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Evaluation of Minnelide As a Potential Therapeutic Agent for Preventing the Relapse of AML


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https://ashpublications.org/blood/article/134/Supplement_1/5159/425015/Evaluation-of-Minnelide-As-a-Potential-Therapeutic

"CONCLUSION: Minnelide is not only successful in reducing tumor burden but it is potentially an effective therapy for preventing relapse of AML. This is evidenced by the reduction in stemness of AML cells treated with triptolide and through the reduction in tumor burden in the bone marrow of mice treated with low doses of Minnelide."


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Daniel
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Thanks Johan. What do you think about the availability and toxicity of these products? Many years ago I spent a lot of time on Minnelide and Triptolide as they looked very promising. Triptolide was available (very expensive) but the issue with it was toxicity. I think they did a clinical trial on that in the Netherlands or Belgium, I should have the article somewhere in my computer. Another option to take this is the plant "thunder god vine" which should be much cheaper, but again I am not sure about the toxicity. Do you have any opinion on that? Are there any new developments on this line? (I think there was a co in US who developed Minnelide based on Triptolide activity.) Thanks.

Kind regards,
Daniel


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I really don't know, Daniel. Tripterygium Wilfordii or Thunder God Vine used as prescribed appears to be safe. Definitely an interesting herb in the treatment of cancer.


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@johan Indeed Johan, Thunder God Vine is an interesting one. When I find time I will check if there are any updates on this line.


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@daniel awesome


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Posted by: @daniel

Thanks Johan. What do you think about the availability and toxicity of these products? Many years ago I spent a lot of time on Minnelide and Triptolide as they looked very promising. Triptolide was available (very expensive) but the issue with it was toxicity. I think they did a clinical trial on that in the Netherlands or Belgium, I should have the article somewhere in my computer. Another option to take this is the plant "thunder god vine" which should be much cheaper, but again I am not sure about the toxicity. Do you have any opinion on that? Are there any new developments on this line? (I think there was a co in US who developed Minnelide based on Triptolide activity.) Thanks.

Kind regards,
Daniel

@daniel

Co-Delivery of Triptolide and Curcumin for Ovarian Cancer Targeting Therapy via mPEG-DPPE/CaP Nanoparticle. https://www.ncbi.nlm.nih.gov/pubmed/30041722?dopt=Abstract

"In conclusion, the TP and Curc-NPs exerted synergistic effects on ovarian cancer in vitro and in vivo, and the toxicity caused by triptolide may be reduced by curcumin through anti-oxidative stress effects. The TP and Curc-NPs could be a promising strategy for ovarian cancer."


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https://www.ncbi.nlm.nih.gov/pubmed/31241707

Protective Effect of Vitamin C on Triptolide-induced Acute Hepatotoxicity in Mice through mitigation of oxidative stress.

"Vitamin C could protect against triptolide-induced liver injury via reducing oxidative stress, and vitamin C may pose a significant health protection in the clinical use of triptolide"


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"Protective effects of silymarin on triptolide-induced acute hepatotoxicity in rats"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780159/


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Shanti
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@johan @daniel

As D pointed out, minnelide current and past clinical trials use minnelide, presumably due to the toxicity of triptolide and the Thunder God Vine itself, for which a therapeutic dose may be difficult to control.  I do not have any experience myself with the vine or its extracted compounds, but I am part of a "Professional Herbalist" online group which contains some of today's most renowned herbalists (mostly, I sit on the sidelines and soak up the knowledge).  In 2013 there was an extensive discussion on the use of Thunder God Vine, so I went back to view the thread. Most participants expressed concern over its toxicity and narrow therapeutic window. There were also concerns about immune suppression, with one of the Chinese Medicine practitioners referring to it as, "Chinese Herbal Prednisone" (another major indication for the vine is autoimmune disorders). 

From the HerbalThink-TCM software (2013):

"Toxicity: The most common reasons for poisonings using this herb are: (1) overdosing on the root bark, which is especially toxic, and which some authors recommend removing and discarding before use; (2) ingesting the fresh twigs, of which 12g can be lethal; (3) consumption of honey contaminated by flower pollen of this plant; (4) failure to cook for the recommended time, which reduces its toxicity; (5) failure to observe contraindications. The fresh form of the plant is more toxic than that which has been dried and stored for a year or more."

"Dosage: 2-4 qian (6-12 g). Preparation: Peel off root bark and discard it before using. Presoak at least 2 hr. in warm water, then simmer at least 4 hr., or pre-cook for 2 hours before adding other ingredients to reduce toxicity."

The post then goes into some detail on the many toxicity symptoms as well as the effects of the herb on different aspects of the immune system. Apparently, many of the Chinese extracts of the vine are purified and more heavily processed to minimize toxicity. 

I did notice that an extract is sold on Amazon: https://www.amazon.com/Thunder-God-Vine-Root-20/dp/B0145XJQZ2 , but don't know how close that product would get someone to a therapeutic dose for cancer. It seems to me that the herb should be used very cautiously, with proper preparation, and ideally with someone who has experience, if at all. 


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Thank you, Shanti. Very helpful information!


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@shanti Indeed very helpful! Thank you! A friend used this some years ago but I am not sure what was the dose he used. I may find that back.

Here is also some extra info from my side that I extracted from my research notes done on Triptolide 5-6 years ago:

 

Dosage & Administration:

Minnelide™ will be given as a single agent intravenously as a 30-minute infusion daily x 21 days followed by a 7-day rest period. One cycle will equal 28 days. https://clinicaltrials.gov/ct2/show/NCT01927965

0.2 mg/kg http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656604/

The triptolide group subjects were injected with 0.2 mg/kg of triptolide dissolved in DMSO and diluted with phosphate buffered saline to a volume of 100 μl, the intraperitoneal injections being daily over a period of 60 days. The compound 1 subjects were intraperitoneally injected daily for 60 days with 0.28 mg/kg of the compound dissolved in phosphate buffered saline diluted to a volume of 100 μl.

Furthermore, it was significant that in both the triptolide and triptolide prodrug group subjects, there was no apparent significant impact on body weight and no apparent signs of toxicity in the subjects. https://www.google.com/patents/US8507552?dq=minnelide&hl=en&sa=X&ei=UXtvVaSOIMavUYSZgZAD&ved=0CCsQ6AEwAg

http://www.naturesfoodpatch.com/ns/DisplayMonograph.asp?StoreID=a5pjlp3me3s92n5800akhlbd34ws3rl1&DocID=bottomline-thundergodvine

Sources:

tbd

Clinical trial

Study of Minnelide™ in Patients With Advanced GI Tumors https://clinicaltrials.gov/ct2/show/NCT01927965

Triptolide-Containing Formulation as Treatment for Autosomal Dominant Polycystic Kidney Disease https://clinicaltrials.gov/ct2/show/NCT02115659?term=triptolide&rank=1 Triptolide-Containing Formulation (1mg/kg/d) was prescribed;

Impact on T Cell Immune Activation and Inflammation of Triptolide Woldifii in HIV-infected Immunological Non-responders (CACTrip12) https://clinicaltrials.gov/ct2/show/NCT01817283?term=triptolide&rank=2 Triptolide wilfordii (20mg tid po) would be given to invention group for 24 weeks.

Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours. http://www.ncbi.nlm.nih.gov/pubmed/19251409/

Resistance of cancer cells to cytotoxic therapy can be caused by the activation of strong anti-apoptotic effectors, for example NF-kappaB. Therefore, compounds that inhibit NF-kappaB stimulation might overcome chemotherapy resistance. F60008, a semi-synthetic derivate of triptolide, is converted to triptolide in vivo and activates apoptosis in human tumour cells. We performed a phase I and pharmacological study of F60008 given intravenously as a weekly infusion for 2 weeks every 3 weeks in patients with advanced solid tumours. Twenty patients were enrolled, and a total of 35 cycles were administered. The most frequent haematological side-effect was mild grade 1-2 anaemia. Non-haematological toxicities included fatigue, nausea, vomiting, diarrhoea and constipation, all grade 1-2. Two lethal events were observed in which an increase in caspase-3 activity and overt apoptosis in monocytes and neutrophils could be seen. Pharmacokinetic studies showed high inter-individual variability and rendered F60008 a far from optimal derivate of triptolide.

Literature: Articles

Anti-Angiogenic Effect of Triptolide in Rheumatoid Arthritis by Targeting Angiogenic Cascade http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0077513

Rheumatoid arthritis (RA) is characterized by a pre-vascular seriously inflammatory phase, followed by a vascular phase with high increase in vessel growth. Since angiogenesis has been considered as an essential event in perpetuating inflammatory and immune responses, as well as supporting pannus growth and development of RA, inhibition of angiogenesis has been proposed as a novel therapeutic strategy for RA. Triptolide, a diterpenoid triepoxide from Tripterygium wilfordii Hook F, has been extensively used in treatment of RA patients. It also acts as a small molecule inhibitor of tumor angiogenesis in several cancer types. However, it is unclear whether triptolide possesses an anti-angiogenic effect in RA. To address this problem, we constructed collagen-induced arthritis (CIA) model using DA rats by the injection of bovine type II collagen. Then, CIA rats were treated with triptolide (11–45 µg/kg/day) starting on the day 1 after first immunization. The arthritis scores (P<0.05) and the arthritis incidence (P<0.05) of inflamed joints were both significantly decreased in triptolide-treated CIA rats compared to vehicle CIA rats. More interestingly, doses of 11~45 µg/kg triptolide could markedly reduce the capillaries, small, medium and large vessel density in synovial membrane tissues of inflamed joints (all P<0.05). Moreover, triptolide inhibited matrigel-induced cell adhesion of HFLS–RA and HUVEC. It also disrupted tube formation of HUVEC on matrigel and suppressed the VEGF-induced chemotactic migration of HFLS–RA and HUVEC, respectively. Furthermore, triptolide significantly reduced the expression of angiogenic activators including TNF-α, IL-17, VEGF, VEGFR, Ang-1, Ang-2 and Tie2, as well as suppressed the IL1-β-induced phosphorylated of ERK, p38 and JNK at protein levels. In conclusion, our data suggest for the first time that triptolide may possess anti-angiogenic effect in RA both in vivo and in vitro assay systems by downregulating the angiogenic activators and inhibiting the activation of mitogen-activated protein kinase downstream signal pathway.

Triptolide functions as a potent angiogenesis inhibitor http://onlinelibrary.wiley.com/doi/10.1002/ijc.24694/full

Triptolide is a key anti-inflammatory compound of the Chinese herbal medicine Tripterygium wilfordii Hook. f. (Celastraceae). It also possesses potent antitumor activity. In this study, we show that triptolide is an angiogenesis inhibitor based on various angiogenesis assays. The IC50 in in vitro assays was 45 nM, which was much lower than the plasma concentrations of triptolide in the rat or human administered with T. wilfordii extracts for treating inflammation. When dosed in vivo, triptolide potently inhibited angiogenesis at 100 nM in Matrigel plug assay. Triptolide at 0.75 mg/kg/day significantly blocked tumor angiogenesis and tumor progression in murine tumorigenesis assay. The underlying mechanism of triptolide correlated with downregulation of proangiogenic Tie2 and VEGFR-2 expression in human umbilical vein endothelial cell by semiquantitative RT-PCR and western blot analysis. Although Tie2 inhibition appeared to be a later event as compared with VEGFR-2, Tie2 overexpression significantly attenuated the inhibitory effect of triptolide on endothelial proliferation and network formation. By contrast, Tie2 knockdown mimicked the inhibitory effect of triptolide on endothelial network formation. Our findings suggest that antitumor action of triptolide is partly via inhibition of tumor angiogenesis by blocking 2 endothelial receptor-mediated signaling pathways, and triptolide can be a promising antiangiogenic agent.

Targets and molecular mechanisms of triptolide in cancer therapy http://www.ncbi.nlm.nih.gov/pubmed/25400429

Triptolide (TPL/TL) is a natural drug with novel anticancer effects. Preclinical studies indicated that TPL inhibits cell proliferation, induces cell apoptosis, inhibits tumor metastasis and enhances the effect of other therapeutic methods in various cancer cell lines. Multiple molecules and signaling pathways, such as caspases, heat-shock proteins, NF-κB, and deoxyribonucleic acid (DNA) repair-associated factors, are associated with the anti-cancer effect. TPL also improves chemoradiosensitivity in cancer therapy. Phase I trials indicate the potential clinical value of TPL use. However, further trials with larger sample sizes are needed to confirm these results.

Triptolide: A new star for treating human malignancies http://www.cancerjournal.net/preprintarticle.asp?id=188427;type=0

In recent years, cancer has become the most common human disease worldwide, and great attentions have been paid to clarifying the carcinogenesis and identifying new effective antitumor therapy. Although great progress has been made in this research field, human malignant diseases could still not be radically cured. Thunder god vine is a herbal medicine, which has proved to exert efficient antitumor activity in various human cancers such as lung cancer, pancreatic cancer, and colon cancer. In vivo and in vitro experiments showed that thunder god vine extract triptolide could inhibit tumor cell proliferation, cell migration, and cell invasion. Here, we overviewed the functional role of triptolide in human malignancies and its promising therapeutic potential in treating such deadly diseases.

 

 

 

This post was modified 12 months ago by Daniel

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Shanti
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Thanks for the additional information D!


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