro, essentially blocked subcutaneous tumor growth in vivo without evident signs of toxicity. Orthotopic intraocular injection resulted in invasive tumors that destroyed ocular architecture by the control cells while the IL-12 transduced cells rarely formed tumors. Histological analysis revealed highly invasive and angiogenic tumor growth in the controls and poorly vascularized tumors in the presence of IL-12. The tumor repression effect could be reproduced by a systemic anti-angiogenic effect, where controlateral injection of IL-12 expressing cells strongly repressed growth in tumors formed by parental 99E1 cells. This was associated with significantly lowered tumor vessel densities, a trend toward lower VEGF levels in the lesion, and significantly decreased NK cells in the parental tumors exposed to systemic IL-12. Taken together, our data suggest that IL-12 gene transfer can provide anti-angiogenic effects without toxicity and may be particularly suited for therapy of vascularized ocular tumors

The Akt inhibitor deguelin, is an angiopreventive agent also acting on the NF-kappaB pathway

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