Malignant Cancer Stem Cells (CSCs) can be attacked by Doxycycline, changing the way they produce their energy, leading to the use of secondary compounds (such as vitamin C, berberine and Azithromycin) to cause CSC death. While very promising, to date only a very little work has been performed on human subjects and doxycycline must be used with care as it can damage the microbiome, damage lymphocyte levels reducing cancer survival, cause antibiotic resistance and even promote cancer.
Chris Woollams explains here the good and bad in the use of doxycycline with cancer.
What is Doxycycline?
Doxycycline is a tetracycline antibiotic, which has been used for decades without causing severe illness or death. As such, Doctors would regard doxycycline as a 'safe' antibiotic.
Doxycycline is also known to have several ‘side-effects’ useful in fighting cancer and its ability to attack cancer stem cells has been known for more than 15 years.
In particular, it was used as part of the Care Oncology COC protocol with the aim of killing Cancer Stem Cells.
Cancer Stem Cells – the real problem in cancer
Everybody has non-malignant Stem Cells in their bodies. They are the basic blank cell which can convert (differentiate) into any cell in the body and thus repair tissue in a damaged area.
However, there are also malignant stem cells - termed Cancer Stem Cells.
Cancer Stem Cells (CSCs) have been identified at the heart of almost all cancers, from breast cancer to brain tumours, and in blood and lymph cancers such as multiple myeloma. Cancer stem cells have the capacity to self-renew, to give rise to progeny that may have altered. Cancer stem cells may also be the source of cells that give rise to metastases, and they are believed to be the cvells that prevent radiotherapy killing 100% of targeted cells.
Different cancers have different levels of CSCs at their heart. According to various estimates, pancreatic cancer have the highest number of CSCs at 22%, with Brain and Prostate at 12%. Cancer such as breast cancer may be as low as 5%.
One of the biggest issues is that current conventional cancer drugs may kill 60 or 70 per cent of the cancer cells in tumours, but do not kill the heart - the cancer stem cells. Indeed, CSCs seem to be the main reason for drug resistance. In fact, the use of certain drugs, while killing 'ordinary' cancer cells, actually makes cancer stem cells more and more resistant! And cancer stem cells can cause the caner to re-grow.
Of importance is that CSCs also over-express certain key mitochondrial proteins. Because mitochondria are believed to have evolved from bacteria, the idea that anti-bacterial agents might inhibit mitochondrial function grew. For 'anti-bacterial agents', read antibiotics.
Doxyclycline and vitamin C, or Berberine
In research in Oncotarget (2017), Professor Michael Lisanti and his team in Salford used the increasing drug resistance against the CSCs (1). By providing Doxycycline to breast cancer cell line MCF7, they killed many cells, but those left behind were more drug (antibiotic) resistant. They then allowed those remaining cells to regrow and repopulate, then subjected them to a higher dose of doxycycline. Repeating this cycle again, they ended up with a few CSCs left but all of them were resistant to Doxycycline – they had become immune to the antibiotic.
Lisanti’s team found that all these remaining CSCs had changed and now assumed a purely glycolytic form. Glycolysis is the metabolic pathway that converts glucose into energy via a multi-step pathway. These DOX-Resistant cells were then treated with glycolysis inhibitors – 8 compounds (for example, Berberine, Niclosamide, Chloroquine) or intravenous vitamin (IVC).
Berberine was the compound of choice by Lisanti, and it should be noted here that metformin does NOT work in the same way with CSCs. For example, 2015 research from Patricia Sancho showed CSCs in pancreatic cancer were dependent upon oxidative phosphorylation (OXPHOS). This could be blocked by Metformin causing apoptosis, but the cells that escaped were glycolytic and ultimately resistant to metformin (2). So, while Metformin may sometimes be able to play a role against 'normal CSCs, its natural rival berberine is better at providing the 'coup de grace' and can perform both jobs.
2019 results (3) from another in vitro study at the Biomedical Research Centre in the University of Salford used two antibiotics – doxycycline and azithromycin, plus vitamin C (DAV). This inhibited propagation of over 90% of CSCs in breast cancer cell lines. This has not been studied in real life.
Restricting CSCs in human breast cancer patients
However, not all research on doxycycline has been performed in the laboratory. In a 2018 pilot study (4) by Lisanti's team, with 15 newly diagnosed breast cancer women, doxycycline was administered at 200 mg per day for 14 days prior to breast surgery to 9 women, with 6 acting as controls.
Known biomarkers of ‘Stemness’ (CD44 and ALDH1) and other mitochondrial factors were compared from the biopsy and then the removed tissue.
In 8 of the 9 doxycycline-user patients, the CSC marker CD44 fell between 17.65% and 66.67%. However, in one woman it increased by 15%.
Similar results were shown with ALDH1, while all other mitochondrial markers stayed the same between the two test points. Patient ages were 42-65.
The conclusion for this was that the doxycycline was killing off, or inhibiting, at least one fifth to two thirds of the cancer stem cells in the breast cancer tumours, though no explanation for the woman with increased 'stemness' markers was provided. The researchers talked of the doxycycline 'eradicating' cancer stem cells, which seems rather over-exuberant. Worse, if you really want to stop cancer progression, your target should be 100%, nothing less.
The National Cancer Institute refers (5) to two Clinical Trials currently underway (August 2020) – one with patients with malignant pleural effusions (MD Anderson). Doxycycline is already known to suppress malignant effusions by suppressing tumour growth.
A second Clinical Trial involves doxycycline with metformin and patients with localised breast, cervical or uterine cancer (Thomas Jefferson Medical School). There is already some evidence that doxycycline may work synergistically with metformin against uterine, breast and cervical cancer.
In another 2017 in vitro study (6), doxycycline was shown to target mitochondrial biogenesis, inhibiting breast cancer development and migration, while causing apoptosis.
Doxycycline and Myc
Myc is a transcription factor that is both over-expressed and un-regulated in cancer cells. While Myc is involved in all cellular growth, it is particularly involved in cancer cell progression. When Myc is deactivated, tumour growth and progression stops, the microenviroment changes, blood supply ceases, and tumours regress. Using mice with NSCLC - typically with a KRAS mutation - researchers used doxycycline to block Myc and the tumours regressed (9).
There was comment about inhibiting Myc simultaneously in normal healthy tissue, which the researchers described as having 'profound effects'. The researchers found it 'well tolerated', and 'easily reversible' over time!
Doxycycline and metastasis
Doxycycline also inhibits enzymes called matrix metalloprotieinases (MMPs), which are involved in metastases and tissue invasion, especially in the bones. Research has shown the reduction in bone metastases in mice with breast cancer.
In a 2007 study (7), the use of Zoledronic acid was shown to reduce breast cancer metastases in bones by 43%. When doxycycline was added alongside the Zoledronic acid, that figure increased to 74%.
There was also a laboratory study from Indiana Medical School back in 1998 showing that doxycycline could inhibit prostate cancer metastases in vitro.
There is also research on doxycycline suppressing migration, invasion and metastases of lung cancer cells in mice.
Dose of Doxycycline in cancer treatment
This is where it becomes really confusing. Sometimes 100 mg per day is recommended, other times 300 mg. If you extrapolated some of the mice studies, the dose for a 60-80 kg human would be 1200 mg!
These levels are certainly not used when fighting cancers. The human trial above on breast cancer used 200 mg per day for 14 days.
Doxycycline as a cancer treatment - the real dangers
There is also a lot of research on the dangers of taking antibiotics for more than 10 days. Chris Woollams, former Oxford University Biochemist commented, "As many of my patients who have PPs know, I do NOT recommend Doxycycline as an off-label drug for cancer. Doxycycline has been shown to reduce cancer cell stemness by 63%. And what of the remaining 37%? Can they not continue to drive metastases? Worse, after doxycycline treatment, remaining CSCs can become stronger as shown above.
There are three main reasons for my concerns:
1. No antibiotic is 'safe' - especially one used the way Care Oncology used it - one month on, one off, for 2 years. This can ruin the microbiome in that time and The Human Microbiome Project has told us that "you can't get better until your gut gets better". Also, doxycycline doesn't just lower the volume and diversity of the good guys in the gut, it causes antibiotic resistance in the microbiome and this leads to a higher level of pathogenic infections in the body! And doxycycline has aslso been shown to cause antibiotic resistance in the remaining Cancer Stem Cells. To see the damage caused by antibiotics go here.
No oncologist ever repairs your microbiome. It doesn't recover on its own! Research on blood and lymph cancer shows that after 4 rounds of just two cancer drugs, and 2 weeks of antibiotics, one year later, only 27% of the microbiome remains; and some bacterial members required for good health are now extinct and may be impossible to fully replenish!
2. Doxycycline is known to damage your Lymphocyte levels - and this reduces your survival time.
No oncologist has compounds that can restore your lymphocytes.
3. Doxycycline has been shown to make some cancers WORSE. One study showed that doxycycline-treated rats unexpectedly increased tumor multiplicity, stimulated tumor growth and increased metastasis in small intestine as determined by macroscopic and histopathological analysis. But then we know taking antibiotics can cause cancer.
In my opinion, it is madness to use Doxycycline in monthly doses as a Cancer Stem Cell Killer - rather like using a nuclear bomb to kill a single terrorist in Manchester - especially when good natural compounds such as Holy Basil, genistein, turmeric, resveratrol and more have been shown to work safely. Even off label drug Ivermectin was shown in research on rats with breast cancer to kill 100% of Cancer Stem Cells and causes no gut or lymphocyte damage or resistance.
Everywhere you look on doxycycline, it says that it is a perfectly safe antibiotic that has been used in some cases for several years, for example with acne. Yes, these users with acne are the women I see 20 years later who have higher rates of breast cancer or colorectal cancer, because their microbiomes are shot to pieces! No doctor thinks this is worth worrying about at the time. Long-term antibiotic use can cause real problems in the body. Even with cancer stem cell research in humans, the trials to date have been limited to just a few weeks.
Thirdly, most of the doxycycline research has been done in the laboratory. Pro-pharma skeptics would criticise this type of research heavily if it were for a herb or vitamin. Also there is nothing like the volume of research on doxycycline as there is on turmeric, berberine or vitamin C, but oncologists are getting excited because doxycycline is an already approved drug.
We will, of course, cover the research studies now coming through.
I am also really concerned that using doxycycline for every person, young or old, male or female, and for any cancer - brain colorectal or prostate - is misguided. Certainly, it is without precedent in the world of cancer - one drug that can work on every cancer? The study referred to above, on rats, showed that doxycycline promoted chronic inflammation in the gut and tumour generation (8). I would never use doxycycline for colorectal cancer.
Another aspect of the research that is ignored is that doxycycline (and metformin) can kill CSCs but simultaneously build drug resistance in the remaining CSCs, so you MUST use a follow up attack on glycolysis. This conclusion receives little or no mention in the recommendations of oncologists or in the literature of Clinics using antibiotics against cancer.
I am also looking into some research from Pennsylvania, where studies were trying to get rid of dormant cancer cells so that women with breast cancer could feel safer that their cancer was less likely to return. After the first studies failed, they decided they needed to first 'wake up' the dormant cancer cells. What did they use? The used Doxycycline to wake up the dormant cancer cells.
Please be careful. Antibiotics are only really be said to be 'safe' in 5 day doses".
Go to: Care Oncology Clinic Protocol
Go to: Ten natural compounds that tackle Cancer Stem Cells
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References
- Vitamin C plus antibiotic doxycycline, a lethal combination to cancer stem cells
- Sancho et al; Cell matabolism – pancreatic cancer stem cells and metformin
- Doxycycline, Azithromycin and Vitamin C (DAV): A potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs)
- Scatena C, Roncella M, Di Paolo A, et al. Doxycycline, an inhibitor of mitochondrial biogenesis, effectively reduces cancer stem cells (CSCs) in early breast cancer patients: a clinical pilot study.
- NCI – 2 Clinical Trials on doxycycline use with cancer
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405729/
- https://www.nature.com/articles/6603740
- https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151539
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485609/