Abstract
"The effective and economical therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC) is still requested from patients, who are not available for Lu-177 or Ra-223 treatment. Drug repurposing as a cost-effective and time-saving alternative to traditional drug development has been increasingly discussed. Proton pump inhibitors (PPIs) such as pantroprazole, which are commonly used as antacids, have also been shown to be effective in cancer chemoprevention via induction of apoptosis in multiple cancer cell lines. Vitamin C is an essential micronutrient for human body, has been proposed as a potential anti-cancer agent. In this context, have we investigated the combination of vitamin C and pantoprazole for the management of metastatic castration-resistant prostate cancer (mCRPC). Six chosen human adenocarcinoma cell lines were used to investigate the influence of pantoprazole on the microenvironment of cancer cells (extracellular pH and production of exosomes). Tumor growth and tumor 18F-FDG uptake in PC3 xenografts were analyzed following varied treatment. Our in vitro Results have suggested that pantoprazole enhanced the cytotoxic activity of vitamin C by regulating pH values and production of exosomes in cancer cells. Moreover, the synergistic effect of pantoprazole and vitamin C was pH-dependent since pantoprazole was more effective at a slightly acidic pH. In vivo, the combined treatment using pantoprazole and vitamin C produced better therapeutic outcomes than treatment with vitamin C or pantoprazole alone, as demonstrated via tumor growth and uptake of 18F-FDG. Therefore, we suggest that pantoprazole combined with vitamin C could be as a possible strategy to manage mCRPC."
https://www.frontiersin.org/articles/10.3389/fonc.2021.660320/full
what do you think of taking lactoferrin right before doing an IV of high dose vitamin C? The below linked post mentions that lactoferrin in like a proton pump inhibitor. Also, I have read that lactoferrin binds iron. So, would this work like chelator, and make more vitamin C available to react with iron in the cancer cell?
https://www.cancertreatmentsresearch.com/community/postid/6000/
possibly, what do you think @daniel? But there are probably more proven methods to chelate iron, even curcumin could be used, or pharmaceutical drugs such as deferasirox. IVC to kill cancer is tough, likely mainly because of the iron, and it can backfire. I think one of the reasons why Pauling & Cameron got good results during their study with vitamin C (seventies) is that a) these were late-stage cancer patients and quite a few were close to death so they would have been iron depleted probably with their cancers absorbing as much of it and b) they didn't receive chemo, and chemotherapy can increase iron.
possibly, what do you think @daniel? But there are probably more proven methods to chelate iron, even curcumin could be used, or pharmaceutical drugs such as deferasirox. IVC to kill cancer is tough, likely mainly because of the iron, and it can backfire. I think one of the reasons why Pauling & Cameron got good results during their study with vitamin C (seventies) is that a) these were late-stage cancer patients and quite a few were close to death so they would have been iron depleted probably with their cancers absorbing as much of it and b) they didn't receive chemo, and chemotherapy can increase iron.
Another mechanism of action could be the effect ascorbic acid has on histamine. Histamine will decrease as ascorbic acid increases and vice versa. With IVC you may achieve a bigger decrease but once AA starts decreasing again histamine will increase rapidly. With continuous (daily) oral vitamin C intake it would probably be easier to manage AA to drop below a certain level.
Histamine and ascorbic acid in human blood
https://pubmed.ncbi.nlm.nih.gov/7365537/
"Histamine levels increased exponentially as plasma ascorbate decreased to <1 mg/dL, and a further reduction to <0.7 mg/dL resulted in a highly significant increase in the blood histamine level."
@j my wife had very low iron levels around the time they diagnosed the tumor. We got the iron levels back up, and now I learned to limit iron intake.
I am looking to use immune boosting supplements concurrent with the vitamin C infusions. I think that would be complementary without interfering with the mechanism. that is how I landed on lactoferrin.
university of Iowa is doing a phase 2 study on IV vitamin C. they had positive results from the phase 1 study.
@jdubw sounds great. I think Lf is a great option for anemia which is so common in cancer, and iron supplements don't resolve the issue and they can make cancer grow even faster. Your idea is interesting since you could possibly use it to enhance IVC.
Naringin is also good at chelating iron and provides many other benefits as an anti-cancer substance.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310324/
Translational downregulation of HSP90 expression by iron chelators in neuroblastoma cells
https://pubmed.ncbi.nlm.nih.gov/25564462/
Inhibiting hsp90 downregulates DNA replication.
@j gosh I keep getting an error message that says “forbidden” when I try to post a reply.
in case it works this time, I read that Lactoferrin was too large of a molecule to get much beyond the GI tract. Since that is where it stays I will just probably use it at meal times if at all.
@j I don’t think that Naringen gets much past metabolism intact. It gets converted into something else that I’m confident that you will get the same results. You could inject Naringen as an alternative I guess, but that is beyond my comfort and understanding. Here is a study that shows some issues.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265019/
i meant to say not confident
seems like the antispam settings are a bit too strict. I didn't know that about Lf, that limits its use.
@j I don’t think that Naringen gets much past metabolism intact. It gets converted into something else that I’m confident that you will get the same results. You could inject Naringen as an alternative I guess, but that is beyond my comfort and understanding. Here is a study that shows some issues.
Have you seen this study?
https://www.scielo.br/j/bjps/a/QCq7fk6CszPnvHNr7RfFWCG/?format=pdf&lang=en
"Naringin has been shown to exhibit satisfying iron chelation capacity. Considering the side
effects of routinely-used iron chelator (desferrioxamine, DFO), we decided to evaluate the
iron chelation potency of naringin to discover whether or not it can be a promising natural
substitute for treatment of excessive iron-related diseases. is being used Therefore, we provided
35 mice were classified into and they were divided into 5 five groups of 7 and subjected to iron
dextran administration to induce the iron-overload condition. Iron-overloaded mice were then
threated with normal saline (as control), naringin or DFO (n=7). Group A treated by normal
saline, the others treated with iron dextran. After that group A and B treated with normal slaine,
group C received desferal, group D and E received high and low dose of naringin respectively.
Morphology changes, and iron deposition in liver tissues were studied using H&E and Perl’s
staining.after The results revealed that naringin is more potent thant DFO in removing excessive
iron ions deposited in liver tissues, indicating indication that naringin is a promising natural
compound for therapy of iron overload disorders."
@j that is cool, but it looks like they are injecting Narinjin again. Hesperidin is a close cousin of Narinjin, and they developed a methylated product to deal with the metabolism issue: hesperidin methyl chalcone. I would like someone to do that with Naringen as well, because outside of GI or liver cancer, I don’t see it being much more than a general antioxidant/anti-inflammatory
they administered the substance with intraperitoneal injections, not intravenous. Ideally, you'd like to see this type of test done using oral administration or oral gavage. The liver is the storage for iron, apart from haemoglobin most iron is found in the liver.
"It is generally considered that, pharmacokinetics of small molecular drugs administered through the IP route resemble that of orally administered drugs in terms of metabolic fate and high rate of first pass metabolism, which leads to lower systemic exposure of IP-administered substances"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412579/
In the study I mentioned above they used 30mg/kilo. HED would be approx 180mg. The other day you asked why not to do a linear calculation and that's because the average mouse weighs 20-35 grams.
I.p. injection usually will lead to increased bioavailability, how much probably depends on many factors including the actual substance. I think generally you could take the HED figure and take a multiple of that number, 2-fold, or 6-fold, or more, I don't know. One could start at a 2-fold dose and then up titrate.
rifaximin seems an interesting antibiotic, it is worth researching, can lower ammonia, help restore the integrity of the BBB, improve gut microbiome, etc. Maybe in combination with phenylbutyrate.
@j what do you think about combining IP6 prior to Vitamin C infusions? IP6 is touted as binding to iron, and as being anti-cancer.
There are so many unknowns with Naringin. I do like the VEGF inhibitor aspect, but I’m not confident that it is going to get out of the liver and into the brain in a form and concentration to have that effect. Do you know of any other natural VEGF inhibitors?
A common clinical response to VEGF inhibitor, Avastin, is that patients report feeling better. So even though the tumor fighting aspect is questionable, due to the clinical trials, it improves the quality of life. Unfortunately, it is costly and full of side effects.
If a natural VEGF inhibitor could be composed then I think it could be anecdotally tested quickly for efficacy by finding out if it causes patients to feel better
I think that your best option would be to combine different natural products, we've already talked about theobromine which is a potent inhibitor of angiogenesis (for example chlorogenic acid and theobromine).
I like the idea of using IP6, indeed it binds iron and the research on its anticancer effects is solid.
An interesting synergy of IP6 is with Pterostilbene, which is a small molecule and passes the BBB.
Avastin can make hypoxia much worse, you've probably the study of Avastin in combo with CCNU, and there was no difference in overall survival.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5782502/
Overall survival did not differ between the two study arms, with a median overall survival of only 8.6 months for the lomustine-alone study group and 9.1 months for the bevacizumab/lomustine study group.
Theobromine could be combined with shark cartilage or shark liver oil
Alkylglycerols
Alkylglycerols are ether lipids abundant in purified shark liver oil. Researchers have found the alkyl-lipids
have a direct effect on glioma cells, reducing glioma growth by up to 50% and inhibiting the invasion of
glioma cells into healthy brain tissue.53 In this study, biopsy samples of glioblastoma multiforme and
anaplastic astrocytoma were cultured with healthy Glioblastoma Multiforme
INTEGRATIVE CANCER THERAPIES 3(2); 2004 157 brain tissue and treated with alkylglycerols. The results
showed a 7-fold preservation of normal brain tissues compared to controls not treated with alkylglycerols.
Alkylglycerols are mildly immune boosting and can help elevate a low platelet count, which may be particularly useful for this client (current platelet at 161 µ/ L) with continued chemotherapy. Care should be
taken to select a product that is carefully purified of heavy metals, toxicants, and excess amounts of vitamin
A and D. A dose of 500 mg purified shark liver oil 3 times a day with meals is recommended; the dose may
be doubled if the platelet count falls below normal.
https://journals.sagepub.com/doi/pdf/10.1177/1534735404264968
@j wow, and I thought nothing could really increase platlets. Wish I saw this when she was on chemo
@j avastin is a double edge sword, and I have been weighing it back and forth for a while. Fortunately, we are still seeing shrinking per our recent MRI, and we are not in a place where it makes sense to use avastin. although I think that in the right combination and situation it may be useful.
I had written off pterostilbene thinking that it cannot be practically consumed in enough quantity to have a significant effect on the tumor. Although now I am getting interested again. I read that it could be synergistic with an EGFR inhibitor drug. We have been using liposomal Quercitin recently. Quercitin is thought to be a natural EGFR inhibitor. If I could use a highly absorbed pterostilbene (liposomal etc) that would be interesting.
Chloroquine Potentiates the Anticancer Effect of Pterostilbene on Pancreatic Cancer by Inhibiting Autophagy and Downregulating the RAGE/STAT3 Pathway https://pubmed.ncbi.nlm.nih.gov/34771150/
Case-specific potentiation of glioblastoma drugs by pterostilbene
@j I think we will try the trans- form of pterostilbene. We are not using sertraline, but perhaps it may potentiate the fluoxetine that is being used.
Also, I have been reading on TGF-b inhibition. Theoretically doing so may help Natural Killer immune cells to avoid being inactivated by late-stage tumors. Take a look at the list below that I found on the web. These are pretty much all that are looked at as potentially fighting GBM.
Proposed Inhibitors
Based on research in animals and cells, scientists think these may inhibit TGF in different places (but not necessarily systemically):
- PPAR gamma and PPAR alpha agonists [35, 36, 37, 38]
- Vitamin D Receptor activation [39], Angiotensin II type 1 receptor antagonism [40]
- Sun/UV [41, 42] (skin cells)
- Klotho (may bind to the TGF-β1 receptor to inhibit TGF-β1 binding) [32].
- Curcumin [43]
- Black Cumin Seed Oil /Thymoquinone [44] (rat model of allergic airway inflammation)
- Andrographis/Andrographolide [45]
- Ursolic acid [46]
- Extra Virgin Olive Oil [47]
- Reishi [48]
- Fucoidan [49]
- Resveratrol [50]
- Apigenin [51]
- Berberine [52]
- Quercetin[53]
- Grape Seed Extract
- Ginkgo [54]
- Astragalus [55, 56]
- Zinc
- Silymarin/Silibinin
- Hesperidin
- Garlic
- Gotu Kola /Asiatic Acid,
- Emodin (found in Fo-Ti, Resveratrol, Rhubarb, Aloe)
- Theanine [57]
- Naringenin
- Ginseng [58]
- Kudzu root/Puerarin
- Angelica S, Hydrangea, Dan Shen, Almond, Cordyceps, Butein, Betulinic acid
- These growth factors inhibited a TGFbeta1 increase in cells: IGF-I, EGF, and Growth Hormone(cellular model) [59]
The effect of these substances or pathways on TGF-beta in humans is unknown.
