Foods/Supplements-Vitamins: Parthenol... - Advanced Prostate...

Advanced Prostate Cancer

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Foods/Supplements-Vitamins: Parthenolide - Feverfew

8 years ago•0 Replies

"Parthenolide is a sesquiterpene lactone ... which occurs naturally in the plant feverfew (Tanacetum parthenium), after which it is named." [1]

"Lack of solubility in water and bioavailability limits the potential of parthenolide as a drug. Drug researchers are trying to develop synthetic analogs instead that will be absorbed to a more useful extent."

"It also inhibits HDAC1 protein ..."

{I have mentioned HDAC inhibitors in previous posts, particularly in:

"Non-PCa Prescription Drugs: Valproic Acid / Valproate".

Many changes that occur as PCa develops are of an epigenetic nature - i.e. they do not involve mutation. Genes that protect against cancer are silenced by HDAC (histone deacetylase). DNA is stored wrapped around proteins (histones). Acetylase loosens the DNA so that it can be read & acted on. Histone deacetylase prevents this. The affected areas are specifically the promoter regions for tumor suppressor genes.}

On the issue of bioavailability, feverfew "is a traditional medicinal herb which is commonly used to prevent migraine headaches". [2]

"The active ingredients in feverfew include parthenolide."

It is interesting to note that supplement labels make a big thing about the parthenolide content, & mention no other constituents. e.g. "Standardized for 0.5% parthenolides" [3] & "extract standardized to 0.7% parthenolides" [4].

"Feverfew helps maintain normal blood vessel tone. Parthenolides also help normalize the functions of platelets in the blood system by inhibiting platelet aggregation and reducing serotonin release from platelets." [4]

Having never suffered from migraines, I can't swear to its efficacy. A 2004 Cochrane analysis of five trials (three reported benefit) was not overly impressed:

"Although five of the trials were generally of good methodological quality, all studies were either of unclear or high risk of bias with regards to sample size."

In 2015, the report was updated [5] to include an additional trial [6]:

"The most recent trial added to this version of the review is rigorous and larger (n = 218), using a stable feverfew extract at a dose determined by a previous dose-finding trial. It reports that feverfew reduced migraine frequency by 1.9 attacks from 4.8 to 2.9 ..."

Apologies for belaboring the bioavailability issue, but it seems that parthenolide can get through, although the brand used may be very important.

[7] Parthenolide as an inhibitor of NF-kB.

{It seems odd that most of the 15 PubMed papers should make such a big thing about parthenolide as a NF-kB inhibitor. There are numerous natural polyphenols that can do that. Many with better bioavailability.}

[7a] (2004 - U.S.)

"The transcription factor nuclear factor-κB (NF-κB) promotes the production of angiogenic, antiapoptotic, and prometastatic factors that are involved in carcinogenesis."

"... confirmed the presence of NFκB DNA binding in all four prostate cancer cell lines tested. The binding was inhibited by parthenolide, and this agent also decreased multiple gene transcripts under the control of NF-κB and inhibited proliferation of prostate cancer cells."

"NF-κB is constitutively activated in prostate cancer and functionally relevant in vitro. Immunohistochemistry of human prostatectomy specimens demonstrated overexpression of the active subunit of NF-κB, p65, and that this occurs at an early stage in the genesis of prostate cancer. This work supports the rationale for targeting NF-κB for the prevention and/or treatment of prostate cancer."

[7b] (2006 - U.S.)

"Parthenolide at low micromolar concentration inhibited proliferation of {the androgen independent cell line} CWR22Rv1 .., promoted apoptosis and abrogated NFkappaB-DNA binding. Parthenolide downregulated anti-apoptotic genes under NFkappaB control, TRAF 1 and 2, and promoted sustained activation of c-jun-NH2 kinase (JNK). Parthenolide also augmented the in vivo efficacy of docetaxel and restored sensitivity to anti-androgen therapy."

[7c] (2009 - U.S.)

"In this study, we show that inhibition of the nuclear factor-kappaB (NF-kappaB) pathway is a common mechanism for the radiosensitization effect of parthenolide in prostate cancer cells LNCaP, DU 145, and PC3. Parthenolide inhibits radiation-induced NF-kappaB DNA-binding activity and the expression of its downstream target sod2, the gene coding for an important antiapoptotic and antioxidant enzyme (manganese superoxide dismutase) in the three prostate cancer cells."

[7d] (2008 - U.S.)

"To functionally assess the effects of blocking NF-κB signaling, cells were treated with the sesquiterpene lactone parthenolide (PTL). As NF-κB is known to promote cell survival [16], we determined whether its inhibition by PTL could preferentially induce cell death in primary tumor cells while sparing normal cells."

"Parthenolide treatment affects cancer stem cells but not normal progenitor and stem cell activity":

"Although normal CD133+ cells show almost no loss of viability in the presence of PTL, the cancer CD133+ cells were strongly induced to undergo apoptosis (from 88% to 22% viability after treatment) as were the progenitor cells from cancer and normal cultures."

"... our data suggest that the transcription factor NF-κB may be a promising therapeutic target as PTL, which acts directly on NF-κB and prevents it entering the nucleus, appeared to promote selective cell death of the cancer-specific CD133 population. Similar results have been demonstrated for leukemic CD34+ stem cells, with normal CD34 cells spared from apoptosis "

[7e] (2009 - U.S.)

"We propose that the suppression of radiation-induced NF-kappaB activity by parthenolide leads to X-ray sensitization through inhibition of split-dose repair in p53 null PC-3 prostate cancer cells."

[7f] (2009 - U.S.)

"Pathenolide, an NF-κB Inhibitor, Decreases AR {Androgen Receptor} Expression, PSA Secretion and Cell Proliferation in Prostate Cancer Cells"

"Parthenolide Treatment Inhibits AR Expression, PSA Secretion, and Tumor Growth in a Xenograft Model of {CRPC}"

"There is growing evidence that the expression of NF-κB/p65 correlates with prostate cancer progression and the development of androgen deprivation resistance. It is tempting to speculate that constitutive activation of NF-κB, which is known to induce potent anti-apoptotic effects, may contribute to prostate cancer cell survival following androgen withdrawal. Increased AR expression is also a critical event in the development of prostate cancer resistance to androgen deprivation therapy. However, the signaling pathways and transcription factors involved in the regulation of AR expression are not clear. Our findings provide mechanistic support for a role of NF-κB in regulation of the AR in human prostate cancer that could contribute to prostate cancer growth and {CRPC}."

[7g] (2010 - U.S.)

"A water-soluble parthenolide analogue suppresses in vivo prostate cancer growth by targeting NFkappaB and generating reactive oxygen species."

[7h] (2014 - Italy)

"The role of HIF1α and NF-kB, the master regulators of hypoxia and inflammation respectively, in sustaining the hypoxic pro-inflammatory phenotype was different according to cell type. NF-kB was observed to play a main role in DU145 and PC3 cells in which treatment with the NF-kB inhibitor parthenolide was able to counteract both the hypoxic pro-inflammatory shift and HIF1α activation but not in LNCaP cells. Our data highlight that tumor prostate cell phenotype contributes at a different degree and with different mechanisms to the hypoxic pro-inflammatory gene expression related to tumor progression."

[8] Parthenolide & PCa Stem Cells. See also [7d].

[8a] (2009 - U.S.)

"This is the first study to demonstrate that the phytochemical parthenolide is able to induce cell death in prostate TICs {tumor-initating cells}. After 72 hrs of treatment with PTL (10 µM), we determined that it is toxic (>90%) to most of the TICs and non-TICs in both cell lines and primary prostate cancer cells (see Figure 2). The significance of these in vitro studies was validated using in vivo models. Mice engrafted with TICs and treated with PTL showed a marked decrease in tumor incidence and latency (see Figure 3). This suggests that PTL is a potential anti-prostate cancer agent that can target both the TICs and their differentiated progeny."

[9] Parthenolide & Radiosenstization. See also [7c] & [7e]. & [9b]

[9a] (2010 - U.S.)

"... the results show that parthenolide selectively activates NADPH oxidase and mediates intense oxidative stress in prostate cancer cells by both increasing ROS generation and decreasing antioxidant defense capacity."

"The selective cytotoxicity of parthenolide to cancer cells has been reported in human acute myelogenous leukemia stem and progenitor cells [36]. Our current study confirms these findings in prostate cancer cells and extends to demonstrate that the radiosensitization effect of parthenolide is selective to prostate cancer cells but not normal prostate epithelial PrEC cells (Fig. 1). Our results also indicate that parthenolide “rejuvenates” irradiated normal prostate cells since cell growth rate after radiation is restored to the untreated control level when combined with parthenolide treatment. Parthenolide decreases radiation-induced ROS in PrEC cells (Fig. 2A), which correlates with increased GSH levels (Fig. 3A). Thus, the apparent antioxidant property of parthenolide in normal prostate cells may be due, in part, to the increased GSH level and may account for the “rejuvenation” of irradiated PrEC cells."

[10] Parthenolide & Hypoxia. Quotes are from [7h].

"Hypoxia activates the NF-kB pathway in DU145 and PC3 but not in the androgen-dependent LNCaP cells."

{These are the standard PCa cell lines: LNCaP from lymph node, PC-3 from bone & DU145 from brain. But they are used because of their properties - not because they are truly representative. LNCaP is a better-differentiated cell & androgen dependent, i.e. not CRPC.}

-Patrick

[1] en.wikipedia.org/wiki/Parth...

[2] en.wikipedia.org/wiki/Tanac...

[3] swansonvitamins.com/swanson...

[4] swansonvitamins.com/natures...

[5] ncbi.nlm.nih.gov/pubmed/258...

[6] ncbi.nlm.nih.gov/pubmed/162...

[7a] clincancerres.aacrjournals....

[7b] ncbi.nlm.nih.gov/pubmed/169...

[7c] ncbi.nlm.nih.gov/pmc/articl...

[7d] ncbi.nlm.nih.gov/pmc/articl...

[7e] ncbi.nlm.nih.gov/pubmed/193...