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The COC Protocol™ in Ovarian Cancer

This document is a summary of the rationale and some of the current scientific evidence which supports the use of the COC Protocol medications alongside standard-of-care treatments for ovarian cancer. We understand that cancer is a very personal condition, and every patient has a unique set of challenges. For more information regarding your own personal situation please get in touch with the Care Oncology Clinic at +44 20 3855 5939 in the UK or 800-392-1353 in the United States, or visit the website at https://careoncology.com.

If you are new to Care Oncology please note the following:

  1. You do not need to travel. You can meet with our team of oncologists and oncology nurses through secure video for ongoing support.
  2. The Care Oncology adjunct protocol medications are shipped directly to your home from our US Partner Pharmacies and can be used alongside your standard of care treatment.
  3. We are incredibly proud to announce that we have passed the Validation Institute’s extremely rigorous validation process of data analysis, outcome claims, and value calculation. We have worked hard to get to this point. Early on, we recognized the tremendous value a responsibly delivered program of repurposed drugs offered to cancer patients, yet, it was not being offered at scale. Four years ago, we set out to change this knowing it was a marathon, not a sprint.

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The COC Protocol and ovarian cancer: Key points

  • The COC Protocol is a combination of four commonly prescribed medications (atorvastatin, metformin, mebendazole, and doxycycline) with the potential to target ovarian cancer and help improve the effectiveness of standard anticancer therapies.
  • A number of observational studies have linked metformin or statin use to improved survival outcomes in patients with ovarian cancer.
  • Laboratory studies using ovarian cancer cells grown in the lab show that metformin and statins can directly target and damage ovarian cancer cells – weakening them and making them more vulnerable to standard treatments.
  • Other cell-based studies show that doxycycline can target hard-to-treat ovarian cancer stem cells, and can help stop ovarian cancer cells producing MMP molecules, which are used by the cancer cell to spread around the body.
  • Mebendazole-related drugs have been shown to suppress tumor blood vessel growth in a mouse model of ovarian cancer.
  • One study has found that metformin can enhance the activity of the PARP inhibitor olaparib in BRCA positive ovarian cancer cells grown in the lab, and in mice with BRCA positive ovarian cancer tumors. Other lab studies have also shown that doxycycline itself can have PARP inhibitor-like activity on ovarian cancer cells.
  • Ascites (i.e. abdominal fluid build-up) can be a problem for some patients with ovarian cancer, and there is some early-stage evidence which suggests the COC Protocol medications may have a role to play in managing or potentially reducing ascites volume.
  • Laboratory and observational data for the COC Protocol medications in ovarian cancer are encouraging. More patient data from randomized clinical trials and other relevant clinical studies are needed.
  • Safety is our top priority. Care Oncology doctors supervise your treatment to minimize risk of polypharmacy.

The COC Protocol and ovarian cancer: Published evidence

The COC Protocol is a combination regime of four commonly prescribed medications, each with evidence of metabolically-based anticancer activity, and well understood safety profiles. These medications are: metformin, atorvastatin, doxycycline, and mebendazole. Some of the studies which support the use of the COC Protocol as an adjunctive therapy alongside current standard treatments for ovarian cancer are presented below. This evidence mainly comes from laboratory studies and large epidemiological studies (which investigate links between taking medications and ovarian cancer outcomes in groups of individuals).

You may notice that many of the studies below only focus on individual COC Protocol medications. We are the first to design an adjunct therapy which combines all four. We believe that combining these medications will achieve the greatest results, and our own research program, called METRICS, is already producing more of the evidence needed to show this. You can read more about why we believe these medications work together so well to help target cancer, and about the METRICS program itself, in further sections below.

Metformin and ovarian cancer

Observational studies associate metformin with improvements in ovarian cancer survival

Metformin is a very widely used as a treatment for type 2 diabetes to lower blood glucose levels. Observational studies in groups of diabetic patients with ovarian cancer have associated the use of metformin following diagnosis of cancer with better cancer survival outcomes in these patients, including improved overall survival and longer time before cancer progresses (Gong et al., 2019). Some of the beneficial effect of metformin reported by these observational studies may partly be due to the fact that metformin can control the patients’ underlying diabetes and help reduce other associated risk factors which are linked to worse outcomes in ovarian cancer (Irie et al., 2016). However, there is observational evidence that better rates of survival are linked specifically to metformin use, and not just diabetes management. For example, Kumar et al (2013) found that in patients with ovarian cancer, those who were diabetic and took metformin had a higher rate of cancer survival over 5 years (67%) compared to either non-diabetics who did not take metformin (47%), or diabetics who took other types of diabetic treatment (40%) (Kumar et al., 2013).

Metformin can enhance chemotherapy and PARP inhibitor effectiveness in cell studies

Cancer cells require huge amounts of energy, and laboratory studies using ovarian cancer cells grown in dishes show that metformin can inhibit their growth, survival and potential ability to spread by targeting and blocking a number of different molecular processes, including those involved in energy metabolism (Fu et al., 2017; Lengyel et al., 2015; Ma et al., 2019; Tang et al., 2018; Zou et al., 2019). Evidence from cell and small animal studies also suggests that metformin can work in combination with standard ovarian cancer therapies, helping to improve their sensitivity and decrease resistance of cancer cells to these treatments (Lee et al., 2019; Xu et al., 2018; Yang et al., 2019). This is how we believe metformin can bring the most benefit to patients with ovarian cancer – by helping to improve the effectiveness of their usual treatments. For example, in a study in mice with ovarian cancer, the combination of metformin and chemotherapy drug paclitaxel reduced tumor weight by as much as 60%, greater than either drug alone (Lengyel et al., 2015). In another study, cancer cells which had spread were isolated from a patient with advanced ovarian cancer and tested for sensitivity to metformin in combination with different chemotherapies. The researchers found that metformin enhanced the sensitivity of the cells to platinum-based chemotherapies – and they suggested that this method could potentially be used to determine the best combination of treatments for individual patients with ovarian cancer (Liu et al., 2018).

Cell based studies have also showed that metformin can enhance the activity of the PARP inhibitor olaparib in BRCA positive ovarian cancer cells grown in the lab and in mice with BRCA positive ovarian cancer tumors (Hijaz et al., 2016). In this study using both olaparib and metformin in combination inhibited cancer cell growth to a greater extent than using either treatment alone.

Clinical trials for metformin as an adjunctive treatment in ovarian cancer are now underway

Although not all observational studies based on patient populations have found evidence that metformin can benefit survival in ovarian cancer (Wang et al., 2019), the level of positive observational evidence combined with the exciting mechanistic findings from laboratory-based studies have ensured that metformin is now in several clinical trials as an adjunctive treatment for ovarian cancer. Recent results from a small pilot trial in diabetic patients with epithelial ovarian cancer have demonstrated encouraging results showing that patients who took metformin alongside their standard chemotherapy had reduced levels of some molecules which can indicate cancer progression compared to patients who had only standard chemotherapy (Zheng et al., 2019). In this study patients who took metformin also tended to have a slightly longer length of time before their cancer progressed compared to those who did not, although the researchers could not demonstrate whether this was because of metformin, or if these results had just occurred by chance. More studies will help to clarify just how and when metformin can help patients with ovarian cancer.

Statins and ovarian cancer

Statins have been around for decades, and are still in regular use as a long-term treatment to help manage chronic cardiovascular conditions. The potential anticancer properties of statins have also been studied for many years. Laboratory studies show that statins, particularly fat-soluble ‘lipophilic’ statins like atorvastatin (Kato et al., 2010) can block growth, division, and spread of ovarian cancer cells grown in dishes, and slow ovarian tumor growth in mice (Jones et al., 2017; Kobayashi et al., 2015, 2018). In a study in mice with late-stage epithelial ovarian cancer, intraperitoneal (i.e. injected into the abdomen) treatment with statins led to regression of advanced-stage disease and induced death of tumor cells which had spread (Greenaway et al., 2016).

Importantly, work on cells grown in the lab also show that statins can help sensitize ovarian cancer cells to standard ovarian cancer treatments, including doxorubicin, a chemotherapy drug used to treat ovarian cancer that has relapsed (Martirosyan et al., 2010; Taylor-Harding et al., 2010).

Observational studies link statins to better ovarian cancer outcomes

An observational study of older patients who had recently undergone surgery to treat ovarian cancer found that those who were prescribed statins for cardiovascular conditions following surgery were more likely to survive longer than those who did not take statins. This improved survival following statin use was noted regardless of whether the type of ovarian cancer was serous (a more aggressive type of ovarian cancer), or non-serous (Vogel et al., 2017). An observational study which tracked outcomes for patients with epithelial ovarian cancer has also reported similar findings (Couttenier et al., 2017).

Results from other observational studies disagree with these findings however (Chen et al., 2016), or find that patients with some types of ovarian cancer may benefit more than others (Verdoodt et al., 2017).

Nevertheless, a large study which grouped together results from 8 separate studies, including the ones discussed above, to include almost 20,000 patients with ovarian cancer found that overall, use of statins following diagnosis of ovarian cancer was associated with improved survival and reduced likelihood of death (from any cause) during the study follow-up periods (which ranged from 6 months to 4.5 years).

A recently presented preliminary report of a large observational study further supports this finding. The study, which looked at ovarian cancer outcomes for up to 10,000 patients in Finland, found that those who took lipophilic statins (such as atorvastatin) had a 43% reduction in ovarian cancer-related mortality compared to patients who never used statins. Reductions in ovarian cancer-specific mortality were noted across all different types of ovarian cancer studied, including patients with serous tumors. These results were presented at a recent conference and have not yet been published in a peer-reviewed journal (Visvanathan et al., 2020). However, the findings were striking enough for the researchers to call for the initiation of clinical trials investigating statins as a treatment for ovarian cancer.

This promising observational evidence along with encouraging results from mechanistic laboratory studies combine to offer real hope that statins as an adjunctive treatment alongside standard anticancer therapies may help improve results for some patients with ovarian cancer. Further clinical trials in this area are now needed, and underway (Kobayashi et al., 2018).

Mebendazole and ovarian cancer

Mebendazole, a member of the benzimidazole drug family, is widely and safely used to treat parasitic infections in both children and adults. Interest in mebendazole as a potential anticancer treatment is relatively new, and mostly based on promising mechanistic studies and compelling reports from case studies in cancer patients (Nygren and Larsson, 2014; Pantziarka et al., 2014). Based on this preliminary evidence, a number of clinical trials have now been initiated to investigate mebendazole as an adjunctive treatment for cancer.

Emerging laboratory evidence is also starting to show that benzimidazoles may also help to target ovarian cancer. In a screening study, mebendazole was found to have some activity against ovarian cancer cell lines grown in the lab (Nygren et al., 2013). In other studies, the related drug albendazole was able to effectively suppress tumor blood vessel growth in a mouse model of ovarian cancer (Pourgholami et al., 2010), and also blocked the growth of chemotherapy-resistant ovarian cancer cells grown in dishes (Chu et al., 2009).

Doxycycline and ovarian cancer

Apart from being an effective antibiotic, doxycycline also possesses other extremely valuable properties, including anti-inflammatory and anticancer activity. This gives doxycycline real therapeutic potential in treating cancer (Bahrami et al., 2012).

A number of lab studies suggest doxycycline may have anticancer potential against ovarian cancer. A 2010 lab study found that doxycycline was able to block ovarian cancer cell production of molecules called MMPs, which help cancer cells to spread around the body (Roomi et al., 2010). Other studies suggest that doxycycline can target ovarian cancer stem cells. These are a particularly treatment-resistant type of cancer cell which can be responsible for relapse (Lamb et al., 2015a; Sotgia et al., 2018).

Cell work also shows that doxycycline and other tetracyclines are quite potent inhibitors of the enzyme PARP, which is known to be active in cancer (Szabo et al., 2006), and which is the target of ovarian cancer PARP inhibitor therapies (i.e. olaparib). These and other mechanisms of action have led some researchers to suggest that doxycycline may have a role as an effective enhancer of biological anticancer therapies (Tang et al., 2013).

Ascites and the COC Protocol

Ascites is an often uncomfortable build-up of fluid in the abdominal cavity. Ascites can be caused by many different cancers, particularly abdominal cancers such as ovarian and gynecological cancers. Around a third of all patients with ovarian cancer will develop ascites (Kipps et al., 2013). Symptoms can be relieved in various ways, for example by physically draining the fluid, or by using diuretic medications. There is also some evidence that the COC Protocol medications may also have a role to play in managing or potentially reducing ascites volume. Separate studies using mouse models of ovarian cancer and fibrosarcoma have found that both metformin and statins can reduce tumor growth and volume of ascites (Al-Wahab et al., 2015; Wakai et al., 1994; Wu et al., 2014), and an observational study which followed patients with liver cirrhosis (another cause of ascites) associated statin use with a decreased risk of developing ascites (Gu et al., 2019). Mebendazole has also been shown to induce the death and prevent growth of cells derived from malignant ascites (i.e. ascites containing cancer cells) grown in the lab (Pinto et al., 2015, 2019).

Our own evidence: The METRICS Study

What is METRICS?

METRICS is our own in-house research program. A great deal is already known about the safety and effectiveness of the COC Protocol medications in cancer. But it is also our responsibility to acknowledge that we don’t have all the answers, and that we still need to generate good quality clinical research investigating the COC Protocol in patients with cancer, to ensure the COC Protocol is as effective and safe as it can be.

To enable us to fund this research, we have developed a novel, affordable system where our clinical study, METRICS, is essentially ‘patient-funded’. Every consenting patient who enters the clinic is enrolled into METRICS, and these fees are helping to fund the study. This is a new model of clinical research, aimed at bridging the funding and data gaps which are currently hindering the repurposing and further clinical development of already licensed medications.

METRICS first results

In a first success for METRICS, results from our initial pilot study were recently published in the peer-reviewed scientific journal Frontiers in Pharmacology. The paper can be accessed freely online here.

The METRICS pilot study was an observational retrospective study, which means that our researchers looked back and analyzed patient clinical records to find out what happened. They collected data and recorded the outcomes from 95 patients with an advanced type of brain cancer called glioblastoma who attended the Care Oncology Clinic and who took the full COC Protocol alongside their usual standard treatments. This study did not have a control group, so our researchers compared the results from METRICS with previously published results from earlier studies in patients with the same type of cancer, and who also took standard-of-care treatments.

Initial results suggest that patients who attended our clinic and took the COC Protocol as part of their usual care were much more likely to survive at least 2 years (64.0% of patients in our study survived at least 2 years, compared to 27-29% for patients included in previously published studies), and tended to have longer survival times overall than would usually be expected for patients with this type of cancer (patients survived an average of 27 months in our study, compared to 15-16 months in earlier studies)(Agrawal et al., 2019).

These results are extremely promising, but they are also still preliminary. We don’t yet know exactly how the COC Protocol may have impacted survival times for example, or how other factors such as certain patient characteristics may have also influenced these results. But this first, initial evidence is certainly encouraging, and it suggests to us that we are heading in the right direction. Our next planned stage is to conduct a larger, well-designed study. You can find out more about future METRICS plans by looking online or contacting the clinic.

More about the COC Protocol

What is the COC Protocol?

The COC Protocol is a combination treatment regimen comprised of licensed medications, specifically designed by Care Oncology for adjunctive use alongside a patient’s usual treatments (i.e. standard-of-care).

The four medications included in the COC Protocol regimen are: metformin, a very common anti-diabetes drug; atorvastatin, a type of statin used to manage cardiovascular conditions; doxycycline, a type of antibiotic often used to treat chronic infections like acne; and mebendazole, a medicine commonly used to treat parasite infections in children and adults.

We chose these four medications from thousands of potential candidates specifically because they fit our predetermined selection criteria. These criteria include solid evidence of effectiveness against cancer, a coherent mechanism of action, and importantly, a good safety profile. These three central tenets have shaped our approach from the very beginning.

Safety is paramount

Cancer is a complex disease with complex treatments, and we believe that the addition of further therapies alongside standard treatments should be very carefully evaluated. Not just from the perspective of effectiveness, but also, importantly, in terms of safety. This is why our whole approach is based on evidence – mostly published scientific studies, and also, increasingly, our own data.

Many different medications on the market have at least some published evidence supporting their relatively effective use in cancer, but few of these medications have the level of evidence of both safety and effectiveness that we require for the COC Protocol. Large amounts of detailed data already exist for each of the protocol medications, garnered from years of use in the general population – and this helped to give us a crucial head-start during development.

We have painstakingly searched through decades of published data on each of the COC Protocol medications, exploring how they work in different patient populations (including patients with cancer), and on cell and animal models in the lab. These data, alongside our own clinical experience, help to ensure that we have a good understanding of how these medications will behave in patients with differing stages and types of cancer, both in combination with each other and also in combination with numerous other cancer therapies. This knowledge is paramount, and from our studies, this type of evidence is just not there yet for many other off‑label anticancer drug candidates – especially when given in combination.

An anti-metabolic therapy which can potentially target any cancer

The COC Protocol is designed to work by restricting the overall ability of cancer cells to take up and use (i.e. ‘metabolize’) energy.

Cancer cells need huge amounts of energy to survive, and the vast majority of cancers use an adaptive process called aerobic glycolysis to generate the excessive energy they need (Kroemer and Pouyssegur, 2008). Each of the medications in the protocol can target the various molecular metabolic processes involved in and surrounding aerobic glycolysis, and this can help lower the overall metabolic rate of the cancer cell (Jang et al., 2013).

We believe the COC Protocol medications can work in combination to consistently restrict energy supply and use, while simultaneously preventing cancer cells from adapting and using other pathways to take up energy (Jagust et al., 2019). As a result, cancer cells become increasingly weaker and less able to take in and use the nutrients (e.g. such as glucose and essential amino acids glutamine and arginine) they need from their surroundings (Andrzejewski et al., 2018; Liu et al., 2016). This makes it more difficult overall for cancer cells to survive, grow, and spread in the body. Gradually, the weakened cells (including more resilient and previously treatment-resistant cells) become more vulnerable to attack from other cell‑killing cancer therapies such as radiotherapy, chemotherapy, hormonal therapy, and targeted therapies (Bradford and Khan, 2013; Chen et al., 2012; Lacerda et al., 2014; Lamb et al., 2015b; Pantziarka et al., 2014).

By targeting the adapted metabolic mechanisms which are common to most cancers (but not usually healthy cells), we believe that the COC Protocol can be effective and selective for virtually any cancer regardless of specific type, stage, or location of cancer. Published epidemiological and lab studies increasingly support the potentially broad range of this therapy (Chae et al., 2015, 2016; Iliopoulos et al., 2011; Lamb et al., 2015a; Pantziarka et al., 2014).

Mechanistic coherence in action- the power of combination

The true power of the COC Protocol lies in the specific combination of medications we use. We developed the protocol not just as a regimen of four individual treatments each with anticancer activity, but also to work as a single combined treatment – with the potential to produce powerful synergistic effects (Mokhtari et al., 2017).

Each medication in the COC Protocol targets cancer cell metabolism in a distinct and complementary way, and we have termed this action ‘mechanistic coherence’. Put simply, mechanistic coherence describes how each medication can attack the cancer cell from a different angle. For example, cancer stem cells are a particularly resilient type of cancer cell, and each medication targets these cells in a different way: metformin targets the cell’s ‘batteries’ (called mitochondria) by making it very difficult for mitochondria to run the molecular reactions they need to produce energy, doxycycline blocks the cell-DNA machinery that mitochondria need to replicate and repair (Skoda et al., 2019), statins can alter cancer stem cell gene expression, making the cells more sensitive to other cancer therapies (Kodach et al., 2011), and mebendazole can interrupt numerous molecular processes involved in cell division to help block cancer stem cell growth (Hothi et al., 2012; Hou et al., 2015).

By combining all four agents together, the COC Protocol can hit cancer stem cells (and other cancer cells) across multiple ‘weak spots’, and like a one-two punch, this leaves the cells less able to dodge and recover.

Lab studies are beginning to highlight the effectiveness of this approach using COC Protocol medication combinations. In mechanistic studies, combining statin and metformin greatly decreases the growth of prostate and endometrial cancer cells more than either agent alone (Kim et al., 2019; Wang et al., 2017). Observational studies have also reported potentially ‘synergistic’ effects of these medications against various cancers (Babcook et al., 2014; Danzig et al., 2015; Lehman et al., 2012; Nimako et al., 2017). A clinical trial investigating metformin and doxycycline in breast cancer is now underway (NCT02874430), and our own research program, METRICS, is now also beginning to produce promising data.

A long-term adjunctive therapy

The COC Protocol is primarily designed to be a long-term ‘adjunctive’ therapy, to help optimize standard treatments. However, as metabolic treatment with the COC Protocol is intended to run long-term, patients may also take the protocol as a maintenance regime after standard treatment has been completed or during breaks from standard treatment and as part of a long-term strategy to mitigate the risk of recurrence or metastases. For this reason, it is also worth noting that each of the COC Protocol medications also has reported beneficial mechanisms of action in cancer which are not dependent on the co-administration of standard therapies, and which may independently help to reduce the risk of relapse and metastatic spread.

The Care Oncology model

Active medical supervision of each patient

Although the COC Protocol medications have been used safely in the general population for many years, they are not without side-effects. In addition, every patient’s situation is both complex, and unique- requiring careful, personalized assessment. This is why every patient who attends the Care Oncology Clinic is placed under the direct care of clinicians with specialist knowledge of prescribing the COC Protocol medications in the context of cancer. Our clinicians individually assess the potential benefits and risks involved in taking the COC Protocol with each patient. They will only recommend the COC Protocol to patients when they believe it will be safe and beneficial to do so. Each COC Protocol prescription is tailored to the needs of the patient, and doses and regimens are carefully reviewed and adjusted based on how the patient progresses.

It is therefore essential that patients are carefully monitored at our clinic throughout the course of their treatment.


Important Notice

Purpose of this article

This article is an overview of some of the scientific and medical published literature concerning the medications which comprise the patented Care Oncology protocol. Care has been taken to select relevant articles supporting the off-label use of these medicines in a clinical setting for the adjunct treatment of cancer. This article does not purport to be a comprehensive review of all the evidence, nor does it capture all of the potential side-effects of such treatment.

This article is for information purposes only and it does NOT constitute medical advice. The medicines discussed herein are available on prescription-only and should not be taken without consultation with your doctor or other professional healthcare provider. Care Oncology doctors will discuss the suitability of these medicines with you and will liaise with your doctor or oncologist to discuss their suitability for you.

You must NOT rely on the information in this article as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter you should consult your doctor or other professional healthcare provider. If you think you may be suffering from any medical condition you should seek immediate medical attention. You should never delay seeking medical advice, disregard medical advice, or discontinue medical treatment because of information contained in this article.


The copyright in this article is owned by Health Clinics USA Corp and its licensors.


The Care Oncology (“COC”) Protocol is protected by United States patent US9622982B2 and by various additional international patents.




Agrawal, S., Vamadevan, P., Mazibuko, N., Bannister, R., Swery, R., Wilson, S., and Edwards, S. (2019). A New Method for Ethical and Efficient Evidence Generation for Off-Label Medication Use in Oncology (A Case Study in Glioblastoma). Front. Pharmacol. 10.

Al-Wahab, Z., Mert, I., Tebbe, C., Chhina, J., Hijaz, M., Morris, R.T., Ali-Fehmi, R., Giri, S., Munkarah, A.R., and Rattan, R. (2015). Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction. Oncotarget 6, 10908–10923.

Andrzejewski, S., Siegel, P.M., and St-Pierre, J. (2018). Metabolic Profiles Associated With Metformin Efficacy in Cancer. Front. Endocrinol. 9.

Babcook, M.A., Shukla, S., Fu, P., Vazquez, E.J., Puchowicz, M.A., Molter, J.P., Oak, C.Z., MacLennan, G.T., Flask, C.A., Lindner, D.J., et al. (2014). Synergistic Simvastatin and Metformin Combination Chemotherapy for Osseous Metastatic Castration-Resistant Prostate Cancer. Mol. Cancer Ther. 13, 2288–2302.

Bahrami, F., Morris, D.L., and Pourgholami, M.H. (2012). Tetracyclines: drugs with huge therapeutic potential. Mini Rev. Med. Chem. 12, 44–52.

Bradford, S.A., and Khan, A. (2013). Individualizing Chemotherapy using the Anti-Diabetic Drug, Metformin, as an “Adjuvant”: An Exploratory Study. J. Cancer Sci. Ther. 5.

Chae, Y.K., Yousaf, M., Malecek, M.-K., Carneiro, B., Chandra, S., Kaplan, J., Kalyan, A., Sassano, A., Platanias, L.C., and Giles, F. (2015). Statins as anti-cancer therapy; Can we translate preclinical and epidemiologic data into clinical benefit? Discov. Med. 20, 413–427.

Chae, Y.K., Arya, A., Malecek, M.-K., Shin, D.S., Carneiro, B., Chandra, S., Kaplan, J., Kalyan, A., Altman, J.K., Platanias, L., et al. (2016). Repurposing metformin for cancer treatment: current clinical studies. Oncotarget 7, 40767–40780.

Chen, H.-Y., Wang, Q., Xu, Q.-H., Yan, L., Gao, X.-F., Lu, Y.-H., and Wang, L. (2016). Statin as a Combined Therapy for Advanced-Stage Ovarian Cancer: A Propensity Score Matched Analysis. BioMed Res. Int. 2016, 9125238.

Chen, J., Lan, T., Hou, J., Zhang, J., An, Y., Tie, L., Pan, Y., Liu, J., and Li, X. (2012). Atorvastatin sensitizes human non-small cell lung carcinomas to carboplatin via suppression of AKT activation and upregulation of TIMP-1. Int. J. Biochem. Cell Biol. 44, 759–769.

Chu, S.W.L., Badar, S., Morris, D.L., and Pourgholami, M.H. (2009). Potent Inhibition of Tubulin Polymerisation and Proliferation of Paclitaxel-resistant 1A9PTX22 Human Ovarian Cancer Cells by Albendazole. Anticancer Res. 29, 3791–3796.

Couttenier, A., Lacroix, O., Vaes, E., Cardwell, C.R., De Schutter, H., and Robert, A. (2017). Statin use is associated with improved survival in ovarian cancer: A retrospective population-based study. PloS One 12, e0189233.

Danzig, M.R., Kotamarti, S., Ghandour, R.A., Rothberg, M.B., Dubow, B.P., Benson, M.C., Badani, K.K., and McKiernan, J.M. (2015). Synergism between metformin and statins in modifying the risk of biochemical recurrence following radical prostatectomy in men with diabetes. Prostate Cancer Prostatic Dis. 18, 63–68.

Fu, Y.-L., Zhang, Q.-H., Wang, X.-W., and He, H. (2017). Antidiabetic drug metformin mitigates ovarian cancer SKOV3 cell growth by triggering G2/M cell cycle arrest and inhibition of m-TOR/PI3K/Akt signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 21, 1169–1175.

Gong, T.-T., Wu, Q.-J., Lin, B., Ruan, S.-K., Kushima, M., and Takimoto, M. (2019). Observational Studies on the Association Between Post-diagnostic Metformin Use and Survival in Ovarian Cancer: A Systematic Review and Meta-Analysis. Front. Oncol. 9, 458.

Greenaway, J.B., Virtanen, C., Osz, K., Revay, T., Hardy, D., Shepherd, T., DiMattia, G., and Petrik, J. (2016). Ovarian tumour growth is characterized by mevalonate pathway gene signature in an orthotopic, syngeneic model of epithelial ovarian cancer. Oncotarget 7, 47343–47365.

Gu, Y., Yang, X., Liang, H., and Li, D. (2019). Comprehensive evaluation of effects and safety of statin on the progression of liver cirrhosis: a systematic review and meta-analysis. BMC Gastroenterol. 19, 231.

Hijaz, M., Chhina, J., Mert, I., Taylor, M., Dar, S., Al-Wahab, Z., Ali-Fehmi, R., Buekers, T., Munkarah, A.R., and Rattan, R. (2016). Preclinical evaluation of olaparib and metformin combination in BRCA1 wildtype ovarian cancer. Gynecol. Oncol. 142, 323–331.

Hothi, P., Martins, T.J., Chen, L., Deleyrolle, L., Yoon, J.-G., Reynolds, B., and Foltz, G. (2012). High-Throughput Chemical Screens Identify Disulfiram as an Inhibitor of Human Glioblastoma Stem Cells. Oncotarget 3, 1124–1136.

Hou, Z.-J., Luo, X., Zhang, W., Peng, F., Cui, B., Wu, S.-J., Zheng, F.-M., Xu, J., Xu, L.-Z., Long, Z.-J., et al. (2015). Flubendazole, FDA-approved anthelmintic, targets breast cancer stem-like cells. Oncotarget 6, 6326–6340.

Iliopoulos, D., Hirsch, H.A., and Struhl, K. (2011). Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 71, 3196–3201.

Irie, H., Banno, K., Yanokura, M., Iida, M., Adachi, M., Nakamura, K., Umene, K., Nogami, Y., Masuda, K., Kobayashi, Y., et al. (2016). Metformin: A candidate for the treatment of gynecological tumors based on drug repositioning. Oncol. Lett. 11, 1287–1293.

Jagust, P., de Luxán-Delgado, B., Parejo-Alonso, B., and Sancho, P. (2019). Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells. Front. Pharmacol. 10.

Jang, M., Kim, S.S., and Lee, J. (2013). Cancer cell metabolism: implications for therapeutic targets. Exp. Mol. Med. 45, e45.

Jones, H.M., Fang, Z., Sun, W., Clark, L.H., Stine, J.E., Tran, A.-Q., Sullivan, S.A., Gilliam, T.P., Zhou, C., and Bae-Jump, V.L. (2017). Atorvastatin exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer in vitro. Am. J. Cancer Res. 7, 2478–2490.

Kato, S., Smalley, S., Sadarangani, A., Chen-Lin, K., Oliva, B., Brañes, J., Carvajal, J., Gejman, R., Owen, G.I., and Cuello, M. (2010). Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase. J. Cell. Mol. Med. 14, 1180–1193.

Kim, J.S., Turbov, J., Rosales, R., Thaete, L.G., and Rodriguez, G.C. (2019). Combination simvastatin and metformin synergistically inhibits endometrial cancer cell growth. Gynecol. Oncol. 0.

Kipps, E., Tan, D.S.P., and Kaye, S.B. (2013). Meeting the challenge of ascites in ovarian cancer: new avenues for therapy and research. Nat. Rev. Cancer 13, 273–282.

Kobayashi, Y., Kashima, H., Wu, R.-C., Jung, J.-G., Kuan, J.-C., Gu, J., Xuan, J., Sokoll, L., Visvanathan, K., Shih, I.-M., et al. (2015). Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 21, 4652–4662.

Kobayashi, Y., Banno, K., Kunitomi, H., Tominaga, E., and Aoki, D. (2018). Current state and outlook for drug repositioning anticipated in the field of ovarian cancer. J. Gynecol. Oncol. 30.

Kodach, L.L., Jacobs, R.J., Voorneveld, P.W., Wildenberg, M.E., Verspaget, H.W., van Wezel, T., Morreau, H., Hommes, D.W., Peppelenbosch, M.P., van den Brink, G.R., et al. (2011). Statins augment the chemosensitivity of colorectal cancer cells inducing epigenetic reprogramming and reducing colorectal cancer cell “stemness” via the bone morphogenetic protein pathway. Gut 60, 1544–1553.

Kroemer, G., and Pouyssegur, J. (2008). Tumor Cell Metabolism: Cancer’s Achilles’ Heel. Cancer Cell 13, 472–482.

Kumar, S., Meuter, A., Thapa, P., Langstraat, C., Giri, S., Chien, J., Rattan, R., Cliby, W., and Shridhar, V. (2013). Metformin intake is associated with better survival in ovarian cancer: a case-control study. Cancer 119, 555–562.

Lacerda, L., Reddy, J.P., Liu, D., Larson, R., Li, L., Masuda, H., Brewer, T., Debeb, B.G., Xu, W., Hortobágyi, G.N., et al. (2014). Simvastatin radiosensitizes differentiated and stem-like breast cancer cell lines and is associated with improved local control in inflammatory breast cancer patients treated with postmastectomy radiation. Stem Cells Transl. Med. 3, 849–856.

Lamb, R., Ozsvari, B., Lisanti, C.L., Tanowitz, H.B., Howell, A., Martinez-Outschoorn, U.E., Sotgia, F., and Lisanti, M.P. (2015a). Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease. Oncotarget 6, 4569–4584.

Lamb, R., Fiorillo, M., Chadwick, A., Ozsvari, B., Reeves, K.J., Smith, D.L., Clarke, R.B., Howell, S.J., Cappello, A.R., Martinez-Outschoorn, U.E., et al. (2015b). Doxycycline down-regulates DNA-PK and radiosensitizes tumor initiating cells: Implications for more effective radiation therapy. Oncotarget 6, 14005–14025.

Lee, J., An, S., Jung, J.H., Kim, K., Kim, J.Y., An, I.-S., and Bae, S. (2019). MUL1 E3 ligase regulates the antitumor effects of metformin in chemoresistant ovarian cancer cells via AKT degradation. Int. J. Oncol. 54, 1833–1842.

Lehman, D.M., Lorenzo, C., Hernandez, J., and Wang, C. (2012). Statin Use as a Moderator of Metformin Effect on Risk for Prostate Cancer Among Type 2 Diabetic Patients. Diabetes Care 35, 1002–1007.

Lengyel, E., Litchfield, L.M., Mitra, A.K., Nieman, K.M., Mukherjee, A., Zhang, Y., Johnson, A., Bradaric, M., Lee, W., and Romero, I.L. (2015). Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models. Am. J. Obstet. Gynecol. 212, 479.e1-479.e10.

Liu, X., Romero, I.L., Litchfield, L.M., Lengyel, E., and Locasale, J.W. (2016). Metformin targets central carbon metabolism and reveals mitochondrial requirements in human cancers. Cell Metab. 24, 728–739.

Liu, Y., Feng, Y., Liu, H., Wu, J., Tang, Y., and Wang, Q. (2018). 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. Oncol. Lett. 16, 4253–4262.

Ma, L., Wei, J., Wan, J., Wang, W., Wang, L., Yuan, Y., Yang, Z., Liu, X., and Ming, L. (2019). Low glucose and metformin-induced apoptosis of human ovarian cancer cells is connected to ASK1 via mitochondrial and endoplasmic reticulum stress-associated pathways. J. Exp. Clin. Cancer Res. CR 38, 77.

Martirosyan, A., Clendening, J.W., Goard, C.A., and Penn, L.Z. (2010). Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance. BMC Cancer 10, 103.

Mokhtari, R.B., Homayouni, T.S., Baluch, N., Morgatskaya, E., Kumar, S., Das, B., and Yeger, H. (2017). Combination therapy in combating cancer. Oncotarget 8, 38022–38043.

Nimako, G.K., Wintrob, Z.A.P., Sulik, D.A., Donato, J.L., and Ceacareanu, A.C. (2017). Synergistic Benefit of Statin and Metformin in Gastrointestinal Malignancies. J. Pharm. Pract. 30, 185–194.

Nygren, P., and Larsson, R. (2014). Drug repositioning from bench to bedside: Tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer. Acta Oncol. 53, 427–428.

Nygren, P., Fryknäs, M., Ågerup, B., and Larsson, R. (2013). Repositioning of the anthelmintic drug mebendazole for the treatment for colon cancer. J. Cancer Res. Clin. Oncol. 139, 2133–2140.

Pantziarka, P., Bouche, G., Meheus, L., Sukhatme, V., and Sukhatme, V.P. (2014). Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent. Ecancermedicalscience 8.

Pinto, L.C., Soares, B.M., Pinheiro, J. de J.V., Riggins, G.J., Assumpção, P.P., Burbano, R.M.R., and Montenegro, R.C. (2015). The anthelmintic drug mebendazole inhibits growth, migration and invasion in gastric cancer cell model. Toxicol. Vitro Int. J. Publ. Assoc. BIBRA 29, 2038–2044.

Pinto, L.C., Mesquita, F.P., Soares, B.M., da Silva, E.L., Puty, B., de Oliveira, E.H.C., Burbano, R.R., and Montenegro, R.C. (2019). Mebendazole induces apoptosis via C-MYC inactivation in malignant ascites cell line (AGP01). Toxicol. Vitro Int. J. Publ. Assoc. BIBRA 60, 305–312.

Pourgholami, M.H., Cai, Z.Y., Badar, S., Wangoo, K., Poruchynsky, M.S., and Morris, D.L. (2010). Potent inhibition of tumoral hypoxia-inducible factor 1alpha by albendazole. BMC Cancer 10, 143.

Roomi, M.W., Monterrey, J.C., Kalinovsky, T., Rath, M., and Niedzwiecki, A. (2010). In vitro modulation of MMP-2 and MMP-9 in human cervical and ovarian cancer cell lines by cytokines, inducers and inhibitors. Oncol. Rep. 23, 605–614.

Skoda, J., Borankova, K., Jansson, P.J., Huang, M.L.-H., Veselska, R., and Richardson, D.R. (2019). Pharmacological targeting of mitochondria in cancer stem cells: An ancient organelle at the crossroad of novel anti-cancer therapies. Pharmacol. Res. 139, 298–313.

Sotgia, F., Ozsvari, B., Fiorillo, M., De Francesco, E.M., Bonuccelli, G., and Lisanti, M.P. (2018). A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX. Cell Cycle Georget. Tex 17, 2091–2100.

Szabo, C., Pacher, P., and Swanson, R.A. (2006). Novel modulators of poly(ADP-ribose) polymerase. Trends Pharmacol. Sci. 27, 626–630.

Tang, G., Guo, J., Zhu, Y., Huang, Z., Liu, T., Cai, J., Yu, L., and Wang, Z. (2018). Metformin inhibits ovarian cancer via decreasing H3K27 trimethylation. Int. J. Oncol. 52, 1899–1911.

Tang, H., Sampath, P., Yan, X., and Thorne, S.H. (2013). Potential for enhanced therapeutic activity of biological cancer therapies with doxycycline combination. Gene Ther. 20, 770–778.

Taylor-Harding, B., Orsulic, S., Karlan, B.Y., and Li, A.J. (2010). Fluvastatin and cisplatin demonstrate synergistic cytotoxicity in epithelial ovarian cancer cells. Gynecol. Oncol. 119, 549–556.

Verdoodt, F., Kjaer Hansen, M., Kjaer, S.K., Pottegård, A., Friis, S., and Dehlendorff, C. (2017). Statin use and mortality among ovarian cancer patients: A population-based cohort study. Int. J. Cancer 141, 279–286.

Visvanathan, K., Modur, S., Artama, M., and Murtola, T. (2020). Lipophilic Statins show promise for treatment of epithelial ovarian cancer. (Online), p.

Vogel, T.J., Goodman, M.T., Li, A.J., and Jeon, C.Y. (2017). Statin treatment is associated with survival in a nationally representative population of elderly women with epithelial ovarian cancer. Gynecol. Oncol. 146, 340–345.

Wakai, K., Ohmura, E., Satoh, T., Murakami, H., Isozaki, O., Emoto, N., Demura, H., Shizume, K., and Tsushima, T. (1994). Mechanism of inhibitory actions of minocycline and doxycycline on ascitic fluid production induced by mouse fibrosarcoma cells. Life Sci. 54, 703–709.

Wang, Y., Liu, X., Yan, P., Bi, Y., Liu, Y., and Zhang, Z.-J. (2019). No Effect of Metformin on Ovarian Cancer Survival: A Systematic Review and Meta-Analysis of Cohort Studies. Curr. Pharm. Des. 25, 2595–2601.

Wang, Z.-S., Huang, H.-R., Zhang, L.-Y., Kim, S., He, Y., Li, D.-L., Farischon, C., Zhang, K., Zheng, X., Du, Z.-Y., et al. (2017). Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells in Vitro and in Vivo. Biol. Pharm. Bull. 40, 1247–1254.

Xu, S., Yang, Z., Jin, P., Yang, X., Li, X., Wei, X., Wang, Y., Long, S., Zhang, T., Chen, G., et al. (2018). Metformin Suppresses Tumor Progression by Inactivating Stromal Fibroblasts in Ovarian Cancer. Mol. Cancer Ther. 17, 1291–1302.

Yang, C., Zhao, N., Li, D., Zou, G., and Chen, Y. (2019). Metformin improves the sensitivity of ovarian cancer cells to chemotherapeutic agents. Oncol. Lett. 18, 2404–2411.

Zheng, Y., Zhu, J., Zhang, H., Liu, Y., and Sun, H. (2019). Metformin plus first-line chemotherapy versus chemotherapy alone in the treatment of epithelial ovarian cancer: a prospective open-label pilot trial. Cancer Chemother. Pharmacol.

Zou, G., Bai, J., Li, D., and Chen, Y. (2019). Effect of metformin on the proliferation, apoptosis, invasion and autophagy of ovarian cancer cells. Exp. Ther. Med. 18, 2086–2094.