Dr. Weeks’ Comment:  We need to do better by our trusting patients who battle cancer. We need not only to optimally nourish them and offer an anti-inflammatory diet  (since inflammation drives all cancers) but also we need to find safe and effective agents which can potentiate the standard of care (chemo, radiation and surgery). Over the past 3 decades there has been a consistently intriguing and growing body of research endorsing an inexpensive and common antibiotic, Doxycycline, as an anti-cancer drug.  Read below to get caught up and note last article which describes an exciting symbiotic role of vitamin C.

 

 

Effects of doxycycline on human prostate cancer cells in vitro

AuthorRose SFifeet al

https://www.sciencedirect.com/science/article/pii/S0304383598000032

 

Cancer Letters

Volume 127, Issues 1–2, 15 May 1998, Pages 37-41

 

Abstract

Prostate cancer is the most common form of cancer in older men and the major cause of death from prostate cancer is metastatic disease. 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.We also demonstrated that in an in vivo model of metastatic breast cancer in athymic micedoxycycline inhibits tumor size and regrowth after resection. 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 μg/ml of doxycycline, while cell growth was normal in untreated cells. Radioisotopeincorporation 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.

 

 

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Doxycycline Decreases Tumor Burden in a Bone Metastasis Model of Human Breast Cancer

Journal: Cancer Research  March 2002

Wilhelmina C. M.  at al

https://cancerres.aacrjournals.org/content/62/6/1588.short

Abstract

Bone is one of the most frequent sites for metastasis in breast cancer patients,often resulting in significant clinical morbidity and mortality. Increased matrix metalloproteinase (MMP) activity of tumor cells correlates with a higher invasive and metastatic potential.Members of the tetracycline family of antibiotics, including doxycycline, have potential treatment value for bone metastasis; they inhibit cancer cell proliferation, and they are also potent MMP inhibitors and are highly osteotropic.Doxycycline treatment in an experimental bone metastasis mouse model of human breast cancer MDA-MB-231 cells resulted in a 70% reduction in total tumor burden when compared with placebo control animals. In tumor-bearing animals, the amount of doxycycline incorporated into the radius/ulna as assessed by ELISA was lower than in non-tumor-bearing animals. In doxycycline-treated mice, bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface, and volume, whereas a decrease in bone resorption was also observed. Doxycycline treatment may be beneficial for breast cancer patients with or at risk for osteolytic bone metastasis; it greatly reduces tumor burden and could also compensate for the increased bone resorption associated with the disease.

 

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Doxycycline as Potential Anti-cancer Agent

Source:Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry – Anti-Cancer Agents), Volume 17, Number 12, 2017,

Authors:Ali, Isra;

DOI: https://doi.org/10.2174/1871520617666170213111951

• Abstract
• Cancer cells do create hostile microenvironment (deprivation of nutrients,
• accumulation of acidity, anoxic habitat). Those cells are not only adapted to
• this sanctuary environment, blunting of immunity but also, grow, migrate to
• the distal area (metastasis) and communicate with each other in a unique
• population structure and organization too (clonal expansion). The adaptation
• requirements push those types of adaptable cells (cancer cells) to be
• primitive cells. The prevailing pharmacological approach in treating cancer
• is developing a chemotherapeutic agent that acts on rapidly proliferating
• cells that are stuck with normally growing epithelium and bone marrow too.
• The latter approach has been drafted to work on cellular target under the
• term of “targeted therapy” believing that each target represents Achilles
• Heels of cancer. In this article, we try to introduce a new concept of cancer
• pharmacology, by offering new off-label use of Doxycycline, which is
• characterized by selective toxicity, as potential anticancer agents. This
• notion is relying on the absence of taxonomic barriers.

 

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Doxycycline, an Inhibitor of Mitochondrial Biogenesis, Effectively Reduces Cancer Stem Cells (CSCs) in Early Breast Cancer Patients: A Clinical Pilot Study

 

Cristian Scatenaet ak

Front. Oncol., 12 October 2018 | https://doi.org/10.3389/fonc.2018.00452

 

https://internal-journal.frontiersin.org/articles/10.3389/fonc.2018.00452/full

 

 

Background and objectives:Cancer stem cells (CSCs) have been implicated in tumor initiation, recurrence, metastatic spread and poor survival in multiple tumor types, breast cancers included. CSCs selectively overexpress key mitochondrial-related proteins and inhibition of mitochondrial function may represent a new potential approach for the eradication of CSCs. Because mitochondria evolved from bacteria, many classes of FDA-approved antibiotics, including doxycycline, actually target mitochondria. Our clinical pilot study aimed to determine whether short-term pre-operative treatment with oral doxycycline results in reduction of CSCsin early breast cancer patients.

 

Conclusions:Quantitative decreases in CD44 and ALDH1 expression are consistent with pre-clinical experiments and suggest that doxycycline can selectively eradicate CSCs in breast cancer patients in vivo.Future studies (with larger numbers of patients) will be conducted to validate these promising pilot studies.

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Doxycycline Induces Apoptosis in PANC-1 Pancreatic Cancer Cells

Kyonsu Sonet al

Anticancer Research October 2009,  29 (10) 3995-4003;

 

Abstract:  Tetracyclines such as doxycycline are reported to possess cytotoxic activity against mammalian tumor cells,but the mechanism of their effects on cell proliferation remains unclear.

 

Materials and Methods: The antitumor effect of doxycycline was investigated in human pancreatic cancer cell line, PANC-1. We also investigated the effect of doxycycline on expression of a potent proangiogenic factor, interleukin (IL)-8.

 

Results: In excess of 20 μg/ml, cytotoxic effects of doxycycline were accompanied by G₁-S cell cycle arrest and DNA fragmentation in PANC-1 cells. Doxycycline consistently activated transcription of p53, p21 (both tumor suppressor genes) and Fas/FasL-cascade-related genes, while reducing the expression of Bcl-xL and Mcl-1.Doxycycline (5 μg/ml) below the cytotoxic level suppressed endogenous and paclitaxel-induced IL-8 expression. In the mouse xenograft model, doxycycline treatment was shown to suppress tumor growth by 80%.

 

Conclusion: These data suggest that doxycycline exerts its antitumor effect by activating proapoptotic genes, inhibiting IL-8 expression, and suppressing antiapoptotic genes.

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Doxycycline, salinomycin, monensin and ivermectin repositioned as cancer drugs

 

Bioorganic & Medicinal Chemistry Letters

Volume 29, Issue 13, 1 July 2019, Pages 1549-1554

https://doi.org/10.1016/j.bmcl.2019.04.045Get rights and content

Abstract

Chemotherapy is one of the standard methods for the treatment of malignant tumors. It aims to cause lethal damage to cellular structures, mainly DNA. Noteworthy, in recent years discoveries of novel anticancer agents from well-known antibiotics have opened up new treatment pathways for several cancer diseases.

The aim of this review article is to describe new applications for the following antibiotics:  doxycycline (DOX), salinomycin (SAL), monensin (MON) and ivermectin (IVR) as they are known to show anti-tumor activity, but have not yet been introduced into standard oncological therapy. To date, these agents have been used for the treatment of a broad-spectrum of bacterial and parasitic infectious diseases and are widely available, which is why they were selected. The data presented here clearly show that the antibiotics mentioned above should be recognised in the near future as novel agents able to eradicate cancer cells and cancer stem cells (CSCs) across several cancer types.

 

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Doxycycline and other tetracyclines in the treatment of bone metastasis

Saikali, Zeina^a; Singh, Gurmit^{a b}

Anti-Cancer Drugs: November 2003 – Volume 14 – Issue 10 – p 773-778

 

 

ABSTRACT

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. Col-3, a chemically modified tetracycline, is now the subject of clinical trials in cancer patients. 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 bonemetastasis. 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.

 

 

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Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)

Ernestina Marianna De Francesco,et al

 

Oncotarget. 2017 Sep 15; 8(40): 67269–67286.

Published online 2017 Jun 9. doi: 10.18632/oncotarget.18428

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620172/

 

 

 

Abstract

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.

CONCLUSIONS

Numerous functional studies have now directly shown that mitochondria are an important new therapeutic target in cancer cells [3, 5, 8–21, 40–53].Since Doxycycline, an FDA-approved antibiotic, behaves as an inhibitor of mitochondrial protein translation, it may have therapeutic value in the specific targeting of mitochondria in cancer cells.However, in this paper, we have identified a novel metabolic mechanism by which CSCs successfully escape from the anti-mitochondrial effects of Doxycycline, by assuming a purely glycolytic phenotype. Therefore, DoxyR CSCs are then more susceptible to other metabolic perturbations, because of their metabolic inflexibility, allowing for their eradication with natural products and other FDA-approved drugs. Thus, understanding the metabolic basis of Doxycycline-resistance has ultimately helped us to develop a new synthetic lethal strategy, for more effectively targeting CSCs.