Palm D, Lang K, Niggemann B, et al. The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers

Institute of Immunology, Witten/Herdecke University, Witten, Germany.
International Journal of Cancer (Impact Factor: 5.09). 06/2006; 118(11):2744-9. DOI: 10.1002/ijc.21723
Source: PubMed


The development of metastases is a decisive step in the course of a cancer disease. The detection of metastases in cancer patients is correlated with a poor prognosis, and over 90% of all deaths from cancer are not due to the primary tumor, which often can be successfully treated, but are due to the metastases. Tumor cell migration, a prerequisite for metastasis development, is not merely genetically determined, but is distinctly regulated by signal substances of the environment including chemokines and neurotransmitters. We have shown previously that the migration of breast, prostate, and colon carcinoma cells is enhanced by the stress-related neurotransmitter norepinephrine in vitro, and that this effect can be inhibited by the beta-blocker propranolol. We now provide for the first time evidence for the in vivo relevance of this neurotransmitter-driven regulation using PC-3 prostate carcinoma cells. The development of lumbar lymph node metastases in athymic BALB/c nude mice increased with the application of norepinephrine via microosmotic pumps, while propranolol inhibited this effect. However, the growth of the primary tumor was not affected by either treatment. Additionally, experiments using human tissue microarrays showed that 70-90 percent of breast, colon, and prostate carcinoma tissues express the relevant beta2-adrenoceptor. Thus, our work contributes to the understanding of the basic cellular mechanisms of metastasis development, and furthermore delivers a rationale for the chemopreventive use of clinically established beta-blockers for the inhibition of metastases.

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Available from: Kerstin Lang, Nov 27, 2014
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    • "The microosmotic pumps implanted in the body could keep functional and pump drugs contained continuously for up to 4 weeks. The pumps were filled with 100 μL normal saline containing 56 mM NE, 56 mM propranolol or both of them at a dose of 1 μmol/100 g/day [14]. Ascorbic acid (0.2%) was added as a preservative into every pump. "
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    ABSTRACT: Sunitinib alone exhibits satisfactory efficacy in several mouse homografts and xenografts but unsatisfactory efficacy in many kinds of solid tumors in clinic. Different from animals, receiving a diagnosis of cancer impacts chronic stress on patients. Here, we examine whether norepinephrine (NE), one of the most potent stress related hormones, leads to the difference in the efficacy of sunitinib between clinical and preclinical trials. The influence of NE on mouse melanoma B16F1 cells under sunitinib was evaluated in vitro and in vivo. The beta-AR/cAMP/PKA (beta-adrenoceptor/cyclic adenosine monophosphate/protein kinase A) signaling pathway was also evaluated in human lung adenocarcinoma cells. We found that NE upregulated the expression of VEGF, IL-8 and IL-6 in vitro and stimulated tumor growth in vivo, which was mediated by beta-AR/cAMP/PKA signaling pathway and could be inhibited by propranolol, a beta-blocker for hypertension for decades. This research indicates exogenous norepinephrine attenuates the efficacy of sunitinib, and a combination of sunitinib and propranolol might be suggested as a new strategy in solid tumor in clinic.
    Journal of Experimental & Clinical Cancer Research 02/2014; 33(1):21. DOI:10.1186/1756-9966-33-21 · 4.43 Impact Factor
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    • "Multicenter clinical trials on large samples are needed to confirm existing scientific evidence in this field. Some clinical trials are currently underway to confirm positive effects of paravertebral analgesia on outcome of breast cancer patients, and epidural analgesia on those of colon cancer patients [84–86]. Finally, it is undoubtedly important to verify if local anesthetics can decrease metastatic progression in humans. "
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    ABSTRACT: Many of the most common anesthetics are used in surgical oncology, yet effects on cancer cells are still not known. Anesthesia technique could differentially affect cancer recurrence in oncologic patients undergoing surgery, due to immunosuppression, stimulation of angiogenesis, and dissemination of residual cancer cells. Data support the use of intravenous anesthetics, such as propofol anesthesia, thanks to antitumoral protective effects inhibiting cyclooxygenase 2 and prostaglandins E2 in cancer cells, and stimulation of immunity response; a restriction in the use of volatile anesthetics; restriction in the use of opioids as they suppress humoral and cellular immunity, and their chronic use favors angiogenesis and development of metastases; use of locoregional anesthesia compared with general anesthesia, as locoregional appears to reduce cancer recurrence after surgery. However, these findings must be interpreted cautiously as there is no evidence that simple changes in the practice of anesthesia can have a positive impact on postsurgical survival of cancer patients.
    The Scientific World Journal 02/2014; 2014(5):328513. DOI:10.1155/2014/328513 · 1.73 Impact Factor
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    • "Thus, the experiments presented here identify direct inhibition of apoptosis in prostate epithelial cells as the primary mechanism by which surgical stress delays prostate involution induced by androgen ablation. These results are consistent with earlier studies showing accelerated tumor growth and inhibition of apoptosis by agonists of β-adrenoreceptors in mouse models of prostate cancer [9], [20]. Future studies using primary and metastatic prostate cancer models will determine whether surgical stress impedes inhibition of prostate tumors by androgen ablation as well as by other prostate cancer therapies. "
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    ABSTRACT: Androgens control growth of prostate epithelial cells and androgen deprivation induces apoptosis, leading to prostate involution. We investigated the effects of surgical stress on prostate involution induced by androgen ablation and determined the underlying mechanisms. Androgen ablation in mice was induced by surgical castration and administration of the anti-androgenic drugs bicalutamide and MDV3100. Surgical stress was induced by sham castration under isoflurane anesthesia. Surgical stress delayed apoptosis and prostate involution induced by anti-androgenic drugs. These effects of stress were prevented by administering the selective beta2-adrenoreceptor antagonist ICI118,551 and were also blocked in BAD(3SA/WT) mice expressing phosphorylation-deficient mutant BAD3SA. These results indicate that apoptosis and prostate involution in response to androgen ablation therapy could be delayed by surgical stress via the beta2-adrenoreceptor/BAD signaling pathway. Thus, surgery could interfere with androgen ablation therapy, whereas administration of beta2-adrenoreceptor antagonists may enhance its efficacy.
    PLoS ONE 11/2013; 8(11):e78175. DOI:10.1371/journal.pone.0078175 · 3.23 Impact Factor
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