The Serotonin Receptor 5-HT2B Is Required For Cancer; Can Be Blocked

haidut

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I think this study should be sent to every pharma executive and brainwashed whitecoat who claims that serotonin is a good hormone promoting happiness and health. Actually, pharma companies have no illusions and know very well what's going on. Hence, the recent acquisition of Pfizer to the commercial rights of terguride - a potent antagonist of 5-HT2B, albeit a lot less effective than something like lisuride or non-selective antagonists like cyproheptadine or ritanserin. Pfizer knows quite well that 5-HT2B is required for the development of fibrosis and that antagonizing that receptor can cure fibrosis. Given that fibrosis is the preceding stage to cancer, it is not surprising at all that the studies below found the 5-HT2B receptor to be required for the development of cancer as well. And just as in the case of terguride, blocking said 5-HT2B receptor was therapeutic for the established cancer. The drug used in the study was ritanserin, but any other 5-HT2B antagonist such as cyproheptadine, lisuride, and even ketanserin should work just as well.

Translational Psychiatry - Impulsive alcohol-related risk-behavior and emotional dysregulation among individuals with a serotonin 2B receptor stop codon
"...The 5-HT2B receptor has also been shown to be required to form experimental tumors in nude mice,7 and for the development of pulmonary hypertension through bone-marrow contribution,8 which suggest a potential preventive role of the HTR2B Q20* in some somatic diseases."

http://www.jbc.org/content/271/6/3141.long
"...The stimulation of the 5-HT2B receptor not only triggers the MAP kinase cascade, but also activates the LM5 cell division rate (Fig. 3A). This is confirmed by the enhancement of [3H]thymidine incorporation in response to agonists (data not shown). Therefore, these data demonstrate that 5-HT has a mitogenic effect on LM5 cells. This mitogenic effect probably results from MAP kinase stimulation via Ras, Gα
, and -β
, as already shown in other systems by use of the dominant negative form of Ras (58) or of constitutively active G
(44, 61). In addition to short-term effects, MAP kinase activation may lead to long-term effects, including cell transformation and/or differentiation. LM5 cells grown to confluence are forming foci, an effect which is stimulated by agonist and inhibited by antagonist (Fig. 3B). Surprisingly, the potency of antagonist is greater with regard to the ability to inhibit foci formation than with the rate of cell division (Fig. 3, A and B). This difference may be related to different responses in different physiological states (exponential growth versus quiescent) and probably corresponds to short-term effects versus long-term effects involving different effectors of the receptor. In addition, all nude mice-derived tumor cells express more 5-HT2B binding sites than LM5 cells. This indicates that a threshold level of receptor expression (1 pmol/mg of protein) is probably necessary for transformation. However, these events remain 5-HT and 5-HT2B receptor-dependent (Table 1). Although the contribution of Ras stimulation to the long-term alterations is probable, since activated Ras is known to transform NIH3T3 fibroblasts (62) and since expression of a dominant negative form of Ras inhibits the muscarinic m5 receptor-dependent transformation(60), additional transduction mechanisms are probably involved. Nevertheless, expression of the 5-HT2B receptor triggers both the 5-HT-mediated mitogenicity and the transformed phenotype of the LMTK
cells, indicating that the 5-HT2B receptor behaves as a ligand-dependent proto-oncogene for the LMTK
cell line
."

"...Interestingly, the unstimulated LM5 cells have a higher cell division rate than the parental LMTK
cells. This basal activity is partially reduced in the presence of the antagonist ritanserin (Fig. 3A) (inverse agonist) and probably corresponds to an intrinsic activity of the receptor which has also been shown for the 5-HT2C receptor(63). Similarly, in unstimulated LM5 cells, foci spontaneously appear and the basal level of Ras activity is elevated suggesting intrinsic activity of the 5-HT2B receptor. Therefore, intrinsic activity and a high level of expression may be two important parameters for tumor development. Tumor regression in nude mice induced by ritanserin treatment may open lines of investigation to develop new types of therapeutic agents."

"...Finally, the 5-HT2B receptor is expressed in tumors from both human and M. natalensis species (Fig. 4, B and C). The Mastomys CT expresses a 5-HT2B receptor very similar to the mouse receptor, (4) and the human 5-HT2B receptor cDNA has been found in a cDNA library made from mRNA of a human CT(16). In addition, the pharmacology of the Mastomys CT indicates a high level of 5-HT2B receptor expression.4 Therefore, this report makes, for the first time, a parallel between induced tumorigenicity by expression of the 5-HT2B receptor in nontransformed fibroblasts and its expression by spontaneous tumors, which are both coupled to Ras activation (Fig. 5). However, the participation of the 5-HT2B receptor in enterochromaffin cell malignant transformation remains to be proven."
 
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d1d2

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The drug used in the study was ritanserin, but any other 5-HT2B antagonist such as cyproheptadine, lisuride, and even ketanserin should work just as well.

Will your new supplement also target this receptor? Sorry if this has been mentioned previously and thanks!
 

haidut

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Will your new supplement also target this receptor? Sorry if this has been mentioned previously and thanks!

Both ritanserin and lisuride (which we sell) are potent antagonists of 5-HT2B. The new serotonin antagonist is also a 5-HT2B antagonist. Cyproheptadine is as well. Caffeine is (potentially) too. So, quite a few options to choose from :):
 

yourke

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Thanks Haidut,
seems Terguride shows the same inhibition with many benefits,
" Terguride 1 mg was always preferred to bromocriptine, while the lower doses were indistinguishable from placebo. Terguride is therefore likely to play an important role in the treatment of hyperprolactinemia."Terguride--a new dopamine agonist drug: a comparison of its neuroendocrine and side effect profile with bromocriptine. - PubMed - NCBI
"Our data proposes that 5-HT2BR antagonists and, more specifically, Terguride, which is clinically approved and well tolerated, might serve as a new cardioprotective tool for the treatment of RVF". (right ventricular failure) https://www.hindawi.com/journals/bmri/2015/438403/
 

Soren

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Fascinating and insightful as always. Am interested to see if ritanserin has any hair growth promoting affects the same way that Cyproheptadine does.
 

haidut

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What dosages of eg. Cyproheptadine are we talking about in case of cancer ?

Peat says 2mg, but I know of people who did not notice improvement until they took 4mg for at least 2 weeks. They then went back to a "maintenance" dose of 2mg daily.
 
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