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The COC Protocol™ in Gynecological Cancers

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 endometrial, cervical, and other rarer gynecological cancers. For information about ovarian cancer, please see our separate patient information sheet on this topic, which you can access here.

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 7580 3266 in the UK or 800-392-1353 in the United States, or visit the website at https://careoncology.com.

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The COC Protocol and gynecological cancers: Key points

  • The COC Protocol is a combination of four commonly prescribed medications (atorvastatin, metformin, mebendazole, and doxycycline) with the potential to target gynecological cancers 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 endometrial and cervical cancer.
  • Laboratory studies using endometrial and cervical cancer cells grown in dishes, or in mice, show that metformin and statins can directly target and damage cancer cells- weakening them and making them more vulnerable to standard treatments.
  • Clinical data from trials suggest that metformin may help to slow growth and division of endometrial cancer cells, and also delay relapse. More trials are needed to confirm this, and are underway.
  • Although most research focuses on endometrial and cervical cancer as these are more common, occasional laboratory studies which have focused on more rare gynecological cancers such as peritoneal cancer, fallopian tube cancer, and vulvar cancer are also encouraging.
  • Ascites (i.e. abdominal fluid build-up) can be a problem for some patients with gynecological cancers, and there is some early-stage evidence to suggest that the COC Protocol medications may have a role to play in managing or potentially reducing ascites volume.
  • Laboratory, observational and early-stage clinical data for the COC Protocol medications in gynecological cancers are encouraging. More patient data from randomized clinical trials and other relevant clinical studies are needed.

The COC Protocol and gynecological cancers: 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 gynecological cancers are presented below. This evidence mainly comes from laboratory studies and large epidemiological studies (which investigate links between taking medications and gynecological cancer outcomes in groups of individuals), and also some smaller clinical trials.

Much of the research published, and presented here, focuses on endometrial and cervical cancer, as these are the most common of the gynecological cancers. Where possible, we have also included any evidence we have found which investigates the less common forms of gynecological cancer, including fallopian tube cancer, primary peritoneal cancer, and vulvar and vaginal cancers. You may also want to see our related article about the COC Protocol in ovarian cancer, which is available online, here.

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 do 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 the sections below.

Metformin and gynecological cancers

Metformin is a very widely used as a treatment for type 2 diabetes to lower blood glucose levels. Diabetes and associated conditions such as obesity are established risk factors for gynecological cancers, including endometrial cancer, cervical cancer, and vulvar cancer (Anastasi et al., 2018; Jiamset and Hanprasertpong, 2016). Metformin is also well understood to have anticancer activity at the cellular level, and this has fueled research investigating whether metformin could be of benefit to patients with gynecological cancers.

Observational studies associate metformin with improvements in endometrial cancer survival

Many observational studies in patients with diabetes have associated the use of metformin with better outcomes for patients who develop gynecological cancers, especially for endometrial cancers, where studies have associated metformin use with improved overall survival and longer time before disease progression (Meireles et al., 2017; Xie et al., 2017), as well as reduced chance of cancer relapse for some patients (i.e. for obese patients with estrogen-dependent endometrial cancer (Chu et al., 2018; Hall et al., 2016)).

In one retrospective study which looked at outcomes for diabetic patients with advanced endometrial cancer, average (median) overall survival time was longer for those who used metformin (45.6 months), compared to those who did not use metformin (12.5 months), and also patients who did not have diabetes and did not use metformin (28.5 months) (Ezewuiro et al., 2016).

Positive findings for ‘window-of-opportunity’ clinical studies for metformin in endometrial cancer

The evidence record associating metformin use with better outcomes for patients with endometrial cancer is especially well progressed- and at least five small open-label ‘window-of-opportunity’ trials in patients have shown that women who took metformin in the few weeks between their diagnosis of endometrial cancer and treatment-related surgery had molecular changes suggestive of reduced endometrial cancer cell growth and division (i.e. proliferation)(Laskov et al., 2014; Mitsuhashi et al., 2014; Schuler et al., 2015; Sivalingam et al., 2016; Zhao et al., 2018).

Two window-of-opportunity clinical studies, including one randomized controlled trial did not find any difference with metformin (Kitson et al., 2019; Soliman et al., 2016). However this result could partially be explained by the results of a recently published analysis on patients with endometrial cancer which found molecular differences in the tumors of patients who responded well to metformin vs. those who did not (Bateman et al., 2019).

Clinical data hints that metformin may help to delay relapse in endometrial cancer

In an interesting Phase 2 study from 2016, patients with atypical endometrial hyperplasia or endometrial cancer took metformin alongside standard fertility-sparing hormone-based therapy. Metformin was then continued after the hormone-based therapy had finished until the patient had conceived or disease had relapsed. Just 10% of patients relapsed during the follow-up time (average 3 years), compared to an expected 26-47% relapse rate found in other studies where patients had only hormone-based therapy. The authors suggest that metformin helped to inhibit endometrial cancer recurrence following successful hormone-based treatment (Mitsuhashi et al., 2016), and that this combination for treatment of endometrial cancer requires further study.

An interesting published case study also reports that a 79 year old woman with diabetes and advanced endometrial cancer who had curative surgery followed by long-term metformin therapy (as she was not able to have standard chemo/radiotherapy), had no signs of disease relapse after 45 months (Sato et al., 2017). The authors speculate that although this result cannot necessarily be attributed to metformin, it nevertheless adds weight to the call for more investigation in clinical trials.

Metformin and cervical cancer- encouraging observational results

A few observational studies have investigated the association between metformin use and better outcomes for cervical cancer, with generally positive findings (Han et al., 2016; Hanprasertpong et al., 2017) (although one study found no effect (Takiuchi et al., 2017)). In the 2017 Hanprasertpong study, which involved 248 diabetic patients diagnosed with cervical cancer, researchers found that metformin use was associated with a lower cancer recurrence rate following treatment with standard therapies. A total of 81.6% patients who took metformin were free of disease for 5 years following standard treatment, compared to 65.1% of patients who did not take metformin (Hanprasertpong et al., 2017).

More robust and well-controlled trial data are obviously needed, and studies are now underway for both endometrial cancer and cervical cancer, including one Phase II trial investigating if metformin can help make cervical tumors more susceptible to chemo-radiotherapy (trial no. NCT02394652). These and other trials will help to clarify just which patients with endometrial and cervical cancer could benefit most from metformin, and how.

Metformin can enhance chemotherapy effectiveness in cell studies

The encouraging clinical results for metformin use in patients with gynecological cancers are underpinned by solid mechanistic evidence from cell and animal studies.

Cancer cells require huge amounts of energy to thrive, and metformin is thought to slow cancer cell activity by targeting and blocking a number of different molecular processes the cell needs to generate and metabolize that energy. Lab studies report that metformin can reduce the ability of endometrial and cervical cancer cells grown in dishes or animal models to survive, grow, divide, and move (Imai et al., 2015; Irie et al., 2016; Kim et al., 2019b; Xia et al., 2017; Yudhani et al., 2019). The cells also become more vulnerable to standard treatments such as chemotherapy, hormone-based therapy, and radiation therapy (Bai et al., 2018; Dong et al., 2012; Liu et al., 2017; Tyszka-Czochara et al., 2017; Zhuo et al., 2016). In this way, metformin can potentially help to improve standard treatment effectiveness at the cellular level, and decrease levels of treatment resistance.

Importantly, one recent laboratory study on endometrial cancer cells grown in dishes has also investigated the addition of metformin and statin in combination (similar to the combination found in the COC Protocol). The study found that treating the cells with both drugs together helped to block endometrial cancer cell growth to a greater extent than was found using either medication alone (Kim et al., 2019a), an effect which is known as ‘synergism’. This finding aligns with predictions and emerging data from our own research, that combining COC Protocol medications can potentially produce the greatest effect (you can read more about this theory, and our own data, below).

Metformin and rare gynecological cancers

Some observational studies have also included patients with more rare gynecological cancers as part of their study cohort. Fallopian tube cancer and peritoneal cancer are sometimes associated with ovarian cancers, and you may wish to see our paper on COC Protocol metabolic treatment of ovarian cancer, which is available online here. Briefly, Wang et al (2017) measured associations between metformin use and survival in a group of over 500 diabetic patients with either ovarian cancer, fallopian tube cancer, or peritoneal cancer, and found that patients who continuously took metformin were more likely to have a longer time before their cancer returned and longer overall survival times than those not taking metformin (Wang et al., 2017a).

Studies in mice have also shown that metformin can help to suppress peritoneal tumor growth and increase survival in these animals, and also reduce the spread (metastasis) of ovarian cancer cells to the peritoneum, possibly in part by helping to modulate the body’s own immune system (Al-Wahab et al., 2015; Hirayama et al., 2019; Sun et al., 2019).

Statins and gynecological cancers

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 and interestingly, some types of statin seem to work better than others. For example, fat-soluble ‘lipophilic’ statins (i.e. such as atorvastatin, which is used in the COC Protocol) have been shown to reduce survival of endometrial and cervical cancer cells grown in dishes with much more efficiency than non-lipophilic statins (Kato et al., 2010; Schointuch et al., 2014).

Evidence for statin benefits in cervical cancer is building

For cervical cancer, results of a laboratory screening study hint that statins may be particularly effective against this type of cancer (Dimitroulakos et al., 2002), while other cell studies have found that that statins can block the growth and division and induce cell death of both HPV positive and HPV negative cervical cancer cells (Crescencio et al., 2009; Lin et al., 2019). At least one observational study also adds weight to these findings, reporting that in patients with stage 1B to IV cervical cancer who had undergone treatment-related surgery, time until disease progression and overall survival time was significantly longer for the group of patients who also took lipophilic statins (from before cancer diagnosis) than for those who did not take statins at all (Song et al., 2017). Results of a small early-stage Phase 1 (i.e. primarily safety focused) clinical trial in patients with very advanced squamous cell carcinomas of the head and neck or the cervix who were treated with lovastatin were also reported as ‘encouraging’, with 23% of these end-stage patients achieving stable disease for 3 or more months (Knox et al., 2005).

Observational studies link statins to better endometrial cancer outcomes

A number of observational studies link statin use to improved outcomes for patients with endometrial cancer (Arima et al., 2018; Feng et al., 2016; Nevadunsky et al., 2015; Sperling et al., 2018). For example, one study which compared outcomes for patients with high-grade endometrial cancer who took statins for cardiovascular conditions found that statin use was associated with improved overall survival and increased time before disease progression, compared to those who did not use statins (Feng et al., 2016). In a separate observational study which compared a group of 424 newly diagnosed patients with ovarian or endometrial cancer with a group of 341 control patients who had similar lifestyle and other characteristics but who did not have cancer, statin use for more than one year was associated with a reduced risk of being diagnosed with either cancer, and statin use post-cancer diagnosis was associated with better survival of both ovarian and endometrial cancer (Lavie et al., 2013).

As always however, the evidence is not completely clear cut and some studies have found little or no suggested benefit of statins on endometrial cancer outcomes (Segev et al., 2019; Yoon et al., 2015).

Nevertheless, the weight of promising observational evidence combined with encouraging results from mechanistic laboratory studies does offer real hope that statins as an adjunctive treatment alongside standard anticancer therapies may help improve results for some patients with endometrial and cervical cancers. Further clinical trials in this area are now needed to help boost support for statin use in this context.

Evidence for statins and rare gynecological cancers

Elmore et al (2008) retrospectively reviewed cancer outcomes for a group of 126 patients with either epithelial ovarian cancer or primary peritoneal cancer, and found that statin use was associated with longer average (median) time before disease progression (24 months compared to 16 months for non-statin users) and longer overall survival (62 months compared to 46 months for non-statin users) for this group of patients (Elmore et al., 2008). And cell and mouse studies also hint that statins can be effective against rare types of gynecological cancer. Although little research has been done directly investigating metabolic treatment of primary peritoneal cancer, high levels of a protein called RhoA have been found in some cancers, including ovarian cancers which have spread to the peritoneum. Statins can block the activity of RhoA, and lovastatin was shown to decrease metastasis to the peritoneum in a mouse model of ovarian cancer (Horiuchi et al., 2008). Similarly, high RhoA levels have also been found in vulvar cancer cells, and lovastatin was able to decrease the growth and movement of these cells grown in the lab. The authors suggest lovastatin may be a useful treatment to target some types of vulvar cancer (Wang et al., 2016). In a different cell-based lab study, simvastatin reduced the ability of invasive ovarian cancer cells to ‘stick’ to the peritoneal-like membrane, suggesting another way that statins may help to reduce tumor growth in the peritoneum following metastasis (Wagner et al., 2011).

Mebendazole and gynecological cancers

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.

Very little data currently exists for mebendazole in endometrial and other gynecological cancers, however emerging laboratory evidence is starting to show that benzimidazoles may help to target other types of cancer which can be hormone-dependent, such as ovarian cancer and breast cancer. For example, 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).

And studies on breast cancer cells grown in the lab show that mebendazole and other benzimidazoles can slow the growth and division of several different types of breast cancer cells, including cells resistant to chemotherapy (Coyne et al., 2013; Hou et al., 2015; Mukhopadhyay et al., 2002). In one study, mebendazole potently reduced survival of chemotherapy-resistant breast cancer cells by as much as 63.1% (Coyne et al., 2013). Emerging laboratory-based evidence also suggests that benzimidazoles can enhance the activity of standard breast cancer (and gynecological cancer) treatments such as doxorubicin and fluorouracil (Hou et al., 2015).

Doxycycline and gynecological cancers

Aside from being an effective antibiotic, doxycycline also has real therapeutic potential in treating cancer (Bahrami et al., 2012).

At least three lab studies using cells grown in dishes have shown that doxycycline has anticancer potential against cervical cancer. One cell-based study reported that doxycycline blocked cervical cancer cell growth and division, and induced programmed cell death. In this study both HPV positive and negative cervical cancer cell lines were found to be susceptible to doxycycline (Zhao et al., 2016). In a different lab study, doxycycline blocked cervical cancer cell production of molecules called MMPs, which help the cancer cell to spread around the body (Roomi et al., 2010). And a third lab study found that doxycycline can target cervical cancer stem cells- these are a particularly treatment-resistant type of cancer cell which can be responsible for relapse (Yang et al., 2015).

Doxycycline has just reached early clinical trials in breast cancer patients. Results from the first small study, published in October 2018, show that patients with early-stage breast cancer who took doxycycline for just 14 days before surgery reduced levels of molecular markers for presence of cancer stem cells by an average of around 40%. Beneficial effects were noted for all but one of the patients treated (8/9) (Scatena et al., 2018). Larger clinical trials are now underway.

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. For example, around a third of all women 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., 2015a; 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., 2015b; 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., 2019a; 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.

 

 

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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.

Copyright

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

Patent

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

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References

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.

Anastasi, E., Filardi, T., Tartaglione, S., Lenzi, A., Angeloni, A., and Morano, S. (2018). Linking type 2 diabetes and gynecological cancer: an introductory overview. Clin. Chem. Lab. Med. 56, 1413–1425.

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

Arima, R., Marttila, M., Hautakoski, A., Arffman, M., Sund, R., Ilanne-Parikka, P., Kangaskokko, J., Urpilainen, E., Läärä, E., Hinkula, M., et al. (2018). Antidiabetic Medication, Statins and the Risk and Prognosis of Non-endometrioid Endometrial Cancer in Women with Type 2 Diabetes. Anticancer Res. 38, 4169–4178.

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.

Bai, M., Yang, L., Liao, H., Liang, X., Xie, B., Xiong, J., Tao, X., Chen, X., Cheng, Y., Chen, X., et al. (2018). Metformin sensitizes endometrial cancer cells to chemotherapy through IDH1-induced Nrf2 expression via an epigenetic mechanism. Oncogene 37, 5666–5681.

Bateman, N.W., Teng, P.-N., Hope, E., Hood, B.L., Oliver, J., Ao, W., Zhou, M., Wang, G., Tommarello, D., Wilson, K., et al. (2019). Jupiter microtubule-associated homolog 1 (JPT1): A predictive and pharmacodynamic biomarker of metformin response in endometrial cancers. Cancer Med.

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, 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, D., Wu, J., Wang, K., Zhao, M., Wang, C., Li, L., and Guo, R. (2018). Effect of metformin use on the risk and prognosis of endometrial cancer: a systematic review and meta-analysis. BMC Cancer 18, 438.

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.

Coyne, C.P., Jones, T., and Bear, R. (2013). Gemcitabine-(C4-amide)-[anti-HER2/neu] Anti-Neoplastic Cytotoxicity in Dual Combination with Mebendazole against Chemotherapeutic-Resistant Mammary Adenocarcinoma. J. Clin. Exp. Oncol. 2.

Crescencio, M.E., Rodríguez, E., Páez, A., Masso, F.A., Montaño, L.F., and López-Marure, R. (2009). Statins inhibit the proliferation and induce cell death of human papilloma virus positive and negative cervical cancer cells. Int. J. Biomed. Sci. IJBS 5, 411–420.

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.

Dimitroulakos, J., Marhin, W.H., Tokunaga, J., Irish, J., Gullane, P., Penn, L.Z., and Kamel-Reid, S. (2002). Microarray and biochemical analysis of lovastatin-induced apoptosis of squamous cell carcinomas. Neoplasia N. Y. N 4, 337–346.

Dong, L., Zhou, Q., Zhang, Z., Zhu, Y., Duan, T., and Feng, Y. (2012). Metformin sensitizes endometrial cancer cells to chemotherapy by repressing glyoxalase I expression. J. Obstet. Gynaecol. Res. 38, 1077–1085.

Elmore, R.G., Ioffe, Y., Scoles, D.R., Karlan, B.Y., and Li, A.J. (2008). Impact of statin therapy on survival in epithelial ovarian cancer. Gynecol. Oncol. 111, 102–105.

Ezewuiro, O., Grushko, T.A., Kocherginsky, M., Habis, M., Hurteau, J.A., Mills, K.A., Hunn, J., Olopade, O.I., Fleming, G.F., and Romero, I.L. (2016). Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy. PloS One 11, e0147145.

Feng, C.H., Miller, C.M., Tenney, M.E., Lee, N.K., Yamada, S.D., and Hasan, Y. (2016). Statin Use Significantly Improves Overall Survival in High-Grade Endometrial Cancer. Int. J. Gynecol. Cancer Off. J. Int. Gynecol. Cancer Soc. 26, 1642–1649.

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.

Hall, C., Stone, R.L., Gehlot, A., Zorn, K.K., and Burnett, A.F. (2016). Use of Metformin in Obese Women With Type I Endometrial Cancer Is Associated With a Reduced Incidence of Cancer Recurrence. Int. J. Gynecol. Cancer Off. J. Int. Gynecol. Cancer Soc. 26, 313–317.

Han, K., Pintilie, M., Lipscombe, L.L., Lega, I.C., Milosevic, M.F., and Fyles, A.W. (2016). Association between Metformin Use and Mortality after Cervical Cancer in Older Women with Diabetes. Cancer Epidemiol. Biomark. Prev. Publ. Am. Assoc. Cancer Res. Cosponsored Am. Soc. Prev. Oncol. 25, 507–512.

Hanprasertpong, J., Jiamset, I., Geater, A., Peerawong, T., Hemman, W., and Kornsilp, S. (2017). The Effect of Metformin on Oncological Outcomes in Patients With Cervical Cancer With Type 2 Diabetes Mellitus. Int. J. Gynecol. Cancer Off. J. Int. Gynecol. Cancer Soc. 27, 131–137.

Hirayama, T., Nagata, Y., Nishida, M., Matsuo, M., Kobayashi, S., Yoneda, A., Kanetaka, K., Udono, H., and Eguchi, S. (2019). Metformin Prevents Peritoneal Dissemination via Immune-suppressive Cells in the Tumor Microenvironment. Anticancer Res. 39, 4699–4709.

Horiuchi, A., Kikuchi, N., Osada, R., Wang, C., Hayashi, A., Nikaido, T., and Konishi, I. (2008). Overexpression of RhoA enhances peritoneal dissemination: RhoA suppression with Lovastatin may be useful for ovarian cancer. Cancer Sci. 99, 2532–2539.

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.

Imai, A., Ichigo, S., Matsunami, K., Takagi, H., and Yasuda, K. (2015). Clinical benefits of metformin in gynecologic oncology. Oncol. Lett. 10, 577–582.

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.

Jiamset, I., and Hanprasertpong, J. (2016). Impact of diabetes mellitus on oncological outcomes after radical hysterectomy for early stage cervical cancer. J. Gynecol. Oncol. 27, e28.

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. (2019a). Combination simvastatin and metformin synergistically inhibits endometrial cancer cell growth. Gynecol. Oncol. 0.

Kim, M.Y., Kim, Y.S., Kim, M., Choi, M.Y., Roh, G.S., Lee, D.H., Kim, H.J., Kang, S.S., Cho, G.J., Shin, J.K., et al. (2019b). Metformin inhibits cervical cancer cell proliferation via decreased AMPK O-GlcNAcylation. Anim. Cells Syst. 23, 302–309.

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.

Kitson, S.J., Maskell, Z., Sivalingam, V.N., Allen, J.L., Ali, S., Burns, S., Gilmour, K., Latheef, R., Slade, R.J., Pemberton, P.W., et al. (2019). PRE-surgical Metformin In Uterine Malignancy (PREMIUM): a Multi-Center, Randomized Double-Blind, Placebo-Controlled Phase III Trial. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 25, 2424–2432.

Knox, J.J., Siu, L.L., Chen, E., Dimitroulakos, J., Kamel-Reid, S., Moore, M.J., Chin, S., Irish, J., LaFramboise, S., and Oza, A.M. (2005). A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix. Eur. J. Cancer 41, 523–530.

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.

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., 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. (2015a). Doxycycline down-regulates DNA-PK and radiosensitizes tumor initiating cells: Implications for more effective radiation therapy. Oncotarget 6, 14005–14025.

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

Laskov, I., Drudi, L., Beauchamp, M.-C., Yasmeen, A., Ferenczy, A., Pollak, M., and Gotlieb, W.H. (2014). Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer. Gynecol. Oncol. 134, 607–614.

Lavie, O., Pinchev, M., Rennert, H.S., Segev, Y., and Rennert, G. (2013). The effect of statins on risk and survival of gynecological malignancies. Gynecol. Oncol. 130, 615–619.

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.

Lin, C.-K., Liu, S.-T., Chang, C.-C., and Huang, S.-M. (2019). Regulatory mechanisms of fluvastatin and lovastatin for the p21 induction in human cervical cancer HeLa cells. PloS One 14, e0214408.

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., Murray-Stewart, T., Casero, R.A., Kagiampakis, I., Jin, L., Zhang, J., Wang, H., Che, Q., Tong, H., Ke, J., et al. (2017). Targeting hexokinase 2 inhibition promotes radiosensitization in HPV16 E7-induced cervical cancer and suppresses tumor growth. Int. J. Oncol. 50, 2011–2023.

Meireles, C.G., Pereira, S.A., Valadares, L.P., Rêgo, D.F., Simeoni, L.A., Guerra, E.N.S., and Lofrano-Porto, A. (2017). Effects of metformin on endometrial cancer: Systematic review and meta-analysis. Gynecol. Oncol. 147, 167–180.

Mitsuhashi, A., Kiyokawa, T., Sato, Y., and Shozu, M. (2014). Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial. Cancer 120, 2986–2995.

Mitsuhashi, A., Sato, Y., Kiyokawa, T., Koshizaka, M., Hanaoka, H., and Shozu, M. (2016). Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 27, 262–266.

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.

Mukhopadhyay, T., Sasaki, J., Ramesh, R., and Roth, J.A. (2002). Mebendazole Elicits a Potent Antitumor Effect on Human Cancer Cell Lines Both in Vitro and in Vivo. Clin. Cancer Res. 8, 2963–2969.

Nevadunsky, N.S., Van Arsdale, A., Strickler, H.D., Spoozak, L.A., Moadel, A., Kaur, G., Girda, E., Goldberg, G.L., and Einstein, M.H. (2015). Association Between Statin Use and Endometrial Cancer Survival. Obstet. Gynecol. 126, 144–150.

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.

Sato, E., Nakayama, K., Nakamura, K., Ishikawa, N., Ishikawa, M., Minamoto, T., Ishibashi, T., and Kyo, S. (2017). Efficacy of metformin for advanced-stage endometrial cancer: A case report. Mol. Clin. Oncol. 6, 441–443.

Scatena, C., Roncella, M., Di Paolo, A., Aretini, P., Menicagli, M., Fanelli, G., Marini, C., Mazzanti, C.M., Ghilli, M., Sotgia, F., et al. (2018). Doxycycline, an Inhibitor of Mitochondrial Biogenesis, Effectively Reduces Cancer Stem Cells (CSCs) in Early Breast Cancer Patients: A Clinical Pilot Study. Front. Oncol. 8.

Schointuch, M.N., Gilliam, T.P., Stine, J.E., Han, X., Zhou, C., Gehrig, P.A., Kim, K., and Bae-Jump, V.L. (2014). Simvastatin, an HMG-CoA reductase inhibitor, exhibits anti-metastatic and anti-tumorigenic effects in endometrial cancer. Gynecol. Oncol. 134, 346–355.

Schuler, K.M., Rambally, B.S., DiFurio, M.J., Sampey, B.P., Gehrig, P.A., Makowski, L., and Bae-Jump, V.L. (2015). Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer. Cancer Med. 4, 161–173.

Segev, Y., Gemer, O., Helpman, L., Hag-Yahia, N., Eitan, R., Raban, O., Vaknin, Z., Arie, A.B., Amit, A., Levy, T., et al. (2019). An Israeli Gynecologic Oncology Group study of statin use and endometrial cancer prognosis. Int. J. Gynaecol. Obstet. Off. Organ Int. Fed. Gynaecol. Obstet.

Sivalingam, V.N., Kitson, S., McVey, R., Roberts, C., Pemberton, P., Gilmour, K., Ali, S., Renehan, A.G., Kitchener, H.C., and Crosbie, E.J. (2016). Measuring the biological effect of presurgical metformin treatment in endometrial cancer. Br. J. Cancer 114, 281–289.

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.

Soliman, P.T., Zhang, Q., Broaddus, R.R., Westin, S.N., Iglesias, D., Munsell, M.F., Schmandt, R., Yates, M., Ramondetta, L., and Lu, K.H. (2016). Prospective evaluation of the molecular effects of metformin on the endometrium in women with newly diagnosed endometrial cancer: A window of opportunity study. Gynecol. Oncol. 143, 466–471.

Song, M.-K., Shin, B.-S., Ha, C.-S., and Park, W.-Y. (2017). Would Lipophilic Statin Therapy as a Prognostic Factor Improve Survival in Patients With Uterine Cervical Cancer? Int. J. Gynecol. Cancer Off. J. Int. Gynecol. Cancer Soc. 27, 1431–1437.

Sperling, C.D., Verdoodt, F., Kjaer Hansen, M., Dehlendorff, C., Friis, S., and Kjaer, S.K. (2018). Statin use and mortality among endometrial cancer patients: a Danish nationwide cohort study. Int. J. Cancer 143, 2668–2676.

Sun, C., Li, X., Guo, E., Li, N., Zhou, B., Lu, H., Huang, J., Xia, M., Shan, W., Wang, B., et al. (2019). MCP-1/CCR-2 axis in adipocytes and cancer cell respectively facilitates ovarian cancer peritoneal metastasis. Oncogene.

Takiuchi, T., Machida, H., Hom, M.S., Mostofizadeh, S., Frimer, M., Brunette, L.L., and Matsuo, K. (2017). Association of Metformin Use and Survival Outcome in Women With Cervical Cancer. Int. J. Gynecol. Cancer Off. J. Int. Gynecol. Cancer Soc. 27, 1455–1463.

Tyszka-Czochara, M., Bukowska-Strakova, K., and Majka, M. (2017). Metformin and caffeic acid regulate metabolic reprogramming in human cervical carcinoma SiHa/HTB-35 cells and augment anticancer activity of Cisplatin via cell cycle regulation. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 106, 260–272.

Wagner, B.J., Löb, S., Lindau, D., Hörzer, H., Gückel, B., Klein, G., Glatzle, J., Rammensee, H.-G., Brücher, B.L., and Königsrainer, A. (2011). Simvastatin reduces tumor cell adhesion to human peritoneal mesothelial cells by decreased expression of VCAM-1 and β1 integrin. Int. J. Oncol. 39, 1593–1600.

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, J., Wu, Q., Zhang, L.-H., Zhao, Y.-X., and Wu, X. (2016). The role of RhoA in vulvar squamous cell carcinoma: a carcinogenesis, progression, and target therapy marker. Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med. 37, 2879–2890.

Wang, S.-B., Lei, K.-J., Liu, J.-P., and Jia, Y.-M. (2017a). Continuous use of metformin can improve survival in type 2 diabetic patients with ovarian cancer: A retrospective study. Medicine (Baltimore) 96, e7605.

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. (2017b). 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.

Wu, W., Yu, L.-H., Ma, B., and Xu, M.-J. (2014). The inhibitory effect of doxycycline on cisplatin-sensitive and -resistant epithelial ovarian cancer. PloS One 9, e89841.

Xia, C., Chen, R., Chen, J., Qi, Q., Pan, Y., Du, L., Xiao, G., and Jiang, S. (2017). Combining metformin and nelfinavir exhibits synergistic effects against the growth of human cervical cancer cells and xenograft in nude mice. Sci. Rep. 7, 43373.

Xie, W., Li, T., Yang, J., Shang, M., Xiao, Y., Li, Q., and Yang, J. (2017). Metformin use and survival outcomes in endometrial cancer: a systematic review and meta-analysis. Oncotarget 8, 73079–73086.

Yang, B., Lu, Y., Zhang, A., Zhou, A., Zhang, L., Zhang, L., Gao, L., Zang, Y., Tang, X., and Sun, L. (2015). Doxycycline Induces Apoptosis and Inhibits Proliferation and Invasion of Human Cervical Carcinoma Stem Cells. PloS One 10, e0129138.

Yoon, L.S., Goodman, M.T., Rimel, B.J., and Jeon, C.Y. (2015). Statin use and survival in elderly patients with endometrial cancer. Gynecol. Oncol. 137, 252–257.

Yudhani, R.D., Astuti, I., Mustofa, M., Indarto, D., and Muthmainah, M. (2019). Metformin Modulates Cyclin D1 and P53 Expression to Inhibit Cell Proliferation and to Induce Apoptosis in Cervical Cancer Cell Lines. Asian Pac. J. Cancer Prev. APJCP 20, 1667–1673.

Zhao, Y., Wang, X., Li, L., and Li, C. (2016). Doxycycline inhibits proliferation and induces apoptosis of both human papillomavirus positive and negative cervical cancer cell lines. Can. J. Physiol. Pharmacol. 94, 526–533.

Zhao, Y., Sun, H., Feng, M., Zhao, J., Zhao, X., Wan, Q., and Cai, D. (2018). Metformin is associated with reduced cell proliferation in human endometrial cancer by inbibiting PI3K/AKT/mTOR signaling. Gynecol. Endocrinol. Off. J. Int. Soc. Gynecol. Endocrinol. 34, 428–432.

Zhuo, Z., Wang, A., and Yu, H. (2016). Metformin targeting autophagy overcomes progesterone resistance in endometrial carcinoma. Arch. Gynecol. Obstet. 294, 1055–1061.