Vitamin C and Doxycycline: A Synthetic Lethal Combination Therapy Targeting Metabolic Flexibility in Cancer Stem Cells (CSCs)

E.M. DeFrancesco, et. al., Oncotarget, 2017; 8:67269-67286


Here, we developed a new synthetic lethal strategy for further optimizing the eradication of cancer stem cells (CSCs). Briefly, we show that chronic treatment with the FDA-approved antibiotic Doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation. The expression of four mitochondrial DNA encoded proteins (MT-ND3, MT-CO2, MT-ATP6 and MT-ATP8) is suppressed, by up to 35-fold. This high selection pressure metabolically synchronizes the surviving cancer cell sub-population towards a predominantly glycolytic phenotype, resulting in metabolic inflexibility. We directly validated this Doxycycline-induced glycolytic phenotype, by using metabolic flux analysis and label-free unbiased proteomics.

Next, we identified two natural products (Vitamin C and Berberine) and six clinically-approved drugs, for metabolically targeting the Doxycycline-resistant CSC population (Atovaquone, Irinotecan, Sorafenib, Niclosamide, Chloroquine, and Stiripentol). This new combination strategy allows for the more efficacious eradication of CSCs with Doxycycline, and provides a simple pragmatic solution to the possible development of Doxycycline-resistance in cancer cells. In summary, we propose the combined use of i) Doxycycline (Hit-1: targeting mitochondria) and ii) Vitamin C (Hit-2: targeting glycolysis), which represents a new synthetic-lethal metabolic strategy for eradicating CSCs.

This type of metabolic Achilles’ heel will allow us and others to more effectively “starve” the CSC population.


Above you have the Abstract and Reference of a very important article. This article should have made headlines in the evening news and in the medical journals, but sadly it didn’t receive much attention at all. You would think the medical oncology world would be jumping for joy, but they are not.

In Chapter 9 of our book, we discuss extensively the dilemma of cancer stem cells (CSCs) which cancer cells generally survive toxic cancer therapies such as chemotherapy and radiation. They survive because they cells are “slow growing” tumor cells. Chemo and radiation kill off (rather effectively) the “fast growing” tumor cells which comprise the bulk of the cancer but leave the slow growing CSCs behind. The slow growing remaining viable CSC tumor cells – that is, chemo-resistant and radio-resistant – are then responsible as the “root cause” of cancer relapses months and even years later. The question for those of us that practice Integrative Oncology has always been: how do we effectively eliminate the CSCs and thereby reduce the chances cancer future relapse and/or recurrence? This is what virtually all people with cancer fear: what if the cancer returns?The reason this article is so critical is that it outlines a very simple, minimally-toxic, and inexpensive Integrative Oncology medical plan that would substantially reduce cancer stem cell (CSC) viability and survivability. In other words, it is our view that this article holds the exciting key to how the dread CSCs can finally be successfully addressed.

In this discussion we wish to explain the findings of the Oncotarget article and then outline a simple program that use in our office to implement this truly remarkable discovery authored by Dr. DeFrancesco and her research group. In Chapter 9 our book, this therapy comes under the category of Specific Recommendation Two (and is probably best utilized after completion of chemo and/or radiation in our opinion with the goal of “finishing off” remaining CSCs not eradicated by chemo or radiation).


To better understand the following discussion, the reader may need to refer back to Chapter 2 of our book where we discussed Mitochondria and Metabolism of cancer.

The essence of the article is this. CSCs have two basic vulnerabilities that can be exploited by the concomitant use of BOTH vitamin C and Doxycycline:

  1. They utilize the same metabolic pathway of the fast-growing tumor cells, that is, aerobic glycolysis. Normal cells don’t use this method of producing energy. It turns out, according to their study, that vitamin C (ascorbic acid) inhibits aerobic glycolysis. And vitamin C does this in concentrations that can be achieved by high oral doses of vitamin C. In other words, vitamin C therapy does not require IV vitamin C in order to work. For vitamin C to work most effectively in inhibiting aerobic glycolysis, the CSCs needed to also be exposed to Doxycycline at the same time. It’s the combination that seems to work best.
  2. Their metabolic mitochondrial pathway is vulnerable. Yes, CSCs have mitochondria, and they are more numerous and work much better than fast-growing tumor cells’ mitochondria. These CSC mitochondria can be sabotaged by the simple, safe, and inexpensive “re-do” antibiotic, Doxycycline. This antibiotic is strongly anti-mitochondrial. The only problem with the use of Doxycycline (aka Doxy) is that the mitochondria (in order to survive) become Doxy-resistant. In other words, Doxy needs some help when CSCs learn to resist it. But there are several substances (natural and pharmaceutical) that help navigate around the Doxy-resistance by attacking the CSC mitochondria in other ways.What the researchers found was the foundational combination is always vitamin C and Doxy. And then adding a third agent was most effective in eradicating CSCs. They even found that berberine, an herbal substance that has been used for thousands of years, worked well when higher concentrations were used.

    Two commonly used anti-parasitic medications can be helpful: atovaquone (Mepron®) was found to be very effective against the CSC mitochondria (Complex 3 of mitochondria) and chloroquine was found to be an inhibitor of autophagy. These prescription meds have side effects, however. For that reason, we don’t use these medications often, although they certainly could be utilized if needed.







Here is how we utilize the vital information from the Oncotarget study. We have found no toxicity whatsoever with the following approach. However, we recommend only embarking on this protocol only under the direct supervision of your practitioner.

  1. Vitamin C – ideally achieve a “bowel-tolerance” dosage which is usually between 6,000 to 12,000 mg SPREAD THROUGHOUT THE DAY (taking too much at once will most assuredly cause diarrhea). This particular vitamin C method can be discussed in more detail in a Cancer Coaching session with us.
  2. Doxycycline 100 mg twice a day (be sure to avoid taking with dairy products and take probiotics between doses of Doxy)
  3. Berberine 500 mg twice a day (very effective but dosage needs to be between 500-1,000 mg per day)
  4. Metformin 500 mg. one time a day (inhibits the mTOR pathway and affects CSC mitochondria). Several studies have demonstrated the anti-CSC value of Metformin, even when combined with chemo.
  5. Paw Paw (works against Complex I of mitochondria)
  6. Vitamin E succinate 400 mg per day (works against Complex II of mitochondria)