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Schuller Neurotransmitter receptors and cancer

differentiated cancer cells as well as cancer stem cells. Beta-blockers should not be used for the general
prevention/therapy of cancer because they are
There is an ongoing international discussion on the selectively effective only in cancers that are stimulated
potential usefulness of beta-blockers for cancer by beta-adrenergic agonists. In fact, without prior
intervention, with numerous preclinical studies testing of patients for increased stress neurotransmitter
reporting significant cancer inhibition whereas and cAMP levels, beta-blocker treatment is contra-
clinical investigations have generated controversial indicated because it can promote certain cancers due
data with some even reporting cancer promoting to the fact that cAMP functions as a tumor promoter
effects. [28,29,64,67-71] The potential usefulness of in some cancers while acting as a tumor suppressor
beta-blockers for adjuvant cancer treatment has in others. It has thus been shown that cAMP inhibits
[78]
additionally been discussed in depth based by the growth/progression of squamous cell carcinoma,
comprehensive reviews of published preclinical small cell lung carcinoma, [79,80] medulloblastoma and
[81]
2+
and clinical literature. [67,72,73] By contrast, the current basal cell carcinoma. The arbitrary use of Ca -
review analyzes mechanistic aspects of G -coupled channel blockers for cancer prevention and therapy is
s
receptors and their physiological inhibitors and their equally ill advised. While preclinical investigations have
2+
modulating effects on cancer. The discrepancies identified cancer preventive effects of Ca -channel
[82-84]
between preclinical and clinical findings are thus not blockers in a large spectrum of cancers, these
only triggered by the potential sensitization of β-ARs in agents not only suppress molecular targets studied
in these cancers but additionally inhibit the release
response to long-term beta-blocker therapy (decades of Nor and Epi from sympathetic nerves, thereby
[85]
of treatment in people as opposed to a few weeks in suppressing the beta-adrenergic receptor-mediated
experimental animals), but also by the potential impact formation of cAMP. In turn, this effect can selectively
of factors unrelated to β-ARs. Preclinical studies that promote the development and progression of cancers
have employed agonists of receptors coupled to the in which cAMP has tumor suppressor function.
inhibitory G-protein G (GABA-B receptors, opioid
i
peptide receptors) for the inhibition of β-AR-mediated In summary, successful cancer prevention and
progression of adenocarcinoma of the lungs and improved therapeutic outcomes can be achieved
pancreas in vitro and in vivo have repeatedly by strategies that aim to maintain/restore cAMP
shown that increases in intracellular cAMP and the homeostasis. Too much cAMP will promote the
associated activation of its downstream effectors development and progression of cAMP-driven cancers
are key molecular events that activate β-AR-driven (e.g. adenocarcinoma of the lungs, pancreas, colon,
development and progression of both cancers and can stomach and prostate) while too low cAMP levels will
be successfully inhibited by agonists of G-coupled increase the risk for development and progression of
i
receptors that inhibit the formation of cAMP by blocking cancers in which cAMP has tumor suppressor function
the activation of adenylyl cyclase. [41,42,51,54,55,66,74-76] A (e.g. small cell lung cancer, squamous cell carcinoma,
host of non-β-AR receptors coupled to the stimulatory medulloblastoma, basal cell carcinoma). In analogy
G-protein G increase intracellular cAMP, [3,77] a to the long-term management of diabetes by insulin
s
reaction not inhibited by beta-blockers but effectively injections that are based on blood glucose testing,
counteracted by agonist-induced signaling of G- this approach requires routine testing of cAMP levels.
i
coupled receptors. There is also a host of non-beta- Beta-blockers will only be beneficial if elevated levels
adrenergic agents that increase intracellular cAMP of Nor/Epi indicate hyperactive β-AR signaling.
directly. Among such agents are caffeine, theophylline
and theobromine contained in numerous beverages, Authors’ contributions
weight loss medications, sweets and candies. These H.M. Schuller contributed solely to the paper.
naturally occurring phosphodiesterase inhibitors Financial support and sponsorship
block the enzymatic breakdown of cAMP which None.
then accumulates inside the cells. In addition,
pharmacological phosphodiesterase inhibitors are Conflicts of interest
widely used for the therapy of chronic obstructive There are no conflicts of interest.
pulmonary disease because of their anti-inflammatory
and broncho-dilating properties. None of the clinical Patient consent
investigations on beta-blockers and cancer conducted Not applicable.
to date have adjusted their data to exclude the cancer
promoting effects of such non-beta-adrenergic Ethics approval
agents. Not applicable.
74 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ April 28, 2017