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    NN-DMT (N,N-Dimethyltryptamine) and 5-MeO-DMT (5-Methoxy-N,N-Dimethyltryptamine) found to modulate innate and adaptive inflammatory responses


    Attila Szabo, Attila Kovacs, Ede Frecska, Eva Rajnavolgyi

    Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.

    The function of dimethyltryptamines may extend CNS activity and may play a more universal role in immune regulation. Here we demonstrate for the first time that NN-DMT and 5-MeO-DMT have potent immunomodulatory effects on the functional activities of human dendritic cells operating through the sigma-1 receptor. We also show that DMT-mediated sigmar-1 activation can interfere with both innate and adaptive immune responses.

    NN-DMT and 5-MeO-DMT have potent immunomodulatory effects on the functional activities of human dendritic cells operating through the sigma-1 receptor. We also show that DMT-mediated sigmar-1 activation can interfere with both innate and adaptive immune responses. On the one hand, it strongly decreases the levels of pro-inflammatory cytokines and chemokines such as IL-1B, IL-6, TNFa and IL8, while upregulates the production of the anti-inflammatory cytokine IL-10. On the other hand, NN-DMT and 5-MeO-DMT pre-treatment of pathogen-activated moDCs abolishes their capacity to initiate adaptive immune responses mediated by inflammatory Th1 and Th17 cells. These findings greatly expand the biological role of dimethyltryptamines, which may act not only as neuromodulators or psychedelics, but also as important regulators of both innate and adaptive immunity. Thus, the DMT-sigmar-1 axis emerges as a promising candidate for novel pharmacotherapies of chronic inflammatory and autoimmune diseases.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149582/

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    Voacangine inhibits angiogenesis both in vitro and in vivo

    Yonghyo Kim, Hye Jin Jung, Ho Jeong Kwon

    Voacangine is a tryptamine derivative and iboga alkaloid found in the rootbark of the tree Voacanga africana and Tabernanthe iboga.

    Voacangine exhibits potent anti-angiogenic activity both in vitro and in vivo. Voacangine inhibits tumor-induced angiogenesis by suppressing HIF-1a, and could be the basis for the development of novel anti-angiogenic agents.

    Angiogenesis, the formation of new blood vessels from pre-existing ones, plays a critical role in normal and pathological phenotypes, including solid tumor growth and metastasis. Accordingly, the development of new anti-angiogenic agents is considered an efficient strategy for the treatment of cancer and other human diseases linked with angiogenesis. We have identified voacangine, isolated from Voacanga africana, as a novel anti-angiogenic agent. Voacangine inhibits the proliferation of HUVECs at an IC50 of 18 uM with no cytotoxic effects. Voacangine significantly suppressed in vitro angiogenesis, such as VEGF-induced tube formation and chemoinvasion. Moreover, the compound inhibits in vivo angiogenesis in the chorioallantoic membrane at non-toxic doses. In addition, voacangine decreased the expression levels of hypoxia inducible factor-1a and its target gene, VEGF, in a dose-dependent manner. Taken together, these results suggest that the naturally occurring compound, voacangine, is a novel anti-angiogenic compound.

    https://www.ncbi.nlm.nih.gov/pubmed/22155252
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    UMass Medical School researchers explain why cannabis may relieve intestinal inflammation


    Reports from cannabis users that the drug reduces the symptoms of inflammatory bowel disease (IBD) may finally be explained by new research from UMass Medical School and the University of Bath showing that endocannabinoids help control and prevent intestinal inflammation in mice.

    This is the first time scientists have reported a biological mechanism to explain why some users have reported beneficial effects from cannabis on inflammatory conditions such as ulcerative colitis and Crohn’s disease. Researchers hope their findings will lead to the development of drugs and treatments for gut disorders, which affect millions of people around the world and are caused when the body’s immune defenses mistakenly attack the lining of the intestine.

    The findings appear in the Journal of Clinical Investigation.

    “There’s been a lot of anecdotal evidence about the benefits of cannabis, but not a lot of science to back it up,” said Beth McCormick, Director of the UMass Center for Microbiome Research. “For the first time, we have an understanding of the molecules involved in the process and how endocannabinoids and cannabinoids control inflammation. This gives clinical researchers a new drug target to explore to treat patients who suffer from inflammatory bowel diseases, and perhaps other diseases, as well.”

    The researchers discovered that gut inflammation is regulated by two important processes that are constantly in flux and responding to changing conditions in the intestinal environment. The first process, identified in previous scientific research, promotes an aggressive immune response in the gut that destroys dangerous pathogens, but which can also damage the lining of the intestine when immune cells attack indiscriminately.

    The second pathway, turns off the inflammation response via special molecules transported across the epithelial cells lining the gut by the same process already known to remove toxins from these cells in the intestine cavity. Crucially, this response requires a naturally-produced molecule called an endocannabinoid, which is very similar to cannabinoid molecules found in cannabis.

    If the endocannabinoid isn’t present, inflammation isn’t kept in balance and it can run unchecked, as the body’s immune cells attack the intestinal lining.

    Dr. McCormick and colleagues believe that because cannabis use introduces cannabinoids into the body, these molecules could help relieve gut inflammation, as the naturally produced endocannabinoids normally would.

    “We need to be clear that while this is a plausible explanation for why users have reported cannabis relieves symptoms of IBD, we have so far only evaluated this in mice and have not proven this experimentally in humans. We hope that these findings will help us develop new ways to treat bowel diseases in humans” said Randy Mrsny, PhD, professor of pharmacy and pharmacology at the University of Bath.

    https://www.umassmed.edu/news/news-a...-inflammation/
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    Stanislav Grof


    Ayahuasca and cancer
    *

    Rainforests are known to be an enormous resource and a necessity for upholding the ecosystem of the planet. It is estimated that a very great number of undiscovered plants of medicinal value, are yet to be explored within these forests. Many conventional pharmaceutical medicines originate from substances found in rainforest plants, or their synthesized variants. Ethnopharmacologists have long been aware that there is vast support for the medicinal value of ayahuasca in its use against a number of diseases, but until recently this has been limited to individual claims. Even if a great number of very in-depth and credible personal stories have been available, serious studies have been missing.

    This, however, has come to change over the last few years. Natural substances extracted from the ayahuasca plants have been found to possess unique and strongly antioxidative properties on specific nerve cells in the brain, in areas controlling memory, muscle control and motor activity. This gives probable cause to the theory that ayahuasca could be an effective treatment against neurodegenerative diseases such as ALS, Alzheimers, and Parkinsons disease. Promising results as of date has also been obtained from studying the substance psilocybin, very closely related to the substances found in ayahuasca, naturally occurring in certain species of medicinal mushrooms consumed by the indigenous people where ayahuasca is also used.

    According to Dr. Juan Ramos, head of the neurological disease department at the South Florida university, USA, initial studies show that these substances stimulate the development of new cells in the areas of the brain controlling the above mentioned functions. If this could prove to be an eventual cure through complete restoration of damaged or destroyed cells remains to be seen, but initial results indicate this could potentially be the case. Cancer researchers have also shown interest in B. Caapi, as its different alkaloids has shown to be effective against the growth of cancer cells.

    Eduardo E. Schenberg, Federal University of Sao Paulo:

    There is enough available evidence that the active substances in ayahuasca, especially dimethyltryptamine and harmine, have the positive effect of preventing cancer cells in cultures used for cancer research, and that these substances affect the biochemical processes that are crucial to the treatment of cancer in-vitro as well as in-vivo. The reports available about people with experience from ayahuasca in the treatment of cancer should be taken seriously. The hypothesis is that the combination of (beta-carboline) alkaloids and dimethyltryptamine present in ayahuasca blocks the transportation of nutrients to tumours, lessens the dividing process of cancer cells, and changes the unbalanced mutation-causing metabolism in cancer cells.

    Ayahuasca is proven to be non-addictive, and is even used to aid people in breaking their drug dependencies, as ayahuasca has a detoxifying and documented effect of ridding the user of drug related abstinence issues.

    The MAO-inhibition does, among other things, ensure that the uptake of dimethyltryptamine can occur in the body, as it is otherwise (without MAO-inhibition) broken down in the stomach, unable to cause any effect. Dimethyltryptamine is molecularly near identical with the above mentioned psilocybin in Dr. Ramos research. It is theorized that the unique combination of various harmala-alkaloids from B. Caapi, and dimethyltryptamine from additional plant sources used in ayahuasca, work on a cellular level to repair and restore nerve cells and tissue, and to protect nerve cells and other cells from degenerative damage. This is without doubt valuable from both a neuromedical standpoint, as well as from a cancer research perspective.

    B. Caapi alone has proven to have very positive abilities, potentially effective against neuro and cancer diseases, it is thus something real that may be a valuable alternative treatment option. For someone who experiences positive results to whatever degree, but does not live in a state or country where the use of plants containing dimethyltryptamine is permitted, there is then the possibility to travel to one of the many countries (or states) which by law allows the use of added secondary plants with their combined medicinal properties for evalution of full ayahuasca treatment.

    From the article here: http://www.thisisms.com/forum/natura...opic25343.html
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    Novel therapeutic applications for cannabinoids in cancer treatment


    Walter Milano, Mario Tecce, Anna Capasso

    The endocannabinoid system, comprising the cannabinoid receptors type 1 (CB1) and type 2 (CB2), their endogenous ligands (endocannabinoids), and the proteins that regulate endocannabinoid biosynthesis and degradation, controls several physiological and pathological functions. Indeed, recent evidence indicates that endocannabinoids influence the intracellular events controlling the proliferation and apoptosis of numerous types of cancer cells, thereby leading to both in vitro and in vivo anti-tumor effects. Also, the endogenous ligand arachidonoyl ethanolamide (anandamide; AEA) inhibits the proliferation of human breast cancer cells by blocking the G0/G1-S-phase transition of the cell cycle through interference with cannabinoid CB1 receptor-coupled signal-transducing events. The present review shows that cannabinoids exert their anti-cancer effects in a number of ways and in a variety of tissues. Furthermore, the novel therapeutic applications of cannabinoids in cancer, described here, strongly support the idea that cannabinoids may induce beneficial effect in cancer treatment.

    The endocannabinoid system is an almost ubiquitous signalling system involved in the control of cell fate. Recent studies have investigated the possibility that drugs targeting the endocannabinoid system might be used to retard or block cancer growth. The endocannabinoids have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell signalling pathways. In previous studies, we reported that stimulation of cannabinoid CB1 receptors by the metabolically stable endocannabinoid analogue Met-F-AEA inhibits apex ras activity, prevents proliferation of v-K-ras-transformed rat thyroid cells both in vitro and in vivo and is also able to block the growth of already established tumors.

    Indeed, our very recent data show that Met-F-AEA significantly inhibits, in tumors as well as in transformed cells, the expression of the vascular endothelial growth factor (VEGF). The levels of the cyclin-dependent kinase inhibitor p27, which is down-regulated by p21ras, were instead increased by Met-F-AEA. All these effects were antagonized by the selective CB1 receptor antagonist SR141716A. Met-F-AEA inhibited in vitro the growth of a metastasis-derived thyroid cancer cell line more potently than a primary cancer cell line. Met-F-AEA significantly reduced the number and size of metastatic nodes in an animal model of metastatic spreading (formation of lung nodules after inoculation of 3LL cells), in a way antagonized by SR141716A. Therefore, the present review indicated that cannabinoids exert their anti-cancer effects in a number of ways and variety of tissues to:

    - Stop cells from dividing
    - Prevent new blood vessels from growing into tumors
    - Trigger cell death, through a mechanism called apoptosis
    - Reduce the chances of cancer cells spreading through the body, by stopping cells from moving or invading neighboring tissue
    - Speed up the cell’s internal ‘waste disposal machine’ – a process known as autophagy – which can lead to cell death

    The novel therapeutic application of cannabinoids in cancer treatment strongly suggest that cannabinoids may induce beneficial effect in cancer treatment.

    https://www.oatext.com/novel-therapeutic-applications-of-cannabinoids-in-cancer-disease.php
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    HuaChanSu


    Bufo is a group of over 150 species of toads. Nearly all of these species contain a venom in their skin called bufotoxin, a mild psychedelic, and bufotenin, a tryptamine related to the neurotransmitter serotonin. Similar in chemical structure to the psychedelics psilocin (4-HO-DMT), 5-MeO-DMT, and DMT, bufotenin is also known by the chemical names 5-hydroxy-N,N-dimethyltryptamine (5-HO-DMT), N,N-dimethyl-5-hydroxytryptamine, dimethyl serotonin, and mappine.

    HuaChanSu is a traditional Chinese medicine extracted from the skin of the Bufo toad that is believed to slow the spread of cancerous cells. The skin of the Bufo toad secretes a venom which is dried and dissolved in water. This solution, HuaChanSu, is injected into a cancerous area and targets specific cancer cells. HuaChanSu had been used in China as a therapy for cancer for over 1000 years, and over time spread to other Asian countries. In 1991, HuaChanSu was accepted by China as an official cancer treatment.

    The molecules in HuaChanSu include the cardiac glycosides bufalin, cinobufagin, cinobufotalin and resibufogenin. These molecules are effective due to their lipid-soluble characteristic, which helps them remain in the body longer; they slow the growth of cancer cells and induce cell cycle arrest. Specifically, these molecules suppress the protein Bcl-2, a cancer-prone lymphoma protein, and induce cell death upon melanoma cells. HuaChanSu combined with chemotherapy is superior to simple chemotherapy treatment, reducing gastrointestinal side effects and leucocytopenia. Meta-analysis suggests that HuaChanSu is a promising supplement to routine chemotherapy in treating advanced Non-Small-Cell Lung Cancer.

    Clinical trials held in China have shown between 10% and 16% decrease in lung cancer masses. The toxicity levels of HuaChanSu were also recorded and studied during the various trials. The toad venom was found to have grades 1-2 toxicity levels in the majority of injected areas. No toxicity greater than grade 2 was observed, and the effects subsided within a month.

    https://en.wikipedia.org/wiki/HuaChanSu

    -----

    Bufadienolides

    Bufadienolide is a chemical compound with steroid structure. Its derivatives are collectively known as bufadienolides.

    The skin of Bufo toads is known to be rich in bufadienolide compounds (a group of cardiac glycosides) that exhibit antitumor activity. For example, HuaChanSu, the aqueous extracts from the dried toad skin of Bufo bufo gargarizans Cantor or Bufo melanostictus Schneider, has been widely used in clinical therapy for various cancers in China. Clinical data have indicated that Cinobufacini injection may have significant anticancer activity with low toxicity and few side effects. Data suggests that treatment with Cinobufacini may also enhance the quality of life for patients with cancer. Bufadienolides such as bufalin, cinobufagin, resibufogenin and telocinobufagin are responsible for the anti-cancer properties of HuaChanSu through disruption of the cell cycle and consequent inhibition of cell proliferation, induction of apoptosis, immunomodulation and reversal of multi-drug resistance. The Australian cane toad (Bufo marinus) is also known as a source of bufadienolides, and therefore also considered as a new source of candidate lead compounds for drug development.

    https://www120.secure.griffith.edu.a...0244d100171/1/

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    Evaluating Bufadienolides as the main anti-tumor component in HuaChanSu

    In China, the practice of using toad venom to treat cancer is known as HuaChanSu. Toad venom and toad skin are widely used for treating various cancers in China. Bufadienolides
    are regarded as the main anti-cancer components in toad venom and toad skin.

    Cinobufacin injection, also known as HuaChanSu, is a preparation of Cinobufacini made from Cinobufacin extract liquid. Despite that Cinobufacin injection is shown to shrink liver and gastric tumors, improving patient survival and life quality, the effective components in Cinobufacin remain elusive. In this study, we screen the antitumor components from Cinobufacin injection to elucidate the most effective antitumor components for treatment of liver and gastric cancers.

    Bufadienolides are the most effective components in Cinobufacini injection for the treatment of liver and gastric cancers. This discovery greatly facilitates further research into improving the therapeutic effects of Cinobufacin injection, meanwhile reducing its adverse reaction.

    Bufadienolides are the main material basis in Cinobufacin injection for treating gastric and liver cancer. Further research may give birth to one or more drugs for the treatment of liver and gastric cancer. This would also enable studies on elucidating the mechanism of Cinobufacin injection for inhibiting tumor growth.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5231367/
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    Ayahuasca and cancer treatment
    *

    by Eduardo Schenberg

    Used for centuries in the Amazon by healers and shamans for healing and curing of illnesses, ayahuasca is a plant decoction that may be useful in the treatment of some types of cancer. The decoction is most commonly made of two plants in two possible combinations: Banisteriopsis caapi with Psychotria viridis, or B. caapi with Diplopterys cabrerana. Each plant is known by a different vernacular name, with the most common shown below.




    (a) B. caapi growing in front of a tree, (b) B. caapi flowers, (c) P. viridis shrub, (d) P. viridis leaves with fruits, (e) preparation of ayahuasca brew at a community in Alter do Chao, Para, Brazil, (f) detail of B. caapi leaves, and (g) detail of P. viridis leaves.

    The ayahuasca brew is one of the most sophisticated ethnomedicines known, and more than 20 plants have been identified as part of the preparation. However, it is usually made from only 2 plants, B. caapi and P. viridis. P. viridis and D. cabrerana contain N,N-dimethyltryptamine (DMT) in the leaves, and B. caapi contains β-carbolines such as harmine, harmaline, and tetrahydroharmine in the stem. These harmala alkaloids receive their name from the Peganum harmala plant (Syrian Rue), where they were first identified, which is used to treat cancer since ancient times.

    Given the increasing number of people drinking ayahuasca in the last decade, especially in urban environments, biomedical studies were conducted in humans, repeatedly demonstrating the safety of consuming this brew in a variety of settings.

    DMT is a simple molecule found throughout the plant and animal kingdoms. It is found in human blood and cerebrospinal fluid, and its formation has been proposed to occur in adrenal and lung, where high levels of the enzyme responsible for its synthesis, indole-N-methyltransferase (INMT), have been reported. DMT is the only mammalian N,N-dimethylated trace amine known, and the physiological functions of endogenous DMT remain unclear. However, it is well established that DMT has agonist properties at 5-hydroxytryptamine (5-HT) receptors, mainly 5-HT2A and 5-HT2C. Furthermore, it was recently revealed that DMT binds to the sigma-1 receptor, which provides new opportunities for understanding how ayahuasca may produce its marked effects on the body and mind and what might be the role of endogenous DMT and how ayahuasca may have effects on cancer.

    The human sigma-1 receptor has been cloned and shows no homology with other mammalian proteins. Single-photon emission tomography (SPET) analysis in humans revealed that these receptors are present in organs such as the lung and liver and most concentrated in the brain. Sigma-1 receptor activity has been implicated in a variety of diseases, including cancer, depression, and anxiety. Sigma-1 receptors are found in high densities in many human cancer cell lines, including lung, prostate, colon, ovaries, breast, and brain; thus, sigma ligands are regarded as potential novel antineoplastic tools. Remarkably, there is much overlap between the tissues identified with high sigma-1 receptor densities and the case reports presented here.

    The sigma-1 receptor is a molecular chaperone situated at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM). The spatial and temporal interaction between the ER and mitochondria is crucial for controlling the fate of the cell through the regulation of calcium dynamics, the control of mitochondrial membrane permeabilization, and the initiation and/or propagation of apoptosis by the activation of the Bcl-2 protein family, or by caspase-independent factors, such as apoptosis-inducing factors and endonuclease G. After activation, sigma-1 receptors at the MAM disassociate from the binding immunoglobulin protein (BiP), allowing it to act as a molecular chaperone to inositol 1,4,5-trisphosphate (IP3) receptors, stabilizing them and protecting from degradation by proteasomes. This effect enhances calcium flow from the ER to the mitochondria, activating the tricarboxylic acid (TCA) cycle and increasing the production of adenosine triphosphate (ATP). Importantly, sigma-1 receptors mediate calcium influx to the mitochondria specifically from the ER through 1,4,5-triphosphate receptor type III (IP3R3) but not from the cytosol, which is mediated by 1,4,5-triphosphate receptor type I (IP3R1), indicating a specific mechanism of action for calcium dynamics.

    When stimulated by higher concentrations of its ligands, sigma-1 receptors may translocate from the MAM to the plasma membrane region. After translocation, it can exert inhibitory effects on many ion channels, including N-methyl-d-aspartate (NMDA) receptor modulation through small conductance K+ (SK) channels, the Kv1.4 channel, the NaV1.5 channel, the voltage-gated N-, L-, and P/Q-type Ca2+ channels, the acid-sensing ion channel, and the volume-regulated Cl− channel. The interaction between the sigma-1 receptor and the volume-regulated Cl− channel may have important implications for cancer because these Cl− channels modulate the cell cycle and influence cell volume regulation. Also important for cancer treatment may be the NaV1.5 channel, which is expressed in many cancers, including breast and prostate, and is also associated with metastatic processes. It is important to note that many of these effects were studied in different cells and tissues; therefore, the sigma-1 receptor roles are most likely tissue dependent. Consequently, cell- and tissue-specific effects are important factors that must be considered in oncology studies related to sigma-1 receptors.

    DMT binds sigma-1 receptors with moderate affinity and, at high concentrations, is also capable of inhibiting voltage-gated sodium channels. Thus, DMT may exert two types of effects through sigma-1 receptors: at low concentrations, it regulates calcium flow from the ER to the mitochondria, whereas at higher concentrations, it exerts diverse effects at the plasma membrane region. The effect on calcium influx into the mitochondria may be extremely important for cancer treatment given that an energetic imbalance between excessive cytosolic aerobic glycolysis and reduced mitochondrial oxidative phosphorylation (the Warburg effect) was recently suggested as the seventh hallmark of cancer. This metabolic profile of cancer cells is accompanied by a hyperpolarization of the mitochondrial membrane potential that may be reduced by the calcium influx triggered by DMT binding to the sigma-1 receptor at the MAM. This effect may facilitate the electrochemical processes at the electron transport chain inside the mitochondria, thus increasing the production of reactive oxygen species (ROS) and leading these cells to apoptotic pathways. When high DMT concentrations induce sigma-1 receptor translocation to the plasma membrane, many cellular effects would occur due to the receptor’s interaction with different ion channels. At high concentrations of DMT, a calcium influx and mitochondrial membrane depolarization might be enough to also activate the permeability transition pore (PTP), inducing mitochondria swelling, rupture, and apoptosis.

    For all these effects to help explain the available case reports of ayahuasca on cancer treatment, DMT’s physiological degradation by enteric monoamine oxidase (primarily MAO-A) after oral consumption should be inhibited, thus allowing the DMT to pass into circulation. The pharmacological activity of β-carbolines (primarily harmine) in ayahuasca inhibits MAO, with a high affinity for MAO-A. Therefore, the specific effects of ayahuasca on the different types of cancer could also vary depending on the predominant MAO subtype, given that the ratio of MAO-A to MAO-B varies, for example, from 1:3 in the brain to 4:1 in the intestine, and the placenta has only MAO-A and blood platelets have only MAO-B. Another consequence of inhibiting MAO in different tissues is interference with apoptotic pathways,48 thus strengthening the synergistic action of β-carbolines and DMT.

    In addition to allowing DMT to exert its effects on cancer tissues and cells, β-carbolines may have other important roles. It was recently demonstrated that harmine activates pathways of apoptosis in B16F-10 melanoma cells; it inhibits tumor-specific neo-vessel formation, both in vitro and in vivo in mice, through a series of mechanisms involving decreased serum levels of pro-angiogenic factors and an increase in anti-tumor factors50 and displays an inhibitory effect on cell proliferation against human carcinoma cells. Harmine and harmaline were also shown to reduce cell proliferation in the human leukemia cell line HL60. Harmine was also shown to induce apoptosis in the human hepatocellular carcinoma cell line HepG2. Harmine may also be beneficial in cancer treatment due to its inhibitory effect on the DYRK1A kinase. This kinase is implicated in the resistance of many cancerous tissues to pro-apoptotic stimuli and the enhancement of proliferation, migration, and reduced cell death. Another pharmacological effect of harmine that may be important in brain cancer is its role on the EAAT2 glial glutamate re-uptake transporter. Harmine was identified as one the most efficient molecules to upregulate this transporter in glial cells among a library of 1040 Food and Drug Administration (FDA)-approved substances. This fact may be of importance because most brain tumors are of glial origin and involve excessive glutamate release, causing neurotoxicity. Also important for gliomas may be the binding of harmine to imidazoline I2 receptors. These receptors are highly expressed in gliomas, and their density increases with malignancy in human cells.60 However, their physiological role in these tissues remains unclear.

    Nonetheless, care should be taken because there are also some contradictory reports regarding possible genotoxic or mutagenic effects of β-carbolines in different experiments with cell cultures. Although some of these reports focus specifically on harman and horhaman, which are not found in ayahuasca preparations, others included research into harmine and harmaline. For example, it has been reported that harmine and harman are genotoxic in V79 Chinese hamster fibroblasts and may induce DNA lesions in Saccharomyces cerevisiae cell lines. On the contrary, it was found that harman and harmine do not induce chromosomal alterations in Salmonela typhimurium and Escherichia coli cell lines, and that harmine and harmaline may even have antimutagenic and antigenotoxic activities related to their antioxidant properties. It was also shown that harmine may inhibit tumors as assessed by Lewis Lung Cancer and S180 cell lines, although with some toxic effects.

    In summary, it is hypothesized that the combined actions of β-carbolines and DMT present in ayahuasca may diminish tumor blood supply, activate apoptotic pathways, diminish cell proliferation, and change the energetic metabolic imbalance of cancer cells, known as the Warburg effect. Therefore, ayahuasca may act on cancer hallmarks such as angiogenesis, apoptosis, and cell metabolism. This hypothesis gives some scientific credibility to the cases reported and supports the realization of more scientific studies of ayahuasca and cancer. However, to improve the safety and efficacy of those who eventually search the use of ayahuasca for the treatment of cancer, more studies should be performed considering the remarkable psychological effects of the ritual use of ayahuasca and its possible influences on cancer patients.





    *From the article here: http://journals.sagepub.com/doi/10.1...50312113508389
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    Bufadienolides induce apoptosis in Esophageal Squamous Cell Carcinoma (ESCC)

    Shaohuan Lin, Junhong Lv, Panli Peng, Chanhqing Cai, Jianming Deng, Haihong Deng, Xuejin Li, Xinyue Tang

    Bufo is a group of over 150 species of toads. Nearly all of these species contain a venom in their skin called bufotoxin, a mild psychedelic, and bufotenin, a tryptamine related to the neurotransmitter serotonin. The skin of Bufo toads is known to be rich in bufadienolide compounds that exhibit antitumor activity, but the mechanisms of bufadienolides on esophageal squamous cell carcinoma (ESCC) cells remain unknown.

    In the present study, the anticancer activities of two bufadienolides, bufotalin and bufalin, were examined. The results demonstrated that bufotalin and bufalin effectively inhibited the viability of ESCC cells. However, bufotalin and bufalin exhibited lower toxicity towards human esophageal squamous cells (Het-1A), indicating their high selectivity towards cancer cells. Mechanistic studies revealed that bufotalin effectively induced ESCC cell apoptosis, and markedly activated tumor protein p53 phosphorylation.

    Collectively, these results illustrate the therapeutic potential of bufadienolides against ESCC by regulating the p53 signaling pathway.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774392/
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    Cannabinoid receptors as a novel target for the treatment of Prostate Cancer


    Cannabinoids, the active components of Cannabis sativa and their derivatives have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory effects and tumor regression. Here we show that expression levels of both cannabinoid receptors, CB1 and CB2, are significantly higher in CA-human papillomavirus-10 cells. WIN-55,212-2 and time-dependent inhibition of cell growth, blocking of CB1 and CB2 receptors by their antagonists (CB1) and (CB2) significantly prevented this effect. Extending this observation, we found that WIN-55,212-2 treatment with LNCaP resulted in a dose- and time-dependent induction of apoptosis (a), decrease in protein and mRNA expression of androgen receptor (b), decrease in intracellular protein and mRNA expression of prostate-specific antigen (c), decrease in secreted prostate-specific antigen levels (d), and decrease in protein expression of proliferation cell nuclear antigen and vascular endothelial growth factor (e). Our results suggest that WIN-55,212-2 or other non–habit-forming cannabinoid receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer.

    Because prostate cancer has become the most common cancer diagnosed in men, developing novel targets and mechanism-based agents for its treatment has become a challenging issue. In recent years cannabinoids, the active components of Cannabis sativa and their derivatives have drawn renewed attention because of their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory effects, and tumor regression. Cannabinoids have been shown to induce apoptosis in gliomas, neuroblastoma, hippocampal neurons in vitro, and most interestingly, regression of C6-cell gliomas in vivo. Further interest in cannabinoid research came from the discovery of specific cannabinoid systems and the cloning of specific cannabinoid receptors. These diversified effects of cannabinoids are now known to be mediated by the activation of specific G protein-coupled receptors that are normally bound by a family of endogenous ligands, the endocannabinoids. Two different cannabinoid receptors have been characterized and cloned from mammalian tissues: the “central” CB1 receptor, and the “peripheral” CB2 receptor.

    In the present study, we show for the first time that expression levels of both cannabinoid receptors, CB1 and CB2, are higher in human prostate cancer cells than in normal cells. Importantly, we also show that WIN-55,212-2 (CB1/CB2 agonist) treatment with androgen-responsive LNCaP cells results in a dose- and time-dependent inhibition of cell growth with a concomitant induction of apoptosis, decrease in protein and mRNA expression of androgen receptor and prostate-specific antigen (PSA), decrease in secreted PSA levels, protein expression of proliferating cell nuclear antigen (PCNA), and vascular endothelial growth factor (VEGF). We suggest that cannabinoid receptor agonists may be useful in the treatment of human prostate cancer.

    It is now well accepted that uncontrolled cellular growth, which may be a result of defects in cell cycle and apoptotic machinery, is responsible for the development of most of the cancers including prostate cancer. Thus, the agents which can modulate apoptosis in cancer cells may be able to affect the steady-state cell population and may be useful in the management and therapy of cancer. Consistent with this notion, there is a need to develop novel targets and mechanism-based agents for the management of prostate cancer. One of the most exciting and promising areas of current cannabinoid research is the ability of these compounds to control the cell survival/death decision. In this study, we found that compared with PrEC and PZ-HPV-7 cells, the expression levels of both cannabinoid receptors CB1 and CB2 were significantly higher in CA-HPV-10 and other human prostate cells.

    These data suggest that CB1 and CB2 receptors could be a target for novel treatment options for prostate cancer. We also found that mixed CB1/CB2 agonist WIN-55,212-2 treatment of LNCaP cells resulted in a decrease of cell viability as determined by MTT assay at varying doses and time points, suggesting the involvement of both CB1 and CB2 in the antiproliferative action of cannabinoids. It is widely recognized that apoptosis is an ideal way of elimination of cancer cells and that selective apoptotic events could provide suitable targets for cancer treatment and prevention. In this study, we also observed an increase in apoptosis of LNCaP cells by treatment with WIN-55,212-2. This observation was confirmed by employing confocal microscopy and flow cytometry. This could be an important observation which might be useful for devising strategies for the management of human prostate cancer because apoptosis is a physiological and discrete way of cell death different from necrotic cell death and is regarded to be an ideal way of cell elimination.

    Androgens are essential for the growth, differentiation, and functioning of the prostate as well as in increasing prostate cancer development. Many molecular mechanisms have been suggested for the development of recurrent hormone refractory tumors. Most of these mechanisms postulate an alteration in the function of the androgen receptor and its signaling pathways. The overexpression of androgen receptor in prostate cancer may promote cell growth. Hence, elimination or reducing the androgen receptor in prostate cancer should help in treating this neoplastic disease. As most of the molecular mechanism for the development of prostate cancer involves modulation in the function of androgen receptor and its signaling pathways, we further studied the effect of WIN-55,212-2 on androgen receptor protein and mRNA expression and its subsequent effect on PSA production. Our results indicate that WIN-55,212-2 treatment significantly decreases androgen receptor protein and mRNA expression in LNCaP cells.

    PSA belongs to the kallikrein family, is a serine protease with highly prostate-specific expression, and is the most widely employed marker in the detection of early prostate cancer. For these reasons, it is considered that agents which could reduce PSA levels may have important clinical implications for prostate cancer. Earlier studies reported that PSA is primarily regulated by androgens. This observation was based on the fact that the antiandrogen, cyperoterone acetate, had the ability to induce PSA, and that hydroxyflutamide could block androgen and progesterone induction of PSA glycoprotein, thus suggesting that PSA glycoprotein expression is influenced predominantly by androgens via its receptor, and the mutation of the receptor can affect the expression of this gene by steroids other than androgens.

    Recent studies have established that androgen receptor functions as a transcriptional regulator via its binding to androgen response elements within promoter and enhancer regions of PSA. PSA is currently the most accepted marker for assessment of prostate cancer progression in humans and is being detected in the serum of patients with prostate diseases including prostatitis, benign prostatic hypertrophy, and prostate cancer. It is reported that in LNCaP cells, androgens regulate PSA glycoprotein expression and mRNA via androgen receptor. Our studies show a significant decrease in intracellular, mRN, as well as secreted levels of PSA by WIN-55,212-2 treatment of cells, suggesting that cannabinoid receptor agonists may be exploited to prevent prostate cancer progression.

    PCNA recognizes nuclear antigens and its overexpression is associated with increase in PSA serum levels. PCNA expression has significant prognostic value and it seems to be a significant biomarker in prognosis and treatment of prostate cancer. Our results also suggest that concomitant with the decrease in PCNA protein expression, there was a decrease in PSA serum levels following WIN-55,212-2 treatment.

    VEGF is a ubiquitous cytokine that regulates embryonic vasculogenesis and angiogenesis. Normal prostate epithelium expresses low levels of VEGF, whereas premalignant lesions have increased VEGF expression, which is additionally increased in prostate carcinoma. Studies have shown that cannabinoid treatment markedly reduced the expression of VEGF in gliomas, the most potent proangiogenic factor and also of angiopoietin 2, which contributes to the angiogenic process by preventing vessel maturation. Our results showed that treatment of LNCaP with WIN-55,212-2 inhibits growth and VEGF protein expression.

    Recently, cannabinoids have received considerable attention due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory effects, and tumor regression. Our results suggest that treatment of androgen-responsive human prostate carcinoma LNCaP cells resulted in a decrease in intracellular and secreted levels of PSA, with concomitant inhibition of androgen receptor, cell growth, and induction of apoptosis. We conclude that cannabinoids should be considered as agents for the management of prostate cancer. If our hypothesis is supported by in vivo experiments, then the long-term implications of our work could be to develop non–habit-forming cannabinoid agonist(s) for the management of prostate cancer.

    http://cancerres.aacrjournals.org/content/65/5/1635



    Last edited by mr peabody; Yesterday at 07:24.
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