Malignant Cancer Stem Cells (CSCs) can be exposed 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 and restrict Myc even in healthy cells.
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.
Cancer Stem Cells – the real problem in cancer
Everybody has non-malignant Stem Cells in their bodies. They are the basic blank cell and are used for repair, being directed to a damaged area then converting (differentiating) to healthy replacement cells for that tissue.
However, there are also malignant stem cells - termed cancer stem cells.
Cancer Stem Cells (CSCs) have been identified at the heart of many 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 have altered. Cancer stem cells may also be the source of cells that give rise to metastases.
One of the biggest issues is that current 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 Oncotarget (2017), Professor Michael Lisanti and his team 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 resistant. They then allowed the 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 were 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. 2015 research from Patricia Sancho showed cancer stem cells (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, its natural rival berberine is better at providing the 'coup de grace'.
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.
Restricting CSCs in human breast cancer patients
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 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 must be 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.
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 a 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 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 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!
The human trial on breast cancer used 200 mg per day for 14 days.
There is also a lot of research on the dangers of taking antibiotics for more than 10 days.
Doxycycline as a cancer treatment - the bottom line
Chris Woollams, former Oxford University Biochemist commented, "First, 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 are the women I see 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.
However, if someone is already taking 3 or 4 cancer drugs, I would consider adding doxycycline to the mix, as the microbiome is already heavily compromised.
However, the microbiome would need to be rebuilt after treatment. Research on blood and lymph cancer shows that after 4 rounds of just two cancer drugs, only 27% of the microbiome remains; and some bacterial members required for good health are now extinct and impossible to replenish!
Thirdly, most of the doxycycline research has been done in the laboratory. Pro-pharma keptics 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 somewhat concerned that using doxycycline for every person, young or old, male or female, and for any cancer - brain or prostate - is misguided. Certainly, it is without precedent in the world of cancer - one drug that can work on every cancer? One study, on colorectal cancer using rats, showed that doxycycline promoted chronic inflammation in the gut and tumour generation (8). I wouldn't use doxycycline for colorectal cancer anyway.
Finally, the research evidence 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 oncologiosts or in the literature of Clinics using such treatments against cancer. This is a concern and seems to ignore the research findings.
Please be careful. Talk to an oncologist. Off-label drugs aren't something you should play with on your own".
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/