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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    • "To date, the by far most striking discovery in the context of drug repurposing in oncology is the anti-metastatic function of beta-blockers [8]. Stimulated by results provided by in vitro drug testing systems91011, and confirmed by mice experiments [12], several retrospective patient studies have delivered proof for an anti-metastatic effect in various types of solid tumors, i.e., breast, ovarian, prostate, colorectal, lung, liver, melanoma1314151617181920212223242526272829. The in vitro drug testing systems that initially led to this development were migration analyses, which are currently not a standard drug screening method in oncology, but may constitute such a new model as requested by the EMA. "
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    ABSTRACT: Most patients that die from cancer do not die due to the primary tumor but due to the development of metastases. However, there is currently still no drug on the market that specifically addresses and inhibits metastasis formation. This lack was, in the past, largely due to the lack of appropriate screening models, but recent developments have established such models and have provided evidence that tumor cell migration works as a surrogate for metastasis formation. Herein we deliver on several examples a rationale for not only testing novel cancer drugs by use of these screening assays, but also reconsider established drugs even of other fields of indication.
    Full-text · Article · Jan 2016
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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.
    Full-text · Article · Feb 2014 · Journal of Experimental & Clinical Cancer Research
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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.
    Full-text · Article · Feb 2014 · The Scientific World Journal
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