Serotonin Makes Tumors Happy Too

Serotonin and its Role:

Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter primarily found in the gastrointestinal tract (GI tract), blood platelets, and the central nervous system of humans. Serotonin is manufactured in the brain (dorsal raphe nucleus cells, which are located deep in the brain) and the intestines and is primarily stored in and transported by platelets. It is popularly thought to be a contributor to feelings of well-being and happiness. It regulates human’s mood, sleep patterns, sexual drive and the temperature in the body. Serotonin mediates gut movements and the perceptions of resource availability, and in turn it affects organ development (Ref.)

Next to its well-known functions, serotonin has been shown to be a mitogenic factor for a wide range of normal and tumoral cells. Serotonin exhibits a growth stimulatory effect in aggressive cancers and carcinoids usualy through 5- HT1 and 5-HT2 receptors. In contrast, low doses of serotonin can inhibit tumour growth via the decrease of blood supply to the tumour, suggesting that the role of serotonin on tumour growth is concentration-dependent. Serum serotonin level was found to be suitable for prognosis evaluation of urothelial carcinoma in the urinary bladder, adenocarcinoma of the prostate and renal cell carcinoma (Ref.).

In line with the above, during tumor progression, tyrosine hydroxylase, the rate-limiting enzyme in the serotonin biosynthesis pathway, is often up-regulated (Ref.)

Following experimental results, it has been suggested that serotonin promotes tumor growth and survival in

• Liver Cancer (Ref.)
• Pancreatic Cancer (Ref.)
  • Our data demonstrates significant reductions in PaCa cells growth, invasion and correlated downstream signaling in response to down-regulation of these serotonin receptors expressions, suggesting the significant involvement of these receptors in promoting pancreatic cancer. (Ref.)
• Breast Cancer (Ref.)
• Blader Cancer (Ref.)
  • These results highlight the potential use of 5HT(1A) and 5HT(1B) antagonists in the treatment of bladder cancer.
• Colon Cancer (Ref.)
  • Histologic analyses revealed dramatically larger areas of spontaneous necroses and tissue hypoxia in mice lacking peripheral serotonin, which could be attributed to diminished tumor vascularity pointing to a disturbed angiogenesis in these animals.
• And Others

Anti Cancer Mechanisms and Anti Serotonin Strategies to Stop Cancer Growth:

The mechanism that connect serotonin with tumor evolution seem to be related to

• serotonin impact on tumor associated macrophages
  • Serotonin was shown to suppress MMP-12 production in tumor associated macrophages and as a result inhibit the generation of angiostatin. Conversely, the inhibition of serotonin leads to angiostatin production which reduces tumor growth due to angiostatin’s angiogenesis inhibition activity. (Ref.1, Ref.2). Therefore, this effect is related to tumor associated machrophages (Ref.).
• serotonin direct impact on cell growth via binding to its receptors
  • It was previously indicated that the 5-HT-1 and 2 receptors are extensively expressed in the human breast cancer, prostate cancer, bladder cancer cells and other cancer types (Ref.1, Ref.2).
• serotonin direct impact on vessels perfusing the tumour
  • Intravital microscopy studies have also shown that vessels perfusing the tumour exhibit a specific vasconstrictive response to 5HT1 agonists (Ref.)

According to the above, to prevent cancer cell growth, the following strategies have been proposed:

• use antagonists of serotonin receptors,
• the opposite of above: use agonists of serotonin receptors
• use inhibitors of selective serotonin transporter
• use inhibitors of serotonin synthesis

Serotonin receptors: Antagonists and Agonists

Serotonin (5-HT) signaling is initiated through interaction with its receptors. Note that different 5-HT receptors have been identified (from 1 to 7) based on their structural, functional and pharmacological characteristics. Six of the families of these receptors are G-protein-coupled, including 5-HT-1,2,4,5,6,7. Only 5-HT-3 is uniquely a ligand-gated cation channel. 5-HT receptors are further divided into different subtypes, e.g. 5-HT-1 family has five subtypes, comprising the 5-HT-1A, -1B, -1D, -1E and -1F receptors and couples preferentially to Gi/o to inhibit cAMP formation.

It was previously indicated that the 5-HT-1 and 2 receptors are extensively expressed in the human breast cancer, prostate cancer, bladder cancer cells and other cancer types (Ref.1, Ref.2). Therefore the inhibition of these receptors has been proposed to be a good strategy to stop tumor growth.

• Qunine and Chloroquine: Interestingly, it has been recently reported in the Nature magazine that the antimalaria drug Quinine that is also known to have anti cancer actions (its derivative chloroquine has strong anti cancer effects as well) interferes with serotonin biosynthesis and action (Ref.). I just checked some older studies and it appears that chloroquine is a competitive inhibitor of serotonin uptake by platelets. (Ref.).
• Sorafenib: it has been well-known that sorafenib produces anticancer effects through targeting multiple kinases, but it was shown recently that it has “off-target” 5-HTR binding activity (Ref.)
• Cyproheptadine: sold under the brand name Periactin or Peritol, is a first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties. It is a 5-HT2A receptor antagonists (Ref.) Cyproheptadine can also be used as an appetite stimulant in cancer patients in order to improve their appetite and may be helpful in patients with cancer anorexia/cachexia. (Ref,). It is not know if the anticancer mechanisms of this drug are related to its antiserotonergic or antihistamine action but its potential is clear: Unexpected remission of hepatocellular carcinoma (HCC) with lung metastasis to the combination therapy of thalidomide and cyproheptadine: report of two cases and a preliminary HCC cell line study http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543862/
• Propranolol: I was unaware about the fact that Propranolol which is known to have major anti cancer effects (Ref.) it is also an inhibitor of 5-HT1B. (Ref.).  Others have suggested that propranolol acts as a 5HT1A antagonist and a 5HT1B agonist in the rat cortex (Ref.) Maybe its modulation of the serotonin receptors is the origin of its known anti angiogenesis effect.
• Update 19-Dec-2017: Sceletium tortuosum, traditionally used in Southern Africa for relief of pain-related ailments  and with anti-inflammatory properties (Ref.) it is also a 5-HTR inhibitor (Ref.). Can also be found online supplement (Ref.).

Chloroquine and Propranolol are some of my favorites and the above are additional reasons to maintain that perception I have. However, I also like Cyproheptadine as it is not only a serotonin receptor modulator but also an antihistamine medication which is again highly relevant in cancer (Ref.).

Other inhibitors: Alprenolol (5HT1A antagonist), Dotarizine (5HT1A, 5HT2A and 5HT2C antagonist). A longer list of inhibitors can be found here: https://en.wikipedia.org/wiki/5-HT1A_receptor

An opposite approach using 5HT1 agononists may be useful in inducing hypoxia in tumours, which could be exploited in a strategy using hypoxia-selective cytotoxins or hypoxia-selective gene therapy. (Ref.)

Serotonin transporter: inhibitors

Peripheral serotonin in the blood is carried by platelets and released in high concentrations (micromolar) during various events. Platelets possess the serotonin transporter (SERT), allowing them to uptake serotonin across their plasma membrane.

Antidepressant drugs have been designed to alter serotonergic pathways. Such drugs that are already in the market for long time are SSRIs. Selective-serotonin reuptake inhibitors (SSRIs) are designed to increase serotonin levels in the synaptic cleft by inhibiting SERT reuptake of serotonin. Outside of their designed function, SSRIs decrease reuptake of 5-HT by platelets through binding of SERT.

Recently, it has been found that inhibitors of the serotonin reuptake transporter (SERT, mediates uptake into enterocytes or neurons) and serotonin receptors, which include approved drugs used to treat mood disorders, were potent inhibitors of breast tumor-initiating cells (Ref.)

Here is another study indicating the anti cancer potential behind serotonin reuptake inhibitors (SSRI):

• Use of antidepressants and risk of colorectal cancer: a nested case-control study http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(06)70622-2/abstractWe did a population-based nested case-control study from Jan 1, 1981, to Dec 31, 2000, of people aged 5–85 years who were registered with Saskatchewan Health and eligible for prescription-drug benefit. Conclusion: Serotonin reuptake inhibitors (SSRI) use might inhibit the growth of colorectal tumours through an antipromoter effect or direct cytotoxic effect.

However, there is another side of the coin. While the fact that SSRI decrease blood serotonin content by 90% and inhibit platelet reuptake so that there is little serotonin to be released at the tumor site which is good, SSRIs have been also shown to depress immune cell function probably due to the decrease of Serotonin in the platelet. And this may not be good as it has been shown that there is a suppressed lymphocyte proliferation during SSRI administration, which may allow tumor growth (Ref.). As a result of these considerations, a study has been performed on ovarian cancer patients to investigate the relation between SSRI use and tumor progression:

• We examined the effect of SSRIs on survival and progression in ovarian cancer patients and effects of 5-HT on ovarian cancer cell (OCC) proliferation. Ovarian cancer patients from a 6-site study between 1994 and 2010 were included. conclusion: Patients using SSRIs had significantly decreased time to disease progression.

Based on the above findings, if possible, I would stay away from SSRI antidepressant drugs in case of ovarian cancer patients and if not possible at least carefully monitor the tumor progression. For all the other tumor types I would be careful.

In conclusion SSRIs may lead to both tumor progression and tumor inhibition via two different mechanisms and its a matter of luck (and probably tummor type) regarding which of the mechanism will dominate and the related outcome. If the immune system is already suppressed due to chemo or other reasons, using SSRIs may only help I guess. If the immune system is in a good shape SSRIs would better be avoided in my opinion.

Here is a list of FDA approved SSRI drugs: Citalopram (Celexa); Escitalopram (Lexapro, Cipralex); Paroxetine (Paxil, Seroxat); Fluoxetine (Prozac); Fluvoxamine (Luvox); Sertraline (Zoloft, Lustral). Other drugs such as Tramadol (anti pain medication)may also act as a SSRI. For a larger list of such medication please go to https://en.wikipedia.org/wiki/Serotonin_syndrome

Interestingly, I just checked some older studies and it appears that chloroquine is a competitive inhibitor of serotonin uptake by platelets too (Ref.). In the context of the story above, this means chloroquine may also have immunosuppressive activity. I just checked the literature and here it is: “Immunosuppressive effects of chloroquine: potential effectiveness for treatment of post-transfusion graft-versus-host disease.” (Ref.). I am interested in chloroquine because of its anti cancer activity but this finding indicates that next to its serious anti cancer potential (see this article) there may also be a negative impact on the immune system.

Paroxetine, a SSRI has been found to have cytotoxic activity against tumor cells, both of murine or human origin in the micromolar concentration range (Ref.).

Serotonin synthesis

Inhibition of serotonin synthesis has been suggested as

• a way to treat osteoporosis, since serotonin seems to inhibit bone formation (Ref.)
• a way to improve quality of life in patients with Neuroendocrine Tumors (Ref.)

Case Reports in Humans:

Unexpected remission of hepatocellular carcinoma (HCC) with lung metastasis to the combination therapy of thalidomide and cyproheptadine: report of two cases and a preliminary HCC cell line study http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543862/

Treatment Strategy:

To me, some of the best ways to address the influence of serotonin in cancer is via the inhibition of 5-HT receptors over expressed in many tumor types and not via the inhibition of serotonin transporter.

From a 5-HTR inhibition point of view I would probably use Cyproheptadine + Propranolol. These should address (at least partially) both 5-HT1 and 5-HT2 receptors which seem to be the most relevant in most cancers. Both drugs are widely available. Propranolol administration strategy and source has been discussed here.

Update 19-Dec-2017: Sceletium tortuosum, traditionally used in Southern Africa for relief of pain-related ailments  and with anti-inflammatory properties (Ref.) it is also a 5-HTR inhibitor (Ref.). Can also be found online supplement (Ref.).

Safety:

Specifically Propranolol may be perfect for some but dangerous for others due to its heart rate and blood preasure lowering effects –> its use needs to be cheeked with the medical doctor.

Note that there may be a relation between Serotonin and pain http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811866/

References:

Unexpected remission of hepatocellular carcinoma (HCC) with lung metastasis to the combination therapy of thalidomide and cyproheptadine: report of two cases and a preliminary HCC cell line study http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543862/

We reported two cases of hepatocellular carcinoma (HCC) with lung metastases who were treated with a combination of thalidomide and cyproheptadine. The use of cyproheptadine in these two cases was originally for skin itching. Follow-up CT images revealed a complete remission of HCC in both of them after treatment for 6 months and 6 weeks, respectively. A following experimental cell line study demonstrated that cyproheptadine effectively reduced the viability of two HCC cell lines.

Dopamine and serotonin regulate tumor behavior by affecting angiogenesis. http://www.ncbi.nlm.nih.gov/pubmed/25269824

The biogenic amines dopamine and serotonin are neurotransmitters and hormones, which are mainly produced in the central nervous system and in the gastro-intestinal tract. They execute local and systemic functions such as intestinal motility and tissue repair. Dopamine and serotonin are primarily stored in and transported by platelets. This review focuses on the recently recognized role of dopamine and serotonin in the regulation of tumor behavior by affecting angiogenesis and tumor cell proliferation. Preclinical studies demonstrate that dopamine inhibits tumor growth via activation of dopamine receptor D2 on endothelial and tumor cells. Serotonin stimulates tumor growth via activation of serotonin receptor 2B on endothelial cells and serotonin receptors on tumor cells. Drugs that stimulate dopamine receptor D2 or inhibit serotonin receptors are available and therefore clinical intervention studies for cancer patients are within reach.

Unexpected remission of hepatocellular carcinoma (HCC) with lung metastasis to the combination therapy of thalidomide and cyproheptadine: report of two cases and a preliminary HCC cell line study http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543862/

Impact of serotonin on tumour growth. http://www.ncbi.nlm.nih.gov/pubmed/10821326

Several opposite effects of serotonin (5HT) on tumour growth have been reported. On one hand, 5HT is known as a growth factor for several types of nontumoural cells, and it has been proposed to take part in the autocrine loops of growth factors contributing to cell proliferation in aggressive tumours such as small cell lung carcinoma. Depending on the tumour type either 5HT2 or 5HT1 receptor antagonist have been found to inhibit the 5HT-induced increase in tumour growth. In contrast, several authors have also reported that 5HT and 5HT2 agonist can inhibit tumour growth. Most often this effect has been considered to be related with the specific vasoconstrictive effect of 5HT or 5HT2 agonists on the vessels irrigating the tumour, which has been evidenced by intravital microscopy. Intravital microscopy studies have also shown that vessels perfusing the tumour exhibit a specific vasconstrictive response to 5HT1 agonists. In addition, 5HT has been shown to be involved in the effects of several anticancer treatments associated with the reduction of tumour flow. Finally, the specific vasoconstrictive effect of 5HT or 5HT receptor subtype agonists might also be useful in inducing hypoxia in tumours, which could be exploited in a strategy using hypoxia-selective cytotoxins or hypoxia-selective gene therapy.

Selective serotonin reuptake inhibitor suppression of HIV infectivity and replication. http://www.ncbi.nlm.nih.gov/pubmed/20947783

These studies suggest that an SSRI enhances natural killer/CD8 noncytolytic HIV suppression in HIV/acquired immune deficiency syndrome and decreases HIV viral infectivity of macrophages, ex vivo, suggesting the need for in vivo studies to determine a potential role for agents targeting serotonin in the host defense against HIV.

Serotonin and Cancer: What Is the Link? http://www.eurekaselect.com/127641/article

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine that acts as a neurotransmitter in the central nervous system, local mediator in the gut and vasoactive agent in the blood. Serotonin exerts its multiple, sometimes opposing actions through interaction with a multiplicity of receptors coupled to various signalling pathways. In addition to its well-known functions, serotonin has been shown to be a mitogenic factor for a wide range of normal and tumoral cells. Serotonin exhibits a growth stimulatory effect in aggressive cancers and carcinoids more often through 5- HT₁ and 5-HT₂ receptors. In contrast, low doses of serotonin can inhibit tumour growth via the decrease of blood supply to the tumour, suggesting that the role of serotonin on tumour growth is concentration-dependent. Data are also available on serotonin involvement in cancer cell migration, metastatic processes and as a mediator of angiogenesis. Moreover, the progression of some tumours is accompanied by a dysregulation of the pattern of serotonin receptor expressions. Serum serotonin level was found to be suitable for prognosis evaluation of urothelial carcinoma in the urinary bladder, adenocarcinoma of the prostate and renal cell carcinoma. In some cases, antagonists of serotonin receptors, inhibitors of selective serotonin transporter and of serotonin synthesis have been successfully used to prevent cancer cell growth. This review revaluates serotonin involvement in several types of cancer and at different stages of their progression.

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