Berberine Reverses Breast Cancer Multidrug Resistance Based on Fluorescence Pharmacokinetics In Vitro and In Vivo
"In this work, Ber was demonstrated as an ideal MDR reversing agent. The MDR reversal effect is achieved by inhibiting P-gp and MRP1 functions and their expression in MCF-7/DOXFluc tumor cells. When combininging Ber with DOX to treat DOX-resistant breast cancer, Ber enhanced the intracellular concentration and retention of DOX in tumor cells, which occurred via facilitating the cellular drug uptake and reducing the drug efflux rate in MCF-7/DOXFluc tumor cells. The DOX–Ber combination significantly enhanced the in vivo anticancer efficacy of DOX in a drug-resistant MCF-7/DOXFluc xenograft model."
@j this woudl be a lot for the stomach indeed. Maybe proton pump inhibitors prior to that will help.
However, high dose Aspirin (a few grams at once) is given intravenous as part of the Diflunisal treatment at clinics in Europe including Germany. Diflunisal is a NSAID as Aspirin, so in the end the patient ends up with about 5g of NSAID given intravenously in a few to several hours. In order to lower the chance for potential side effects, they use intravenous Pantoprazole prior to that, as Aspirin and Diflunisal will react stronger in acidic areas (acidity that will be reduced temporarily by the proton pump inhibitor).
This is indeed known as a powerful anti-cancer treatment with important potential.
Kind regards,
Daniel
Epigenetic restoration and activation of ERβ: an inspiring approach for treatment of triple-negative breast cancer
https://link.springer.com/article/10.1007/s12032-022-01765-1
Conclusions
The antiproliferative effect of ERβ could be retained when co-expressed with Erα using a powerful epigenetic combination of Decitabine and vorinostat with DPN.
"Luteolin inhibits the metastasis of triple-negative breast cancer"
https://foodforbreastcancer.com/news/luteolin-inhibits-the-metastasis-of-triple-negative-breast-cancer"Sulforaphane inhibits HER2+ and triple-negative breast cancer"
https://foodforbreastcancer.com/news/sulforaphane-inhibits-her2%2B-and-triple-negative-breast-cancer"Quercetin and fisetin inhibit TN cell migration"
https://foodforbreastcancer.com/news/quercetin-and-fisetin-inhibit-tn-cell-migration
@j Thank you Johan! I was not aware of the effects of Luteolin on TNBC. Very interesting! Thank you also for your input on foods and aspirin - I really appreciate it!
Thank you @daniel and @j for your help! Her docs would not allow aspirin, but were okay with Ibuprofen before and after the surgery. So, she decided to take those instead, since Ibuprofen seems to have similar effects regarding relapse prevention. Additionally she took arginine based on this study: https://pubmed.ncbi.nlm.nih.gov/20881073/
The surgery went well, but they also cut out some muscle tissue as the tumor was located close to the breast muscle. Now we have to wait ~2 weeks for the lab results to see whether the edges were free of tumor cells.
Anyway, I was wondering if there are any supplements that she should take right now. I mean supplements that are anti-cancer but also helping with the wound healing (or at least don't make it worse). If you have any ideas, please let me know.
All the best,
Christian
Anyway, I was wondering if there are any supplements that she should take right now. I mean supplements that are anti-cancer but also helping with the wound healing (or at least don't make it worse). If you have any ideas, please let me know.
Here are some ideas, Chris:
Baking soda
https://www.verywellhealth.com/baking-soda-for-inflammation-5093321
Lycopene
Butyrate
Ellagic acid
Vitamin C from preferably from food sources (Camu Camu, acerola, etc)
Curcumin
Boswellia
DHA
Bovine gelatin
Breathing exercises
There are many options, celecoxib could be very useful also, both as a cox 2 inhibitor and anticancer agent.
Good luck and I hope your wife has a quick recovery from her surgery.
Innate immunity recovers earlier than acquired immunity during severe postoperative immunosuppression
https://www.medsci.org/v15p0001.htm
"Postoperative immune suppression particularly a loss of cell-mediated immunity is commonly seen after surgery due to an increased release of immune suppressing hormones such as catecholamines, prostaglandins and cortisol depending on the amount of surgical stress and tissue damage"
Innate immunity recovers earlier than acquired immunity during severe postoperative immunosuppression
https://www.medsci.org/v15p0001.htm
"Postoperative immune suppression particularly a loss of cell-mediated immunity is commonly seen after surgery due to an increased release of immune suppressing hormones such as catecholamines, prostaglandins and cortisol depending on the amount of surgical stress and tissue damage"
Mistletoe, Chaga, Rosmarinic acid (Rosemary), Cassia cinnamon, and AHCC may boost the immune system and have anticancer properties.
Hello everyone,
here comes a brief update:
- Surgery went well and the tumor (8x13mm) was cut out with clean edges and no access to blood vessels/lymphetic system.
- 6 weeks after surgery her CTCs are stable at 150 (see attached picture), with less cell fragments detected than before surgery (according to the lab professor, this is a good sign and could mean that those remaining CTCs stem from the removed tumor).
- Due to this unnusual case (having a recurrence in the radiated breast) the "tumor board" (several doctors who weekly discuss each case together) could not aggree on a way forward. One recommended capecitabine, another sacituzumab and her oncologist and senologist recommended to not do any treatment.
- However, we were able to convince her senologist to prescribe us the medications for the COC-protocol (Mebendazole, Atorvastatin, Metformin, Doxycycline), since I feel this could be a better treatment in terms of risk/value ratio.
To me, the COC protocol has comparably little side effects, very promising study results and could be combined with some other drugs/supplements. Sacituzumab and capecitabine on the other hand have quiet strong side effects and are damaging the immune system which I think is important to keep strong.
- Which path would you take in her situation (COC-protocol, sacituzumab, capecitabine, no meds, other)?
- Would you rather do the COC protocol as it is or take those meds and use it for a different startegy (e.g. anti-cholesterol, shut down energy engines)?
- Which supplements would you use to boost efficiency of the COC protocol?
Of course I am also grateful for any other comments or ideas!
All the best,
Christian
@chris48 Hi Christian, good to hear the SX went well. Some observations and ideas:
Curcumol enhances the anti-tumor effects of metformin via suppressing epithelial-mesenchymal transition in triple-negative breast cancer.
https://atm.amegroups.com/article/view/49389/html
Interfering with Metabolic Profile of Triple-Negative Breast Cancers Using Rationally Designed Metformin Prodrugs
https://onlinelibrary.wiley.com/doi/10.1002/anie.202102266
Note that:
"type 2 diabetes was associated with a 40% increased risk of triple-negative breast cancer
when compared with women who did not have diabetes."
AND type 2 diabetes treated with metformin: there was a statistically significant 74% increased risk of developing TNBC among those treated with metformin.
https://www.esmo.org/newsroom/press-releases/metformin-may-affect-risk-of-breast-cancer-in-women-with-type-2-diabetes
IMO, METF is likely OK short-term, not long-term.
Chlorogenic acid, an essential component of Annurca apple polyphenol extract
https://www.sciencedirect.com/science/article/pii/S1936523321002850
Synergy with EGCG:
https://www.sciencedirect.com/science/article/pii/S1936523321002850
Epigallocatechin-3-Gallate (EGCG) inhibits cell proliferation and migratory behaviour of triple-negative breast cancer cells
https://pubmed.ncbi.nlm.nih.gov/23646788/
Combinatorial bioactive botanicals re-sensitize tamoxifen treatment in ER-negative breast cancer via epigenetic reactivation of ERα expression
https://www.nature.com/articles/s41598-017-09764-3
Combinatorial epigenetic mechanisms and efficacy of early breast cancer inhibition by nutritive botanicals
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066124/
Nutritional combinatorial impact on the gut microbiota and plasma short-chain fatty acids levels in the prevention of mammary cancer in Her2/neu estrogen receptor-negative transgenic mice
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774855/
Vorinostat and indole-3-carbinol modulate microRNAs and histone deacetylase activity in subtypes of triple-negative breast cancer
https://aacrjournals.org/cancerres/article/78/13_Supplement/5800/630296/Abstract-5800-Vorinostat-and-indole-3-carbinol
Graviola: Effects of Annona muricata Extract on Triple-Negative Breast Cancer Cells Mediated Through EGFR Signaling
https://pubmed.ncbi.nlm.nih.gov/33304106/
In vitro evaluation of Annona muricata L. (Soursop) leaf methanol extracts on inhibition of tumorigenicity and metastasis of breast cancer cells
https://pubmed.ncbi.nlm.nih.gov/33048613/
Gallic acid induces G1 phase arrest and apoptosis of triple-negative breast cancer cell
https://pubmed.ncbi.nlm.nih.gov/28938245/
https://synergiesforcancertreatments.blogspot.com/
Best of luck!
@chris48 Hi Chris.
I have been following your post regarding your wife. Thanks for sharing .Its very similar to my wife. She also has TNBC. Initially diagnosed in 2018- Ned in 2019. Now recurrence in April 2022. She has a tumor accessible under her arm and mets to the lungs. I am following Daniels Shutting Down the Energy Engines Strategy. We are also doing IVC and starting the Metronomic 2DG. I would like to keep in touch with you if you don't mind. We are based in the UK. I just did a CTC test also last month. I want to keep track after her PARP inhibitor stopped. CTC went down to 50 but she has active cancer.
Recently we added Sodium Phenylbutyrate for reducing the Glutamine. I think its an important one. I think you are in a great spot now that she is NED. Unfortunately my wife has a hard time with pills also and completely stopped them after being NED in 2019. So being able to take them now has been a breakthrough.
We have added Proton pump inhibitors to her treatment- a secondary benefit was alleviating some of her stomach issues. 1st- Lansoprazole 80mg(really helped) - plus Omeprazole 40mg and Cimetidine-800mg
Jens
4407936057985
@jens Hi Jens,
thank you very much for your message! I am so sorry that you are in a similar situation with your wife.
Yes, it defintely would be great to keep in touch with you! I am sure we both could benefit from this exchange.
I wish you and your wife all the best for 2023 and hope that your strategies will work!!!
Christian
4915151170062
Hi all,
Bianca started her COC protocol yesterday. On Monday we had a very nice ~1h zoom meeting with the COC Doctor Hariharan Kuhan, who explained everything and answered all our questions. In contrast to our German doctors, he was familiar with almost every study that I mentioned. Later he sent us a summary of our talk and his recommendations for the next weeks:
- Metormin Modified Release (M/R) 500mg once daily for two weeks, followed by 500mg twice daily thereafter.
- Atorvastatin 20mg once daily at night for four weeks, followed by 40mg once daily thereafter (two 20mg tablets taken together at the same time each day)
- Mebendazole 100mg once daily for a month, followed by Doxycycline 100mg once daily for a month, continuing to alternate between Mebendazole and Doxycycline on a monthly basis thereafter.
Dr. Kuhan also seems to genuinly care and explained everything in an empathic, patient and professional manner. So far, this clinic made a very good impression.
We will now do a CTC test and another one in 4 weeks.
All the best,
Christian
PS: I also listed a couple of supplements to use in parallel and I asked him which ones he thought are most promising in this situation. He said Bioperine, Quercetin and Berberine. During the Doxy cycle we will also do Vit C infusions.
I would love to know your thoughts on this. Do you have another drug in mind that could boost the COC protocol?
PS: I also listed a couple of supplements to use in parallel and I asked him which ones he thought are most promising in this situation. He said Bioperine, Quercetin and Berberine. During the Doxy cycle we will also do Vit C infusions.
I would love to know your thoughts on this. Do you have another drug in mind that could boost the COC protocol?
Hey Chris, thanks for the update and I hope the treatment is a success! I'd consider Magnesium with the IV vitamin C and zinc with Berberine.
I wish Bianca a speedy recovery!
@j Very interesting! I will look into that. Thank you so much Johan!
@j Very interesting! I will look into that. Thank you so much Johan!
Here's the study on magnesium in combination with IV C: Enhanced Anticancer Effect of Adding Magnesium to Vitamin C Therapy: Inhibition of Hormetic Response by SVCT-2 Activation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940627/
Abstract: l-Ascorbic acid (vitamin C, AA) is known as an antioxidant, but at high concentrations, AA can kill cancer cells through a prooxidant property. Sodium-dependent vitamin C transporter family-2 (SVCT-2) determines the cellular uptake of AA, and the activity of SVCT-2 is directly related to the anticancer activity of AA. Cancer cells that showed high SVCT-2 expression levels were more sensitive to AA treatment than cancer cells with low SVCT-2 expression levels. Cells with low SVCT-2 expression showed a hormetic response to a low dose of AA. Magnesium ions, which are known to activate SVCT-2, could increase the Vmax value of SVCT-2, so we investigated whether providing magnesium supplements to cancer cells with low SVCT-2 expression that had shown a hormetic response to AA would elevate the Vmax value of SVCT-2, allowing more AA to accumulate. To evaluate the effects of magnesium on cancer cells, MgSO4 and MgCl2 were screened as magnesium supplements; both forms showed synergistic anticancer effects with AA. Taken together, the results of this study suggest that magnesium supplementation enhanced the anticancer effect of AA by inhibiting the hormetic response at a low dose. This study has also demonstrated that AA treatment with magnesium supplementation provided more effective anticancer therapy than AA treatment alone.
Zinc Acts Synergistically with Berberine for Enhancing Its Efficacy as an Anti-cancer Agent by Inducing Clusterin-Dependent Apoptosis in HT-29 Colorectal Cancer Cells
https://pubmed.ncbi.nlm.nih.gov/36394793/
The synergy of berberine and emodin:
"These results show that EMO and BBR significantly reduce breast cancer cell growth of both ER-positive MCF-7 and triple-negative MDA-MB-231 cells."
https://www.sciencedirect.com/science/article/pii/S0925443920302453
I listed a good emodin product here https://synergiesforcancertreatments.blogspot.com/p/special-supplement-formulations.html
Apologies for the long delay. I'm always happy to share my story. I'm attaching my protocol, the spreadsheet format is better, but I don't want to post my personal Gmail publicly. My protocol is more optimized for synergy with immune checkpoint inhibitors since that's what I'm on.
Did her oncologist offer any adjuvant therapy after the recurrence? Off labels are good, but I think you need as much in the arsenal as possible.
I think you should push strongly for a PDL-1 inhibitor in this situation. Recent RCTs are showing significant benefit regardless of PDL-1 status. If onc says no, try getting a second opinion. If cost is an issue, see if there are any clinical trials you could enroll in that would offer it.
Sending you best wishes
@j Thank you Johan.... I too am fighting TNBC. Just diagnosed with a recurrence at my initial tumor site. Emodin does seem interesting. I am taking many of the supplements you mention in your posts.... but I am interested in new ideas. Thank goodness for MCS formulas, this blog and people like you that share some of their latest finds. It is hope to me. My next endeavor will be to figure out "how much" emodine.
@j Thank you Johan.... I too am fighting TNBC. Just diagnosed with a recurrence at my initial tumor site. Emodin does seem interesting. I am taking many of the supplements you mention in your posts.... but I am interested in new ideas. Thank goodness for MCS formulas, this blog and people like you that share some of their latest finds. It is hope to me. My next endeavor will be to figure out "how much" emodine.
I am sorry to hear you´re having to deal with this recurrence. In this review they note that "Recent evidence suggests that emodin exerts its anti-cancer effects through inducing mitochondrial mediated apoptosis, alongside suppressing pathways that promote inflammation, proliferation, angiogenesis, and tumorigenesis (Table 1). Indeed, emodin has been demonstrated to elicit these effects at both low (1-40 mg/kg)13-20 and higher (50-80 mg/kg)16,18-22 doses consistently across pre-clinical models of colon, liver, and pancreatic cancer. "
Although effects are dose-dependent, both low and higher doses have shown anticancer effects.
In this study: Emodin, a natural anthraquinone, suppresses liver cancer
in vitro and in vivo by regulating VEGFR2 and miR-34a (10.1007/s10637-019-00777-5) the mice that got 10mg/kg had their tumors shrink most but the 1mg/kg dose also shrank their tumors (see attachment)
Dose conversion between species isn't easy but I use this tool to get an idea of what could be the equivalent human dose.
For example, using the tool I mentioned previously, for 10mg/kg in mice the human equivalent dose for a 75kg person would be 60.81 mg.
Study: https://doi.org/10.3892/ijmm.2018.3638
"The results of the present study suggested that emodin inhibited TNBC proliferation, migration and metastasis more effectively than epirubicin in adipocyte co-culture conditions. Therefore, the present study investigated the underling mechanisms. The ELISA results showed that emodin inhibited the release of CCL5 from human adipocytes, leading to the investigation of whether emodin inhibited TNBC proliferation, migration and invasion by downregulating the secretion of CCL5. The results of the investigations confirmed this."
"Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748897/#SD1
Abstract
Ammonia is a ubiquitous by-product of cellular metabolism, however the biological consequences of ammonia production are not fully understood, especially in cancer. We find that ammonia is not merely a toxic waste product, but is recycled into central amino acid metabolism to maximize nitrogen utilization. Cancer cells primarily assimilated ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH), and secondary reactions enabled other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer. In mice, ammonia accumulated in the tumor microenvironment, and was used directly to generate amino acids through GDH activity. These data show that ammonia not only is a secreted waste product, but a fundamental nitrogen source that can support tumor biomass.
In this spreadsheet, you'll find some ideas to address ammonia (see strategies sheet -> urea cycle).
I've already mentioned the anticancer potential of the emodin + berberine synergy. In addition, Thymoquinone also works synergistically with emodin:
"We observed that, TQ/Emo causes marked improvement in activation of apoptosis mechanisms, and anti-migratory pathway, indicating that these two agents work in a cooperative fashion to mitigate TNBC cell population"
https://www.sciencedirect.com/science/article/abs/pii/S0304416520302075
See below for the latest update on Pembro+chemo in early-stage TNBC. Unfortunately, you are dealing with recurrences, but the punchline remains the same: Pembro has a significant benefit-- importantly-- (see Fig 2 in the paper), regardless of PD-L1 status. This is a high-quality RCT-- print this paper out, take it to your oncologist, and demand Pembro, and if they say no, get a second and third opinion until you find someone to give it to you.
https://www.nejm.org/doi/full/10.1056/NEJMoa2112651
In this paper, they gave neoadjuvant and adjuvant pembro; I don't think there's any reason to believe that adjuvant-only couldn't do almost as well.
Also have a look at this protocol of off-labels which are synergistic with immunotherapy
https://docs.google.com/spreadsheets/d/1oQSkX6Oqk97ldIvthEskofTX9pOL1ythG_7RTTCmIj8/edit?fbclid=IwAR0fNWPPZaGHAprP4JfwaqBfZSs1bNm3SvIY_mSeuFNHuBr-Yg7p0UStMeQ
I am stage 4 TNBC with mets to brain, lungs, bones, and soft tissue in May 2021. After craniotomy and SRS for the brain, I did eight months of pembro + paclitaxel, after which I dropped the paclitaxel and continued on pembro alone. I am currently NEAD. I attribute pembro + various things that are synergistic (see protocol above and my protocol I posted earlier); the most important was probably ivermectin to increase lymphocyte infiltration, based on this paper:
https://www.nature.com/articles/s41523-021-00229-5
But also cyclophosphamide (to induce immunogenic cell death, which is immunostimulatory) and others. It has been shown that side effects from pembro are correlated with good outcomes, and even two years out, I can still elicit a rash by taking a large ivermectin dose.
If you get on pembro, let me know, and I can go more in-depth on synergizing with it.
Best wishes to all, I'm sorry you're dealing with this.
