The COC Protocol™ in Head and Neck Cancer
This document is a summary of some of the current scientific evidence which supports the use of the COC Protocol medications alongside standard-of-care treatments for head and neck 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 (0) 20 3855 5939 in the UK or 800-392-1353 in the United States, or visit the website at https://careoncology.com.
The COC Protocol and head and neck cancer: Key points
- The COC Protocol is a combination of four commonly prescribed medications (atorvastatin, metformin, mebendazole, and doxycycline) with the potential to target head and neck cancers and help improve the effectiveness of standard anticancer therapies.
- Research suggests that metabolic-targeted treatments may help to improve head and neck cancer outcomes.
- Reports from an early-stage ‘window of opportunity’ clinical trial in patients with head and neck cancer suggest that short term treatment with metformin may have induced biological effects such as altering the way tumor cells can generate and use energy, and also modulating immune cells around the tumor.
- An observational study which followed patients with head and neck cancer undergoing standard treatment found that statin use at the time of cancer diagnosis was linked to better rates of survival at 2 years (81%, compared to 69% for those without statin use).
- Some evidence suggests statins may also help to mitigate certain radiotherapy side-effects for head and neck cancer patients.
- Evidence from a cell and animal studies show each of the COC medications can target and prevent head and neck cancer cell growth and division. In addition, lab studies show that statins and metformin may help to sensitize these cancer cells to standard and targeted therapies.
- Safety is our top priority. Care Oncology doctors supervise your treatment to minimize risk of polypharmacy.
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The COC Protocol and head and neck 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 head and neck cancer are presented below. This evidence mainly comes from cell and animal laboratory studies, large epidemiological studies (a type of patient study which can investigate links between taking medications and cancer outcomes in groups of individuals), and early-stage patient trials.
You may notice that the studies we discuss 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. 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 further sections below.
Types of head and neck cancer
Head and neck cancer is a general term that usually refers to cancers which start in areas related to the mouth, nose, throat and pharynx (the area connecting the nose, mouth, and throat), larynx (voice box), and sinuses.
The most common types of head and neck cancer develop from the cells which line the outer surface of these areas, and are called squamous cell carcinomas (SCC). Cancers which develop in the salivary glands are quite rare, and they are usually classified as adenocarcinomas or adenoid cystic carcinomas.
Head and neck cancers are usually given specific names based on where the cancer develops. These terms can be quite complicated. You can find out more about the different types of head and neck cancers and their locations on the head and neck cancer pages of Cancer.net here, or the Head and Neck Cancer Factsheet at Cancer.gov here.
Metformin and head and neck cancer
Metformin is widely used to lower blood glucose levels in patients with type 2 diabetes. The drug can also target the glucose-based molecular processes cancer cells use to generate energy (called glycolytic metabolism). Cell and animal studies suggest that head and neck cancer cells generally rely on glucose-based metabolism to generate their energy, and may be very sensitive to treatment with metformin (Curry et al., 2013; Verma et al., 2018).
Patient studies for metformin in head and neck cancer
An early-stage ‘window of opportunity’ clinical trial and individual case studies have generated some compelling evidence in support of metformin use for head and neck cancer.
Metformin may alter the way tumor cells can generate and use energy: In a recent small trial, around 40 patients with newly diagnosed head and neck cancer were treated with metformin for at least 9 days before surgery. Cell samples taken pre-and post-metformin treatment were compared. Metformin appeared to increase levels of molecular markers which indicated changes to metabolism in the area surrounding the tumor (tumor microenvironment), and increased levels of cancer cell death (apoptosis)(Curry et al., 2017).
Metformin may modulate the immune environment around tumors: Further analysis of samples from this trial provided additional evidence that metformin might also modulate immune cells in the tumor microenvironment (Curry et al., 2018). Researchers believe that modulating the immune system in this way help to target head and neck cancer (Miyauchi et al., 2019).
Other Phase 1 studies which have treated patients with head and neck SCC with metformin alongside radiotherapy and/or chemotherapy have also reported ‘encouraging’ rates of overall survival and time before disease progression, supporting the growing momentum for larger trials (Gulati et al., 2020; MacKenzie et al., 2012).
Case studies with metformin
Metformin in combination to treat a rare type of head and neck cancer: A published case study reports successful treatment of two patients with sinonasal undifferentiated carcinoma, a rare but aggressive type of cancer which affects the nose and sinuses, using a combination of metformin and chemotherapeutic drugs (Ansari et al., 2013). The specific combination was chosen following protein analysis of the tumor makeup. Metformin was chosen in part because of its known activity against harder to treat cancer stem cells (Patil, 2020; Wu et al., 2019b). Protein analysis of tumor samples from these patients also revealed strong levels of mTOR and other proteins known to be targeted by metformin (Miyauchi et al., 2019).
Metformin for laryngeal (throat) cancer: A different case study series has also reported encouraging outcomes for three non-diabetic patients with mouth or laryngeal SCC. Following standard treatment, each patient was then treated with metformin and followed for between 3 and 33 months. The authors report that all three patients had ‘partial or complete’ regression of their remaining precancerous lesions (and did not require further surgery)(Lerner et al., 2017).
Note: these exciting reports are positive, but not definitive. In the case studies above there are no control data, and we have no real way of knowing exactly how much of each patient’s positive response was down to metformin, for example.
What about other patient studies?
Despite the beginnings of some encouraging findings in patient studies, the results of a different type of patient study, called an observational study, is still mixed. These studies investigate any links between metformin use and cancer outcomes in patients with diabetes who are diagnosed with head and neck cancers.
A number of these studies suggest that metformin use could very well be linked to improved survival and better disease response or relapse rates in these patients (Hu et al., 2020b; Spratt et al., 2016; Stokes et al., 2018; Tsou et al., 2019). However, other trials find no link (Kwon et al., 2015; Lee et al., 2019; Quimby et al., 2018).
A recent systematic review which analyzed the survival data reported by seven high-quality studies did not find a beneficial link between metformin use and survival. However, the authors note that their study may have been underpowered (i.e. they could not be sure they had enough data to ensure their findings are reasonably likely to be correct), and they call for more clinical trials (Wang et al., 2020).
What do cell and animal studies say?
Certainly a large number of cell and animal studies do provide supportive evidence of metformin activity in head and neck cancer (for review of studies see (Rêgo et al., 2015)). The table below outlines the findings of a selection of these studies.
In addition, a number of lab studies also report that metformin can help to sensitize head and neck cancer cells to other standard therapies such as chemotherapy or radiation (Harada et al., 2016; Li et al., 2014). Lab-based cell studies have also found that metformin can improve the effects newer more targeted therapies such as tyrosine kinase inhibitors (Lin et al., 2014), CDK4/6 inhibitors (Hu et al., 2020a), and EGFR inhibitors (Yin et al., 2019) in this setting.
Head and Neck Cancer Type
Metformin activity in cell or animal model
Head and neck SCC
Beneficially influences immune cells in the tumor microenvironment
(Amin et al., 2020)
Decreases tumor volume and alters metabolic signature of tumor microenvironment
(Verma et al., 2018)
Inhibits cancer cell growth
(Sikka et al., 2012)
Decreases markers of cancer stem cells- potentially inhibits progression from pre-cancerous lesions
(Wu et al., 2019b)
Oral (mouth) SCC
Slows tumor growth
(Luo et al., 2012; Madera et al., 2015)
Decreases markers of cancer stem cells (these cells can be harder to treat and more prone to resistance)
Increase programmed cell death (apoptosis)
(Guimarães et al., 2016; He et al., 2019; Wang et al., 2016)
Prevents development of tumors from pre-cancerous lesions
(Vitale-Cross et al., 2012)
Nasopharyngeal (nose and throat) cancer
Inhibits cell growth
(Li et al., 2014; Zhao et al., 2011)
Hypopharyngeal (bottom part of the throat) cancer
Suppresses cell growth
(Wu et al., 2019a)
Table presents selected studies which have reported beneficial effects of metformin in head and neck cancer cell and animal models.
Statins and head and neck cancer
Statins are usually prescribed to patients as a long-term treatment to help manage heart and blood vessel-related 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 cancer cells grown in dishes, and slow tumor growth in mice.
Cell studies suggest that statins can target a number of vital molecular pathways in head and neck cancer cells, including the mevalonate pathway, and also pathways involving PI3K/AKT and mTOR. The mevalonate pathway is an important metabolic pathway involved in synthesis of cholesterol, a fatty building block used by cells to build cell membranes and other bits of cellular machinery. The PI3K/AKT and mTOR pathways play crucial roles in regulating head and neck cancer cell survival, growth, and metabolism (i.e. energy generation and use) (Pavan et al., 2015; Ricco et al., 2019).
Patient studies for statins in head and neck cancer
There is a smaller patient-related evidence base for statins in head and neck cancer, but this is growing. For example, a recent large observational patient study has reported a potential link between statins and better outcomes in head and neck cancer.
Statin use linked to improved survival in head and neck cancer: A 2019 study used a large set of US-based patient data (called the SEER-Medicare linked dataset) to analyze the outcomes of patients who were diagnosed with different types of head and neck cancer, and who were taking statins for high cholesterol (hyperlipidemia). They found that patients taking statins were more likely to have better survival compared to patients with hyperlipidemia who were not taking statins, and also, crucially, patients with no hyperlipidemia at all. A total of 81% of patients taking statins in this study had survived their cancer for at least 2 years following diagnosis, compared to 69% of patients in either of the other groups. When the researchers broke the data down further into more specific cancer types, they found this positive trend was maintained for both oral (mouth) disease and oropharyngeal (mouth and throat) disease (Gupta et al., 2019).
A separate observational study based on data from Canadian patients similarly reported better overall survival and disease specific survival in patients with head and neck SCC who were taking statins at the time of diagnosis (Lebo et al., 2018).
And a Phase 1 clinical trial in 26 patients with end-stage SCC of the head and neck or the cervix treated with a 21-day lovastatin cyclical regimen also reports ‘encouraging’ results, with good tolerance and 23% of patients in this study achieving some form of stable disease. It’s worth noting though that the trial had no control group, and was not designed to adequately measure disease response (Knox et al., 2005).
Statins to offset radiotherapy side-effects?
Patients with head and neck cancer who are treated with radiotherapy may be at increased risk of having complications such as stroke or transient ischemic attack. Some studies have investigated if statin use may potentially help offset these risks. An observational study found that taking statins at the time of radiotherapy treatment was linked with a lowered risk of these events for patients with head and neck cancer (Addison et al., 2018). In contrast, a similar study in a different patient group did not find a protective link between statin use and radiotherapy side-effects (Lee et al., 2018), and further work is needed to understand these different findings. The authors suggest it could be due to different patient characteristics, or disease type, for example.
In addition, a Phase 2 clinical trial has produce supportive results suggesting that statin use for 12 months following radiotherapy helped reverse radiation-induced fibrosis in patients with head and neck cancer (Addison et al., 2016). And a preclinical study in mice also reported that statin therapy helped to protect against radiation-induced salivary gland dysfunction (Xu et al., 2016).
Cell studies show statins can kill head and neck cancer cells
Cell and animal studies do support these early encouraging studies of patient data. An influential 2015 systematic review of ‘preclinical’ (i.e. non-human) cell and animal studies painstakingly analyzed the best quality data from 153 published studies which investigated statin use in head and neck cancers (just 14 out of 153 papers passed its strict criteria) (Pavan et al., 2015). The review concluded that statins have a ‘significant effect’ on head and neck SCC cells grown in the lab, by negatively affecting cell viability, reducing cell division and growth, and encouraging cell death. This paper is available open access, and has a good summary table of study findings (Pavan et al., 2015).
The review also noted that several studies report enhanced activity of standard therapies in the presence of statins, for example, lovastatin and gefitinib together increased cell death to up to 90%. Although results from these studies were mixed for a number of different standard therapies, the systematic review concluded that evidence was sufficient that statins should be assessed clinically (i.e. in patient studies) as an adjuvant agent supporting chemotherapy or radiotherapy treatments in head and neck cancer (Pavan et al., 2015). Other cell studies since then have also continued to add to this supportive evidence. They report potential anticancer effects of statins (alone or in combination with other treatments) for head and neck SCCs (Ricco et al., 2019), nasopharyngeal cancer stem cells (Peng et al., 2017), oral cancer cells (Biselli-Chicote et al., 2019), and others.
Mebendazole and head and neck cancer
Mebendazole, a member of the benzimidazole drug family, is widely 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 (Bai et al., 2011; Nygren and Larsson, 2014; Pantziarka et al., 2014). Based on this preliminary evidence, a number of clinical trials are now currently investigating mebendazole as an adjunctive treatment for cancer.
Benzimidazoles can target head and neck cancer cells in the lab
A 2017 cell-based study found that mebendazole alone was able to slow growth, division, and movement of head and neck SCC cells. When mebendazole was used in combination with cisplatin, both drugs worked together (i.e. ‘synergized’) to block cell growth and induce pre-programmed cell death (apoptosis) (Zhang et al., 2017). In a different study, mebendazole and a related compound called flubendazole both reduced the viability and migratory (movement) ability of oral SCC, and also pre-cancerous oral keratinocyte cells. Normal oral keratinocyte cells were found to be less sensitive to treatment. Further investigation suggested that the benzimidazoles were able to inhibit molecular processes involved in helping cancer cells transition into cells which can invade and spread to other tissues (Kralova et al., 2018).
A conference abstract available online also presents data from research suggesting that mebendazole may be active against adenoid cystic carcinoma (ACC) cells. ACC is a rare cancer which is most commonly diagnosed in the salivary glands, with limited treatment options. In this article (note: which was not published in a scientific journal, and so did not undergo a rigorous review process), mice with tumors grown from patient samples of both aggressive and less aggressive ACC tended to survive longer and had slower tumor growth when treated with mebendazole (Barber et al., 2018).
Doxycycline and head and neck cancer
Apart from being an effective antibiotic, doxycycline, a type of tetracycline, may also have real therapeutic potential in targeting cancer (Bahrami et al., 2012).
Data reported from cell studies also hint at the potential for doxycycline activity against head and neck cancer. A lab study from 2010 investigated doxycycline’s ability to block oral SCC cell production of molecules called MMPs. Increased MMPs have been linked to oral SCC ability to spread (metastasis). Studies on oral SCC cells grown in the lab showed that doxycycline was able to reduce production of MMP2 and MMP9 by different mechanisms, and that this reduced production was linked with decreased invasion-potential the cells. Further studies from the same group also showed that doxycycline had a ‘suppressive effect’ on tumor growth in mice with oral SCC tumors (Shen et al., 2010).
And in an intriguing (and perhaps overlooked) case report from a veterinary journal, veterinary clinicians report treating a case of oral SCC in a bottle nose dolphin with doxycycline and the non-steroidal anti-inflammatory (NSAID) piroxicam. The authors of the report that the combination reduced tumor size and stabilized the disease (March et al., 2016).
Real promise is also emerging through recent research illuminating doxy’s potential to target a harder-to-treat type of cancer cell, called a cancer stem cell. Two recent studies suggest doxy could effectively target cancer stem cells of multiple cancer types (though not yet, as far as we can tell, tested in head and neck cancer cells) by restricting the assembly and activity of important cell components called mitochondria (Lamb et al., 2015a; Scatena et al., 2018; Sotgia et al., 2018). Mitochondria work like ‘batteries’ in cancer cells, generating the energy they need to survive. Restricting mitochondrial activity in cancer cells can severely deplete the cell’s ability to thrive, and particularly to withstand attack by other standard anticancer therapies.
Our own evidence: The METRICS Study
What is METRICS?
METRICS is our own in-house research study. Although our own experience combined with the level of existing research for the individual COC Protocol medications means we are confident prescribing and managing the Protocol for patients with cancer, more good quality clinical research in this area is needed. METRICS helps us to meet this need. Data from METRICS is helping to ensure that our clinicians understand how these medications work in combination, and how best to prescribe the COC Protocol in the context of cancer.
There is a well acknowledged ‘funding gap’ which currently slows down the repurposing and further clinical development of licensed medications for other conditions. We bridge this gap by using patients’ fees to help fund our research. This means METRICS is essentially ‘patient-funded’. This is a new way of funding clinical research.
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.
Why do we only prescribe the COC Protocol?
Cancer is a complex disease with complex treatments, and we believe that the potential benefits and risks of adding any further therapies into this mix should be very carefully evaluated. This is why our whole approach is based on cautious evaluation of evidence. This is also why we only prescribe the COC Protocol, and do not prescribe any other off-label medications.
Our knowledge of the existing research, plus our own clinical experience means we are confident that we have a good understanding how the protocol medications will behave in patients with differing stages and types of cancer, and also in combination with other types of cancer treatments. Although many different medications on the market have at least some published evidence supporting their relatively effective use in cancer, they are not our specialty. Having a solid understanding is extremely important to us. We believe this type and level of evidence is just not there yet for many other off‑label anticancer drug candidates – especially when given in combination.
We chose the four medications included in the COC Protocol from thousands of potential candidates specifically because they fit our predetermined selection criteria. Each medication in the protocol is supported by:
- solid published evidence of effectiveness against cancer. This evidence mainly comes from cell and animal lab studies, observational patient studies, and some small clinical trials (mostly for metformin and statins) and case studies (mebendazole).
- additional evidence of potential ability to work well with the other protocol medications (i.e. a coherent mechanism of action). This evidence is mostly based on cell and animal mechanistic studies, and some observational patient studies (metformin and statins).
- a good overall safety profile in patients. This evidence is mostly based on years of clinical trial and patient study data generated as the medications were originally developed and studied for other conditions. Also some more recent patient data in the context of cancer, including our own recently published research data.
How does the COC Protocol work?
The COC Protocol is designed to work primarily 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).
Why these four medications together?
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 (Mokhtari et al., 2017).
Evidence suggests that each medication in the COC Protocol can target 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 from standard treatments.
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.
Can I take the COC Protocol long-term?
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, and requires 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. We will only recommend the COC Protocol to patients when we 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.
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.
Addison, C.L., Simos, D., Wang, Z., Pond, G., Smith, S., Robertson, S., Mazzarello, S., Singh, G., Vandermeer, L., Fernandes, R., et al. (2016). A phase 2 trial exploring the clinical and correlative effects of combining doxycycline with bone-targeted therapy in patients with metastatic breast cancer. J. Bone Oncol. 5, 173–179.
Addison, D., Lawler, P.R., Emami, H., Janjua, S.A., Staziaki, P.V., Hallett, T.R., Hennessy, O., Lee, H., Szilveszter, B., Lu, M., et al. (2018). Incidental Statin Use and the Risk of Stroke or Transient Ischemic Attack after Radiotherapy for Head and Neck Cancer. J. Stroke 20, 71–79.
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.
Amin, D., Richa, T., Mollaee, M., Zhan, T., Tassone, P., Johnson, J., Luginbuhl, A., Cognetti, D., Martinez-Outschoorn, U., Stapp, R., et al. (2020). Metformin Effects on FOXP3+ and CD8+ T Cell Infiltrates of Head and Neck Squamous Cell Carcinoma. The Laryngoscope 130, E490–E498.
Andrzejewski, S., Siegel, P.M., and St-Pierre, J. (2018). Metabolic Profiles Associated With Metformin Efficacy in Cancer. Front. Endocrinol. 9.
Ansari, M., Guo, S., Fakhri, S., Citardi, M.J., Blanco, A., Patino, M., Buryanek, J., Amato, R., Karni, R., and Brown, R.E. (2013). Sinonasal undifferentiated carcinoma (SNUC): morphoproteomic-guided treatment paradigm with clinical efficacy. Ann. Clin. Lab. Sci. 43, 45–53.
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, R.-Y., Staedtke, V., Aprhys, C.M., Gallia, G.L., and Riggins, G.J. (2011). Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro-Oncol. 13, 974–982.
Barber, J.D., Samizadeh, M., Jia, N., Siders, W., and Kaplan, J. (2018). Abstract 4801: Potential of mebendazole as an anti-tumor agent for adenoid cystic carcinoma and other rare cancers. Cancer Res. 78, 4801–4801.
Biselli-Chicote, P.M., Lotierzo, A.T., Biselli, J.M., Paravino, É.C., and Goloni-Bertollo, E.M. (2019). Atorvastatin increases oxidative stress and inhibits cell migration of oral squamous cell carcinoma in vitro. Oral Oncol. 90, 109–114.
Bradford, S.A., and Khan, A. (2013). Individualizing Chemotherapy using the Anti-Diabetic Drug, Metformin, as an Ã¢ÂÂAdjuvantÃ¢ÂÂ: 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.
Curry, J., Johnson, J., Tassone, P., Vidal, M.D., Menezes, D.W., Sprandio, J., Mollaee, M., Cotzia, P., Birbe, R., Lin, Z., et al. (2017). Metformin effects on head and neck squamous carcinoma microenvironment: Window of opportunity trial. The Laryngoscope 127, 1808–1815.
Curry, J.M., Tuluc, M., Whitaker-Menezes, D., Ames, J.A., Anantharaman, A., Butera, A., Leiby, B., Cognetti, D.M., Sotgia, F., Lisanti, M.P., et al. (2013). Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell Cycle Georget. Tex 12, 1371–1384.
Curry, J.M., Johnson, J., Mollaee, M., Tassone, P., Amin, D., Knops, A., Whitaker-Menezes, D., Mahoney, M.G., South, A., Rodeck, U., et al. (2018). Metformin Clinical Trial in HPV+ and HPV- Head and Neck Squamous Cell Carcinoma: Impact on Cancer Cell Apoptosis and Immune Infiltrate. Front. Oncol. 8, 436.
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.
Guimarães, T.A., Farias, L.C., Santos, E.S., de Carvalho Fraga, C.A., Orsini, L.A., de Freitas Teles, L., Feltenberger, J.D., de Jesus, S.F., de Souza, M.G., Santos, S.H.S., et al. (2016). Metformin increases PDH and suppresses HIF-1α under hypoxic conditions and induces cell death in oral squamous cell carcinoma. Oncotarget 7, 55057–55068.
Gulati, S., Desai, J., Palackdharry, S.M., Morris, J.C., Zhu, Z., Jandarov, R., Riaz, M.K., Takiar, V., Mierzwa, M., Gutkind, J.S., et al. (2020). Phase 1 dose-finding study of metformin in combination with concurrent cisplatin and radiotherapy in patients with locally advanced head and neck squamous cell cancer. Cancer 126, 354–362.
Gupta, A., Stokes, W., Eguchi, M., Hararah, M., Amini, A., Mueller, A., Morgan, R., Bradley, C., Raben, D., McDermott, J., et al. (2019). Statin use associated with improved overall and cancer specific survival in patients with head and neck cancer. Oral Oncol. 90, 54–66.
Harada, K., Ferdous, T., Harada, T., and Ueyama, Y. (2016). Metformin in combination with 5-fluorouracil suppresses tumor growth by inhibiting the Warburg effect in human oral squamous cell carcinoma. Int. J. Oncol. 49, 276–284.
He, Y., Tai, S., Deng, M., Fan, Z., Ping, F., He, L., Zhang, C., Huang, Y., Cheng, B., and Xia, J. (2019). Metformin and 4SC-202 synergistically promote intrinsic cell apoptosis by accelerating ΔNp63 ubiquitination and degradation in oral squamous cell carcinoma. Cancer Med. 8, 3479–3490.
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.
Hu, Q., Peng, J., Jiang, L., Li, W., Su, Q., Zhang, J., Li, H., Song, M., Cheng, B., Xia, J., et al. (2020a). Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma. Cell Death Dis. 11, 925.
Hu, X., Xiong, H., Chen, W., Huang, L., Mao, T., Yang, L., Wang, C., Huang, D., Wang, Z., Yu, J., et al. (2020b). Metformin reduces the increased risk of oral squamous cell carcinoma recurrence in patients with type 2 diabetes mellitus: A cohort study with propensity score analyses. Surg. Oncol. 35, 453–459.
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.
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.
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.
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.
Kralova, V., Hanušová, V., Caltová, K., Špaček, P., Hochmalová, M., Skálová, L., and Rudolf, E. (2018). Flubendazole and mebendazole impair migration and epithelial to mesenchymal transition in oral cell lines. Chem. Biol. Interact. 293, 124–132.
Kroemer, G., and Pouyssegur, J. (2008). Tumor Cell Metabolism: Cancer’s Achilles’ Heel. Cancer Cell 13, 472–482.
Kwon, M., Roh, J.-L., Song, J., Lee, S.-W., Kim, S.-B., Choi, S.-H., and Nam, S.Y. (2015). Effect of metformin on progression of head and neck cancers, occurrence of second primary cancers, and cause-specific survival. The Oncologist 20, 546–553.
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.
Lebo, N.L., Griffiths, R., Hall, S., Dimitroulakos, J., and Johnson-Obaseki, S. (2018). Effect of statin use on oncologic outcomes in head and neck squamous cell carcinoma. Head Neck 40, 1697–1706.
Lee, B.-C., Lin, C.-L., Tsai, H.-H., and Kao, C.-H. (2018). Statin and the Risk of Ischemic Stroke or Transient Ischemic Attack in Head and Neck Cancer Patients with Radiotherapy. J. Stroke 20, 413–414.
Lee, D.J., McMullen, C.P., Foreman, A., Huang, S.H., Lu, L., Xu, W., de Almeida, J.R., Liu, G., Bratman, S.V., and Goldstein, D.P. (2019). Impact of metformin on disease control and survival in patients with head and neck cancer: a retrospective cohort study. J. Otolaryngol. – Head Neck Surg. J. Oto-Rhino-Laryngol. Chir. Cervico-Faciale 48, 34.
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.
Lerner, M.Z., Mor, N., Paek, H., Blitzer, A., and Strome, M. (2017). Metformin Prevents the Progression of Dysplastic Mucosa of the Head and Neck to Carcinoma in Nondiabetic Patients. Ann. Otol. Rhinol. Laryngol. 126, 340–343.
Li, H., Chen, X., Yu, Y., Wang, Z., Zuo, Y., Li, S., Yang, D., Hu, S., Xiang, M., Xu, Z., et al. (2014). Metformin inhibits the growth of nasopharyngeal carcinoma cells and sensitizes the cells to radiation via inhibition of the DNA damage repair pathway. Oncol. Rep. 32, 2596–2604.
Lin, Y.-C., Wu, M.-H., Wei, T.-T., Lin, Y.-C., Huang, W.-C., Huang, L.-Y., Lin, Y.-T., and Chen, C.-C. (2014). Metformin sensitizes anticancer effect of dasatinib in head and neck squamous cell carcinoma cells through AMPK-dependent ER stress. Oncotarget 5, 298–308.
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.
Luo, Q., Hu, D., Hu, S., Yan, M., Sun, Z., and Chen, F. (2012). In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma. BMC Cancer 12, 517.
MacKenzie, M.J., Ernst, S., Johnson, C., and Winquist, E. (2012). A phase I study of temsirolimus and metformin in advanced solid tumours. Invest. New Drugs 30, 647–652.
Madera, D., Vitale-Cross, L., Martin, D., Schneider, A., Molinolo, A.A., Gangane, N., Carey, T.E., McHugh, J.B., Komarck, C.M., Walline, H.M., et al. (2015). Prevention of tumor growth driven by PIK3CA and HPV oncogenes by targeting mTOR signaling with metformin in oral squamous carcinomas expressing OCT3. Cancer Prev. Res. Phila. Pa 8, 197–207.
March, D.T., Blyde, D.J., Bossart, G.D., Begg, A.P., Taylor, D.P., and McClure, V. (2016). Piroxicam and doxycycline treatment for an oral squamous cell carcinoma in an inshore bottlenose dolphin (Tursiops aduncus). Aust. Vet. J. 94, 203–207.
Miyauchi, S., Kim, S.S., Pang, J., Gold, K.A., Gutkind, J.S., Califano, J.A., Mell, L.K., Cohen, E.E.W., and Sharabi, A.B. (2019). Immune Modulation of Head and Neck Squamous Cell Carcinoma and the Tumor Microenvironment by Conventional Therapeutics. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 25, 4211–4223.
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.
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.
Patil, S. (2020). Metformin treatment decreases the expression of cancer stem cell marker CD44 and stemness related gene expression in primary oral cancer cells. Arch. Oral Biol. 113, 104710.
Pavan, L.M.C., Rêgo, D.F., Elias, S.T., De Luca Canto, G., and Guerra, E.N.S. (2015). In vitro Anti-Tumor Effects of Statins on Head and Neck Squamous Cell Carcinoma: A Systematic Review. PloS One 10, e0130476.
Peng, Y., He, G., Tang, D., Xiong, L., Wen, Y., Miao, X., Hong, Z., Yao, H., Chen, C., Yan, S., et al. (2017). Lovastatin Inhibits Cancer Stem Cells and Sensitizes to Chemo- and Photodynamic Therapy in Nasopharyngeal Carcinoma. J. Cancer 8, 1655–1664.
Quimby, A.E., Lebo, N.L., Griffiths, R., Hall, S., Dimitroulakos, J., and Johnson-Obaseki, S. (2018). Does metformin usage improve survival in head and neck squamous cell carcinoma? A population-based study. J. Otolaryngol. – Head Neck Surg. J. Oto-Rhino-Laryngol. Chir. Cervico-Faciale 47, 74.
Rêgo, D.F., Pavan, L.M.C., Elias, S.T., De Luca Canto, G., and Guerra, E.N.S. (2015). Effects of metformin on head and neck cancer: a systematic review. Oral Oncol. 51, 416–422.
Ricco, N., Flor, A., Wolfgeher, D., Efimova, E.V., Ramamurthy, A., Appelbe, O.K., Brinkman, J., Truman, A.W., Spiotto, M.T., and Kron, S.J. (2019). Mevalonate pathway activity as a determinant of radiation sensitivity in head and neck cancer. Mol. Oncol. 13, 1927–1943.
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.
Shen, L.-C., Chen, Y.-K., Lin, L.-M., and Shaw, S.-Y. (2010). Anti-invasion and anti-tumor growth effect of doxycycline treatment for human oral squamous-cell carcinoma–in vitro and in vivo studies. Oral Oncol. 46, 178–184.
Sikka, A., Kaur, M., Agarwal, C., Deep, G., and Agarwal, R. (2012). Metformin suppresses growth of human head and neck squamous cell carcinoma via global inhibition of protein translation. Cell Cycle Georget. Tex 11, 1374–1382.
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.
Spratt, D.E., Beadle, B.M., Zumsteg, Z.S., Rivera, A., Skinner, H.D., Osborne, J.R., Garden, A.S., and Lee, N.Y. (2016). The Influence of Diabetes Mellitus and Metformin on Distant Metastases in Oropharyngeal Cancer: A Multicenter Study. Int. J. Radiat. Oncol. Biol. Phys. 94, 523–531.
Stokes, W.A., Eguchi, M., Amini, A., Hararah, M.K., Ding, D., McDermott, J.D., Bradley, C.J., and Karam, S.D. (2018). Survival impact and toxicity of metformin in head and neck cancer: An analysis of the SEER-Medicare dataset. Oral Oncol. 84, 12–19.
Tsou, Y.-A., Chang, W.-D., Lu, J.-J., Wu, T.-F., Chen, H.-L., Chen, C.-M., and Tsai, M.H. (2019). The effect of metformin use on hypopharyngeal squamous cell carcinoma in diabetes mellitus patients. BMC Cancer 19, 862.
Verma, A., Rich, L.J., Vincent-Chong, V.K., and Seshadri, M. (2018). Visualizing the effects of metformin on tumor growth, vascularity, and metabolism in head and neck cancer. J. Oral Pathol. Med. Off. Publ. Int. Assoc. Oral Pathol. Am. Acad. Oral Pathol. 47, 484–491.
Vitale-Cross, L., Molinolo, A.A., Martin, D., Younis, R.H., Maruyama, T., Patel, V., Chen, W., Schneider, A., and Gutkind, J.S. (2012). Metformin prevents the development of oral squamous cell carcinomas from carcinogen-induced premalignant lesions. Cancer Prev. Res. Phila. Pa 5, 562–573.
Wang, F., Xu, J., Liu, H., Liu, Z., and Xia, F. (2016). Metformin induces apoptosis by microRNA-26a-mediated downregulation of myeloid cell leukaemia-1 in human oral cancer cells. Mol. Med. Rep. 13, 4671–4676.
Wang, Y., Fu, T., Liu, Y., Yang, G., Yu, C., and Zhang, Z.-J. (2020). The Association between Metformin and Survival of Head and Neck Cancer: A Systematic Review and Meta-Analysis of 7 Retrospective Cohort Studies. Curr. Pharm. Des. 26, 3161–3170.
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.
Wu, P., Tang, Y., Fang, X., Xie, C., Zeng, J., Wang, W., and Zhao, S. (2019a). Metformin Suppresses Hypopharyngeal Cancer Growth by Epigenetically Silencing Long Non-coding RNA SNHG7 in FaDu Cells. Front. Pharmacol. 10, 143.
Wu, X., Yeerna, H., Goto, Y., Ando, T., Wu, V.H., Zhang, X., Wang, Z., Amornphimoltham, P., Murphy, A.N., Tamayo, P., et al. (2019b). Metformin Inhibits Progression of Head and Neck Squamous Cell Carcinoma by Acting Directly on Carcinoma-Initiating Cells. Cancer Res. 79, 4360–4370.
Xu, L., Yang, X., Chen, J., Ge, X., Qin, Q., Zhu, H., Zhang, C., and Sun, X. (2016). Simvastatin attenuates radiation-induced salivary gland dysfunction in mice. Drug Des. Devel. Ther. 10, 2271–2278.
Yin, X., Han, S., Song, C., Zou, H., Wei, Z., Xu, W., Ran, J., Tang, C., Wang, Y., Cai, Y., et al. (2019). Metformin enhances gefitinib efficacy by interfering with interactions between tumor-associated macrophages and head and neck squamous cell carcinoma cells. Cell. Oncol. Dordr. 42, 459–475.
Zhang, F., Li, Y., Zhang, H., Huang, E., Gao, L., Luo, W., Wei, Q., Fan, J., Song, D., Liao, J., et al. (2017). Anthelmintic mebendazole enhances cisplatin’s effect on suppressing cell proliferation and promotes differentiation of head and neck squamous cell carcinoma (HNSCC). Oncotarget 8, 12968–12982.
Zhao, L., Wen, Z.-H., Jia, C.-H., Li, M., Luo, S.-Q., and Bai, X.-C. (2011). Metformin induces G1 cell cycle arrest and inhibits cell proliferation in nasopharyngeal carcinoma cells. Anat. Rec. Hoboken NJ 2007 294, 1337–1343.