Why Combine the COC Protocol with Standard of Care?

To maximize potential benefits of the COC Protocol, we recommend taking the Protocol in combination with standard cancer treatments where possible.

We designed the COC Protocol for use alongside all standard cancer treatments, including radiotherapy, chemotherapy, hormonal treatments, and newer therapies (e.g., immunotherapies, targeted therapies). Numerous laboratory-based scientific studies support this approach, and reported results suggest that the COC Protocol medications may help to improve the effectiveness of standard treatments in several different ways:

  • Metformin Along with ‘metabolically reprogramming’ cancer cells to make them potentially more vulnerable to standard of care treatments, metformin may also help to sensitize tumor response to standard therapies by: targeting generally harder to treat cancer stem cells, improving the hypoxic (low-oxygen) state which can often develop around tumors and which hinders the effectiveness of standard treatments, reversing multidrug resistance in cancer cells, and by beneficially modulating the tumor microenvironment (Tang et al, 2021, Jin et al, 2020).
  • Statins can improve the radiation sensitivity of cancer cells grown in the lab by increasing production of cell-damaging oxidative stress molecules (Hosseinimehr et al., 2020). Lab studies also show that statins can help reduce chemotherapy resistance in various different cancer cell types by targeting molecular processes in these cells- including blocking HMG-CoA reductase-dependent molecular pathways (Chen et al 2013, Chen et al, 2012).
  • Mebendazole may help to sensitize cancer cells to radiation therapy by increasing radiation-induced DNA damage. The drug can also work alongside chemotherapy drugs, overcoming cancer cell resistance (Guerini et al, 2019).
  • Doxycycline can help sensitize cancer cells to radiation by decreasing levels of a cell molecule called DNA-PK. Cancer cells are known to need this molecule for DNA repair, and it has been linked to radiation resistance in cancer cells (Lamb et al, 2015). Similar to metformin, doxycycline may also target cancer stem cells in low-oxygen areas that are resistant to traditional chemotherapies, and disrupt the molecular mechanisms that cancer cells use to produce energy (Tan et al, 2017 and De Francesco et al, 2017).

Numerous epidemiological studies support these preclinical potentiation/sensitization findings, as do small clinical studies in patients with cancer. In addition, the extensive evidence base which supports the overall use of the COC Protocol in cancer also includes more extensive epidemiological studies, and a growing number of human clinical trials across a wide range of cancer types.

To get the most out of the COC Protocol, we encourage you to always investigate any standard of care therapy options which may be available to you, whatever your situation now, or in future.

The COC Medical Team are with you every step of the way. As your standard of care treatments and other circumstances evolve over time, our doctors expertly tailor refinements to your Protocol to maximize safety, tolerance of treatment and the potential for positive outcomes.

Selection of Studies

Potentiation of Radiotherapy

Med Paper Conclusions (adapted from paper abstract)
Met and Stat Statin and metformin therapy in prostate cancer patients with hyperlipidemia who underwent radiotherapy: a population-based cohort study

Li et al., 2019
https://doi.org/10.2147/CMAR.S166638

(Observational patient study)

Study results link the use of statins or metformin after prostate cancer diagnosis with increased survival in patients with hyperlipidemia and radiotherapy.
Met Radiosensitization of pancreatic cancer cells by metformin through the AMPK pathway.
Fasih et al., 2014

https://doi.org/10.1667/RR13568.1

(Lab-based cell study)

Study findings suggest that metformin can help to radiosensitize pancreatic cancer cells through the molecular ‘AMPK pathway’, and may also affect how cancer cells repair their damaged DNA. These data indicate that metformin may increase the effectiveness of radiation therapy for pancreatic cancer.
Met Effect of mitochondrial metabolism-interfering agents on cancer cell mitochondrial function and radio/chemosensitivity
Mitrakas et al., 2014

https://pubmed.ncbi.nlm.nih.gov/25035963/
(Lab-based cell study)

Study concludes that amiodarone and metformin deserve further experimental and clinical evaluation as cancer cell sensitizers to chemotherapy and radiotherapy.
Met Antidiabetic Biguanides Radiosensitize Hypoxic Colorectal Cancer Cells Through a Decrease in Oxygen Consumption
De Mey et al., 2018
https://doi.org/10.3389/fphar.2018.01073
(Lab-based cell study)
Study results demonstrate that metformin and phenformin can overcome hypoxic (low-oxygen) induced cancer cell resistance to radiotherapy by decreasing the cell’s need for oxygen to generate energy. These results provide a rationale to explore metformin and phenformin as hypoxic radiosensitizers.
Stat Atorvastatin Sensitizes Breast and Lung Cancer Cells to Ionizing Radiation

Hosseinimehr et al., 2020
http://ijpr.sbmu.ac.ir/article_1101018.html
(Lab-based cell study )

Atorvastatin increased cell-damaging ROS (reactive oxygen species) production in irradiated cells. The study demonstrates that atorvastatin has a radiosensitizing effect on breast and lung cancer cells through increasing programmed cell death (apoptosis), ROS production and cell death induced by ionizing radiation.
Stat Clinical Potential of Statins in Prostate Cancer Radiation Therapy

Hutchinson and Marignol, 2017
https://ar.iiarjournals.org/content/37/10/5363
(Review)

The literature supports the radiosensitizing properties of statins and their potential antitumor effects in prostate cancer. conflicting study results still need to be understood, however
Meb Mebendazole Potentiates Radiation Therapy in Triple-Negative Breast Cancer

Zhang et al., 2018

https://doi.org/10.1016/j.ijrobp.2018.08.046
(Lab-based cell study)

 

Mebendazole (MBZ) efficiently depletes the no. BCIC (breast cancer initiating cells) and prevents the ionizing radiation–induced conversion of breast cancer cells into therapy-resistant BCICs. MBZ sensitizes triple-negative breast cancer (TNBC) cells to ionizing radiation in the lab and in animal studies, resulting in improved tumor control in a small animal model of TNBC.
Meb Microtubule-targeting agents can sensitize cancer cells to ionizing radiation by an interphase-based mechanism

Markowitz et al, 2017

https://doi.org/10.2147/OTT.S143096

(Lab-based cell study)

This study demonstrates that MBZ can sensitize cancer cells to ionizing radiation using mechanisms independent of the induction of growth arrest. In addition, evidence is provided supporting the hypothesis that [MBZ]-induced radiosensitization is mediated by blocking accumulation of DDR protein in the cell nucleus.
Meb Mebendazole as a Candidate for Drug Repurposing in Oncology: An Extensive Review of Current Literature
Guerini et al., 2019
https://doi.org/10.3390/cancers11091284
(Review)
Mebendazole not only exhibits direct cytotoxic (cell-killing) activity, but also works alongside ionizing radiations and different chemotherapeutic agents and stimulates antitumoral immune response.
Doxy Doxycycline down-regulates DNA-PK and radiosensitizes tumor initiating cells: Implications for more effective radiation therapy.
Lamb et al., 2015
https://doi.org/10.18632/oncotarget.4159
(Lab-based cell study)
Study shows that doxycycline effectively inhibits the mammosphere-forming (stem-cell) activity of patient breast cancer cell samples taken from metastatic disease sites. Our results also have possible implications for the radio-therapy of brain tumors and/or brain metastases, as doxycycline is known to effectively cross the blood-brain barrier.

 

Potentiation of Chemotherapy

Med Paper Conclusion
Met The Chemosensitizing Role of Metformin in Anticancer Therapy (Review)

Tang et al., 2020

https://www.eurekaselect.com/186045/article

(Review)

A growing body of evidence indicates that metformin can sensitize tumor responses to different chemotherapeutic drugs, such as hormone modulating drugs, anti-metabolite drugs, antibiotics, and DNA-damaging drugs via selective targeting of cancer stem cells, improving the hypoxic (low-oxygen) microenvironment, and by suppressing tumor metastasis and inflammation.
Met Real-time assessment of platinum sensitivity of primary culture from a patient with ovarian cancer with extensive metastasis and the platinum sensitivity enhancing effect by metformin

Liu et al, 2018
https://doi.org/10.3892/ol.2018.9223
(Cell Study)

Metformin rapidly increased the sensitivity of cells to platinum‑based chemotherapy, and this effect was dose‑dependent. The effect of metformin on chemotherapeutic sensitization of cancer cells is clear in vitro, and the real‑time cell analyzer assay has the potential to assist in determining individualized drug regimens for patients with metastatic ovarian cancer.
Met Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy

Shi et al., 2012

https://www.nature.com/articles/cddis201213
(Lab-based cell study)

Combined treatment of oral metformin with doxorubicin or temsirolimus triggered lymphoma cell autophagy and functioned more efficiently than either agent alone. Taken together, these data provided first evidence for the growth-inhibitory and drug-sensitizing effect of metformin on lymphoma.
Met Association of p53 and mitochondrial gene with chemosensitization by metformin in ovarian cancer
Wei et al., 2018
https://doi.org/10.18632/oncotarget.22863
(Lab-based cell study)
Metformin enhances the sensitivity of drug-resistant ovarian cancer cells to chemotherapy.

 

Stat Anti-tumor effects of statins in triple-negative breast cancer: Apoptosis, chemosensitization and degradation of mutant-p53

O’Grady et al., 2020

DOI: 10.1158/1538-7445.AM2020-1775
(NB non-peer-reviewed abstract)

(Lab-based cell study)

Combination treatment of simvastatin and the chemotherapeutic agents doxorubicin or docetaxel showed synergistic growth inhibition (in triple-negative breast cancer cell lines).
Stat Statin therapy is associated with improved pathologic response to neoadjuvant chemoradiation in rectal cancer

Mace et al., 2013
https://pubmed.ncbi.nlm.nih.gov/24104995/

(Retrospective patient study)

Statin therapy linked to an improved response of rectal cancer to neoadjuvant chemoradiation. These data provide the foundation for a prospective clinical trial.
Doxy Targeting hypoxic cancer stem cells (CSCs) with Doxycycline: Implications for optimizing anti-angiogenic therapy

De Francesco et al., 2017
https://doi.org/10.18632/oncotarget.18445

(Lab-based cell study)

Doxycycline effectively targets the sub-population of hypoxia (low oxygen)-induced cancer stem cells (CSCs) that are paclitaxel-resistant, overcoming hypoxia-induced drug-resistance. Anti-angiogenic therapy often induces tumor hypoxia, allowing CSCs to survive and grow, ultimately driving tumor progression. Therefore, this study suggests that doxycycline could be used in combination with anti-angiogenic agents, to actively prevent or minimize hypoxia-induced treatment failure.
Doxy Induction of Mitochondrial Dysfunction and Oxidative Damage by Antibiotic Drug Doxycycline Enhances the Responsiveness of Glioblastoma to Chemotherapy
Tan et al., 2017
https://pubmed.ncbi.nlm.nih.gov/28842551/

(Lab-based cell study)

Study shows that doxycycline is effective in targeting glioblastoma through inducing mitochondrial (cell-battery) problems and causing oxidative stress.
Meb Anthelmintic mebendazole enhances cisplatin’s effect on suppressing cell proliferation and promotes differentiation of head and neck squamous cell carcinoma (HNSCC)
Zhang et al., 2017
https://www.oncotarget.com/article/14673/text/

(Lab-based cell study)

Mebendazole works alongside cisplatin in suppressing cell growth and division and inducing apoptosis of human HNSCC (Head and neck squamous cell carcinoma) cells.

 

Overcoming Chemo/Radio resistance

Med Paper Conclusion
Met & Stat Combination simvastatin and metformin induces G1-phase cell cycle arrest and Ripk1- and Ripk3-dependent necrosis in C4-2B osseous metastatic castration-resistant prostate cancer cells
Babcook et al., 2014
https://www.nature.com/articles/cddis2014500
(Lab-based cell study)
The cell death-inducing capacity of simvastatin and metformin may make these drugs a highly effective treatment for apoptosis (programmed cell death) and chemotherapy-resistant metastatic castration-resistant prostate cancer cells.
Met Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer
Davies et al, 2017
https://doi.org/10.1371/journal.pone.0187191
(Lab-based cell study)
Demonstration that metformin can prevent multidrug resistance (MDR) development and resensitize MDR cells to chemotherapy in vitro, provides medical relevance towards metformin’s potential clinical use against MDR cancers.
Met Metformin reverses multidrug resistance and epithelial-mesenchymal transition (EMT) via activating AMP-activated protein kinase (AMPK) in human breast cancer cells
Qu et al, 2014
https://link.springer.com/article/10.1007/s11010-013-1845-x
(Lab-based cell study)
Metformin can resensitize multidrug-resistant breast cancer cells due to activating the molecular AMPK cell pathway.
Met Metformin sensitizes hypoxia-induced gefitinib treatment resistance of HNSCC via cell cycle regulation and EMT reversal
Yin et al., 2018
https://doi.org/10.2147/CMAR.S177473
(Lab-based cell study)
Study shows metformin sensitizes HNSCC (head and neck squamous cell carcinoma) to gefitinib treatment, which might serve as a novel combined treatment strategy.
Met Metformin sensitizes endometrial cancer cells to chemotherapy through IDH1-induced Nrf2 expression via an epigenetic mechanism.
Bai et al, 2018
https://www.nature.com/articles/s41388-018-0360-7
(Lab-based cell study)
Findings suggest that rational combination therapy with metformin and chemotherapeutics has the potential to suppress chemoresistance.
Stat Atorvastatin overcomes gefitinib resistance in KRAS mutant human non-small cell lung carcinoma cells

Chen et al., 2013
https://www.nature.com/articles/cddis2013312
(Lab-based cell study)

Atorvastatin overcomes gefitinib resistance in KRAS mutant non-small cell lung carcinoma cells through inhibition of HMG-CoA reductase-dependent molecular pathways.
Stat Atorvastatin sensitizes human non-small cell lung carcinomas to carboplatin via suppression of AKT activation and upregulation of TIMP-1

Chen et al., 2012
https://doi.org/10.1016/j.biocel.2012.01.015
(Lab-based cell study)

Data demonstrate that atorvastatin may overcome carboplatin resistance in lung cancer by suppressing molecular AKT activity and increasing TIMP-1. A combination of atorvastatin and carboplatin may be an effective strategy in clinical therapy against  non-small cell lung carcinomas.
Stat Simvastatin Sensitizes Radioresistant Prostate Cancer Cells by Compromising DNA Double-Strand Break Repair
Chen et al., 2018
https://doi.org/10.3389/fphar.2018.00600
(Lab-based cell study)
Results demonstrated that a combination treatment with simvastatin and ionizing radiation synergistically induced programmed cell-death of radioresistant prostate cancer cells.
Meb Mebendazole is a potent inhibitor to chemoresistant T cell acute lymphoblastic leukemia cells

Wang et al., 2020
https://doi.org/10.1016/j.taap.2020.115001

(Lab-based cell study)

This study demonstrated, for the first time, that mebendazole could inhibit chemoresistant T-cell acute lymphoblastic leukemia cells both in the lab and in mice, and the Notch1 molecular cell pathway was suppressed by mebendazole treatment.
Meb The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma.
Simbulan-Rosenthalet al (2017)

https://doi.org/10.18632/oncotarget.14990
(Lab-based cell study)(Cell Study)

These data suggest that mebendazole could be considered as a therapeutic option in combination with trametinib, for patients with NRASQ61mutant or other non-V600E BRAF mutant melanomas.

 

 

Potentiation of immunotherapies, targeted therapies & hormone therapies

Med Paper Conclusion
Met Efficacy of metformin in combination with immune checkpoint inhibitors (anti-PD-1/anti-CTLA-4) in metastatic malignant melanoma

Afzal et al., 2018
http://dx.doi.org/10.1186/s40425-018-0375-1

(Observational Patient Study)

Study observed favorable treatment-related outcomes (including median progression free survival and median overall survival) in patients who have received metformin in combination with immune checkpoint inhibitors (ICIs) without reaching significance, probably, due to small sample size. Hence, large prospective clinical trials are required to study the effect of metformin in combination with ICIs before it can be recommended as routine additive therapy.
Stat and met The updated landscape of tumor microenvironment and drug repurposing

Jin et al, 2020

https://www.nature.com/articles/s41392-020-00280
(Review)

Discusses how statins and metformin may help to beneficially modulate the tumor microenvironment (which could be potentially beneficial alongside immunotherapies)
Doxy Potential for enhanced therapeutic activity of biological cancer therapies with doxycycline combination
Tang et al, 2013
https://www.nature.com/articles/gt201296
(Lab-based cell study)
Doxycycline enhanced the replication of an experimental viral-based cancer vaccine in many tumor cell lines, leading to increased sensitivity to these therapies. These therapies used in conjunction with doxycycline led to increased anti-tumor effects. The unexpected and pleiotropic beneficial anti-tumor effects of doxycycline on both immune cell and cancer vaccine therapies make it an excellent candidate for rapid clinical testing.
Met Phase II study of medroxyprogesterone (MPA) plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer.
Mitsuhashi et al, 2016
https://doi.org/10.1093/annonc/mdv539
(Small patient trial)
Metformin inhibited disease relapse after MPA therapy. The combination of metformin and MPA in endometrial cancer treatment should be studied further.
Stat Statin use and survival in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone or enzalutamide after docetaxel failure: the international retrospective observational STABEN study
Gordon et al (2018)
https://doi.org/10.18632/oncotarget.24888
(Retrospective patient study)
In this retrospective cohort of 598 patients treated with second-line abiraterone or enzalutamide after docetaxel for metastatic castration-resistant prostate cancer, statin use was significantly associated with both prolonged overall survival and cancer-specific survival and increased early > 30% PSA declines. A clinical trial is now needed.
Met Isolated and combined action of tamoxifen and metformin in wild-type, tamoxifen-resistant, and estrogen-deprived MCF-7 cells
Berstein et al., 2011
https://link.springer.com/article/10.1007/s10549-010-1072-z
(Lab-based cell study)
Metformin interacts additively with tamoxifen to reduce tumor cell growth.