Bottom Line:
Low-dose Doxycycline may be a useful add-on to other therapies, for a number of reasons:
i) inhibition of mitochondrial protein synthesis, with decreased ATP and a slowing of proliferation ...
ii) ... &, with a particularly detrimental effect on PCa stem cell-like cells
iii) inhibition of the matrix metalloproteinases that are needed for cell mobility and metastasis
iv) & perhaps an added benefit in the context of bone mets
***
I have begun to use low-dose Doxycyline (100 mg, 3 times weekly).
Some years back, I posted elsewhere a review of the Tetracycline family of antibiotics & PCa. I subsequently gave Minocycline a trial, without noticeable benefit.
During the summer, I was treated for a tick bite with Doxycycline. It was a large single preemptive dose intended for Lyme disease - it was too early to test for Lyme.
I mentioned this to Nalakrats at our next lunch. He thought that it was a mistake for me to have been on Minocycline earlier, since Doxycycline is much more promising for PCa.
Back in 1986, from a Dutch paper [1]:
{Note that "tetracyclines" refers to the "cycline" family - including Doxycycline.}
"The results described in this paper demonstrate that proliferation arrest by low concentrations of tetracyclines, which has previously been shown in experiments with animal tumor systems, can also be achieved in tumor systems of human origin. Tetracyclines specifically inhibit mitochondrial protein synthesis. Prolonged and continuous impairment of protein synthesis inside the mitochondria leads to reduction of the cellular concentration of the polypeptide products which are coded and synthesized within mitochondria. These products are part of the oxidative phosphorylative system of the cell. Long-term tetracycline treatment leads to a decrease of oxidative ATP-generating capacity as monitored by cytochrome c oxidase activity. This may cause severe energetic or metabolic disturbances which explain the proliferation arrest observed. Proliferation arrest, provided that mitochondrial protein synthesis is blocked effectively, is found in vitro as well as in vivo. It is shown that the effect of doxycycline is not limited to cytostasis; prolonged doxycycline treatment is clearly cytotoxic for the tumor cells."
From 1998 (U.S.) [2]:
"... The matrix metalloproteinases (MMPs) play a significant role in the growth, invasion and metastasis of many tumors, including those of the prostate. We previously demonstrated that doxycycline, a synthetic tetracycline, inhibits MMPs and cell proliferation and induces apoptosis in several cancer cell lines.
"... In the present study, gelatinolytic activity in the human prostate cancer cell line, LNCaP, was suppressed and significant inhibition of cell growth occurred after exposure to 5 or 10 microg/ml of doxycycline, while cell growth was normal in untreated cells. Radioisotope incorporation into proteins was reduced by doxycycline. DNA fragmentation, consistent with apoptosis, was demonstrated in cells treated with doxycycline. These data suggest that doxycycline may have potential utility in the management of prostate cancer."
Note: Prostatic cells are anchored to a "matrix". PCa cells produce matrix metalloproteinases [MMPs]. Each of these proteinase enzymes has a role in freeing the cell from the matrix. MMPs are a major topic in the PCa literature. Inhibition of MMPs translates to inhibition of metastasis.
From 2003 (Canada) [3]:
"The tetracycline family includes tetracycline, doxycycline and minocycline, all of which have been used as antibiotics effectively for decades. New uses emerged for these compounds after their effect on mitochondrial function was discovered. Cytostatic and cytotoxic activity of these compounds was shown against cell lines of various tumor origins. In addition, tetracyclines and chemically modified tetracyclines inhibit the activity of several matrix metalloproteinases (MMPs). Given the importance of these enzymes in tumor cell invasion and metastatic ability, the potential use of tetracyclines in cancer therapy needed to be investigated.
"... However, the potential of tetracyclines in cancer therapy takes on an added dimension in the bone. MMPs have been shown to be important mediators of metastasis formation in the bone, contributing largely to the morbidity of breast cancer and prostate cancer patients. The natural osteotropism of tetracyclines would allow them to be highly effective in the inhibition of MMPs produced by osteoclasts or tumor cells in the bone. This hypothesis has now been confirmed by experimental evidence showing that doxycycline reduces tumor burden in a mouse model of breast cancer-derived osteolytic bone metastasis. This effect is likely due to a combination of multiple roles of doxycycline, including MMP inhibition and a negative effect on osteoclast differentiation and survival. These encouraging results have now paved the way for an ongoing trial of doxycycline in early combination therapy for breast cancer and prostate cancer patients."
From 2017 (Japan) [4]:
"Doxycycline induces apoptosis via ER stress selectively to cells with a cancer stem cell-like properties: importance of stem cell plasticity"
Intro: "Tumor heterogeneity can be traced back to a small subset of cancer stem cells (CSCs), which can be derived from a single stem cell and show chemoresistance. Recent studies showed that CSCs are sensitive to mitochondrial targeting antibiotics such as doxycycline."
From 2018 - Sotgia/Lisanti (U.K. / Italy) [5]:
"Here, we wish to propose a new systematic approach to cancer therapy, based on the targeting of mitochondrial metabolism, especially in cancer stem cells (CSCs). In the future, we envision that anti-mitochondrial therapy would ultimately be practiced as an add-on to more conventional therapy, largely for the prevention of tumor recurrence and cancer metastasis. This mitochondrial based oncology platform would require a panel of FDA-approved therapeutics (e.g. Doxycycline) that can safely be used to inhibit mitochondrial OXPHOS and/or biogenesis in CSCs. In addition, new therapeutics that target mitochondria could also be developed, to optimize their ability to eradicate CSCs. Finally, in this context, mitochondrial-based biomarkers (i.e. "Mito-signatures") could be utilized as companion diagnostics, to identify high-risk cancer patients at diagnosis, facilitating the early detection of tumor recurrence and the prevention of treatment failure. In summary, we suggest that new clinical trials are warranted to test and possibly implement this emerging treatment strategy, in a variety of human cancer types. This general approach, using FDA-approved antibiotics to target mitochondria, was effective in killing CSCs originating from many different cancer types, including DCIS, breast (ER(+) and ER(-)), prostate, ovarian, lung and pancreatic cancers, as well as melanoma and glioblastoma, among others. Thus, we propose the term MITO-ONC-RX, to describe this anti-mitochondrial platform for targeting CSCs. The use of re-purposed FDA-approved drugs will undoubtedly help to accelerate the clinical evaluation of this approach, as these drugs can move directly into Phase II clinical trials, saving considerable amounts of time (10-15 y) and billions in financial resources."
So far, Doxycycline has not become an "add-on" in a clinical trial.
It has become an add-on to my modified BAT protocol. I will report back on my n=1 trial before the year is out.
-Patrick
[1] pubmed.ncbi.nlm.nih.gov/301...
full: watermark.silverchair.com/c...
[2] pubmed.ncbi.nlm.nih.gov/961...
[3] pubmed.ncbi.nlm.nih.gov/145...
