Home » The COC Protocol and Blood Cancer

The COC Protocol™ and Blood 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 blood cancers – including leukemia, lymphoma and myeloma. 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.

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

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

Patient Eligibility Form

The COC Protocol and blood cancers: Key points

  • The COC Protocol is a combination of four commonly prescribed medications (atorvastatin, metformin, mebendazole, and doxycycline) with the potential to target blood cancers and help improve the effectiveness of standard anticancer therapies.
  • A number of observational studies have linked metformin or statin use to improved outcomes in patients with different types of blood cancer, including lymphoma, leukaemia, and myeloma.
  • Laboratory studies on blood cancer cells grown in the lab show that metformin and statins can directly target and damage blood cancer cells – weakening them and making them more vulnerable to standard treatments.
  • Some small early-stage clinical studies in patients with blood cancers have reported that statins given alongside standard treatments may help to improve the effectiveness of the treatment. Other trials are negative. More clinical studies are underway.
  • Laboratory studies show that doxycycline can reduce the survival of blood cancer cells grown in the lab.
  • Mebendazole has been shown to kill cancer cells grown in dishes by disrupting special structures inside the cell, called microtubules. Clinical studies to test the effectiveness of mebendazole in patients with cancer are ongoing.

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

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 further sections below.

Diagram of cell breaking down each part's capabilities

Metformin and blood cancers

Some large scale population studies indicate that taking metformin may help patients with blood cancers (Alkhatib et al., 2017; Wu et al., 2014). These studies also suggest that standard anticancer therapies may sometimes be more effective in patients with blood cancer who are taking metformin. For example, in one population study of patients with diffuse large B‑cell lymphoma who were being treated with standard rituximab-based chemo-immunotherapy, diabetic patients who were also taking metformin had a longer time before their lymphoma progressed compared to non-diabetic patients and diabetic patients on other glucose lowering medications (Singh et al., 2013). Further investigations in the lab found that metformin is more effective at killing lymphoma cells sensitive to rituximab, but not those resistant to rituximab (Singh et al., 2013). This finding might explain some of the differences in the effects of metformin reported in lymphoma patients being treated with rituximab (Hicks et al., 2017; Koo et al., 2011).

In a different population study in patients with multiple myeloma who had undergone stem cell transplant, metformin use was associated with a better response to stem cell transplant and a longer time until disease progression (Duma et al., 2017).

Various laboratory studies support these clinical findings. Many studies have found that metformin blocks growth and induces death in a number of lymphoma and myeloma cell types grown in the laboratory or taken from patients (Gu et al., 2015; Rizzieri et al., 2019; Rosilio et al., 2013; Shi et al., 2012; Zi et al., 2015). Other studies have also found that the metabolic and molecular changes induced by metformin in lymphoma and myeloma cells help to improve the potency of anticancer treatments (Chukkapalli et al., 2018; Jagannathan et al., 2015; Patel et al., 2015; Zi et al., 2015).

Laboratory studies also suggest that metformin can benefit patients with leukemia, both by directly acting on cancer cells, and by helping to lower high blood glucose levels, which are sometimes associated with treatment of leukemia (Rosilio et al., 2014; Wang and Wetzler, 2015). This mode-of-action evidence shows that metformin can target, block growth, and destroy leukemia cells through similar anti-metabolic and molecular mechanisms as it uses to damage lymphoma and myeloma cells (Kirito, 2013; Rodríguez-Lirio et al., 2015). It may also have the power to improve the effectiveness of other therapies used to treat leukemia (Sabnis et al., 2016; Velez et al., 2016; Yi et al., 2017). These effects appear wide ranging across a number of different types of leukemia; one study on cells grown in the lab found that metformin was able to block oxygen uptake in 6 different types of leukemia cell (Scotland et al., 2010).

Clinical trials for metformin in blood cancers are slowly starting to get under way, but more are needed. Andresen and Gjertsen have just published an excellent scientific review paper outlining the current status and challenges of running clinical trials for repurposed medications, including metformin and statins, in acute myeloid leukemia (Andresen and Gjertsen, 2019).

Statins and blood cancers

Statins have been widely prescribed for decades, and a large number of population studies provide evidence suggesting that statins may provide anticancer benefits for some people. These studies consistently seem to show that statin use can reduce the risk of developing any blood cancer (Yi et al., 2014); including lymphoma (Cerhan et al., 2007; Cho et al., 2015; Fortuny et al., 2006; Wallace et al., 2013; Ye et al., 2017), leukemia (Pradelli et al., 2015), and multiple myeloma (Chiu et al., 2015; Epstein et al., 2017). Some studies also directly link statins to improved survival in blood cancer patients (although this evidence is more mixed) (Brånvall et al.; Ennishi et al., 2010; Sanfilippo et al., 2016).

This ‘observational’ evidence is supported by many laboratory studies, which show that some types of statin can actively target and damage blood cancer cells grown in the lab (Burke and Kukoly, 2008; Clutterbuck et al., 1998; Crosbie et al., 2013; Dimitroulakos et al., 2000; Matar et al., 1999; Qi et al., 2013; Sassano et al., 2007), and these findings in turn are supported by some early studies in patients.

For example, in one case study from 2001, lovastatin was given to a 72 year old patient with relapsed acute myeloid leukemia who did not want further induction therapy. The researchers found that the patient’s cells grown in the laboratory were sensitive to lovastatin, a statin similar to atorvastatin, and lovastatin was offered to the patient. Lovastatin appeared to control the patient’s leukemic blast cells, and the author’s suggested lovastatin could potentially provide a new way of controlling leukemic cell growth in acute myeloid leukemia patients (Minden et al., 2001).

High cholesterol levels in and around cancer cells can help them thrive and survive attack by anticancer treatments (Codini et al., 2016; Kuzu et al., 2016). Laboratory studies show that statins (which reduce cholesterol levels) can help keep blood cancer cells sensitive to chemotherapy and other treatments, and reduce resistance to these drugs (Lee et al., 2018; Li et al., 2003). Patient studies are now also beginning to support this. A Phase 1 study where patients with acute myeloid leukemia were given increasing doses of pravastatin alongside a standard chemotherapy regimen had encouraging results, particularly in newly diagnosed patients with unfavorable prognosis due to the molecular makeup of their cancer. A total of 80% of these patients achieved a complete response, compared to just 40% for similar patients used as historical controls who had only a standard chemotherapy regimen (Kornblau et al., 2007).

A subsequent Phase 2 study in patients with relapsed acute myeloid leukemia also achieved good results, with 75% of patients achieving an adequate response (Advani et al., 2014). A second Phase 2 trial in patients with untreated acute myeloid leukemia and high-risk myelodysplastic syndrome was stopped early, as although results were still encouraging, they were unlikely to achieve a predefined level of success specified by researchers as an acceptable level of effectiveness (Shadman et al., 2015). Reasons for this are unclear and could in part be related to patient characteristics or trial methodology. Further, larger trials are ongoing .

Early-stage clinical trials in multiple myeloma have also shown positive results. In one small trial of six patients with refractory (i.e. treatment resistant) lymphoma, cancer resistance to standard treatments of bortezomib or bendamustine was reduced when simvastatin was added alongside (Schmidmaier et al., 2007). In another trial with 91 patients with relapsed or refractory multiple myeloma who were being treated with stem cell transplantation therapy, those who were treated with lovastatin alongside thalidomide and dexamethasone (49 patients) had improved responses and better survival compared to those who were given only thalidomide and dexamethasone without lovastatin (Hus et al., 2011). Subsequent studies in the lab showed that a combination of thalidomide and lovastatin was more toxic to cancer cells than either one alone, underlining the importance and potential benefits of using statins as an adjuvant therapy alongside standard treatments.

Despite the benefits, it is still important these medicines are given by specialists who can tailor dosages and regimens to each individual patient and their situation. For example, two small early stage trials in heavily pretreated patients with myeloma found that high doses of a statin may not be beneficial for some patients (Sondergaard et al., 2009; van der Spek et al., 2008).

Doxycycline and blood cancers

Laboratory studies from as far back as 1985 suggested that doxycycline could stop tumor growth and eradicate tumors in rats with leukemia (van den Bogert et al., 1985). Later studies which have since delved deeper into the mode-of-action of doxycycline and other tetracyclines have found doxycycline can directly target blood cancer cells, over and above the traditional anti-bacterial and anti-inflammatory effects (Bahrami et al., 2012; Ferreri et al., 2006). A small unpublished laboratory study (presented at a conference) has also shown that doxycycline can help improve the ability of lenalidomide (a standard therapy for multiple myeloma) to kill multiple myeloma cells. The researchers suggest that addition of doxycycline alongside lenalidomide could potentially help to reduce the therapeutic dose of lenalidomide required, and so help improve side-effects linked to this treatment (Dorjsuren et al., 2019).

In one clinical trial where doxycycline was shown to help patients with a type of MALT lymphoma associated with certain bacterial infections, researchers initially believed the beneficial effects of doxycycline in this context was mostly down to its antibiotic, bacteria‑eradicating properties (Ferreri et al., 2006). But growing evidence suggests that tetracyclines, and specifically doxycycline, are doing more than that. Numerous studies in the laboratory have now shown that doxycycline can directly damage, kill, or initiate processes which can lead to death (i.e. apoptosis) in a number of different types of cancer, including blood cancers (Alexander-Savino et al., 2016; Bahrami et al., 2012; Lamb et al., 2015a; Pulvino et al., 2015; Song et al., 2014; Wang et al., 2015).

Intriguingly, a recent case study in a patient with B-cell lymphoma linked to a bacterial infection found that the patient’s lymphoma activity (which was being treated with chemotherapy, doxycycline, and hydroxychloroquine) aligned with their blood levels of doxycycline, and relapsed when doxycycline was stopped (Melenotte and Raoult, 2017). The authors state that this phenomenon emphasizes the ‘pro-apoptotic’ benefits of doxycycline. Clinical research is ongoing to establish just how and when doxycycline use can benefit patients with blood cancers.

Mebendazole and blood cancers

Scientific interest in mebendazole as a potential anticancer treatment is relatively new, and is mostly based on promising mode-of-action studies and compelling reports from case studies in cancer patients (Nygren and Larsson, 2014; Pantziarka et al., 2014).

Emerging evidence also suggests that mebendazole may have particularly high levels of activity against blood cancers. This is all down to how mebendazole works. Mebendazole is thought to kill cancer cells by disrupting special structures inside the cell, called microtubules. Vincristine, a chemotherapy treatment often used to treat leukemia, lymphoma, and myeloma, works in a similar way. These mechanistic similarities, combined with mebendazole’s relatively low levels of side-effects and good safety record has led to suggestions that mebendazole could actually be used to replace vincristine for treatment of some cancers (De Witt et al., 2017). Numerous clinical trials are now underway to investigate this possibility.

In addition, two separate large scale screening studies have also independently picked up the potential potency of mebendazole against leukemia (Matchett et al., 2016; Nygren et al., 2013). In one of these studies (Nygren et al., 2013), the leukemia panel was the most sensitive to mebendazole out of all cancer types tested. Both screening studies then went on to show that mebendazole can potently and selectively target animal and human leukemia cells in the lab. Flubendazole, which is from the same family as mebendazole and works in a similar way, has also been shown to kill leukemia and myeloma cells in the lab (Spagnuolo et al., 2010).

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

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

Mechanistic coherence in action – the power of combination

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

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

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

Increasingly, evidence from lab studies are beginning to support the effectiveness of our own combinatorial approach. Mechanistic studies have shown that 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). And observational studies have also reported potentially ‘synergistic’ effects of these medications against various cancers (Babcook et al., 2014; Danzig et al., 2015; Lehman et al., 2012; Nimako et al., 2017). A clinical trial investigating metformin and doxycycline in breast cancer is now underway (NCT02874430), and our own research program, METRICS, is now also beginning to produce promising data.

A long-term adjunctive therapy

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

The Care Oncology model

Active medical supervision of each patient

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

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

 

 

*********************************************************************************

Important Notice

Purpose of this article

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

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

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

Copyright

The copyright in this article is owned by Health Clinics Limited and its licensees.

Patent

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

*********************************************************************************

 

 

References

Advani, A.S., McDonough, S., Copelan, E., Willman, C., Mulford, D.A., List, A.F., Sekeres, M.A., Othus, M., and Appelbaum, F.R. (2014). SWOG0919: A Phase 2 Study of Idarubicin and Cytarabine in Combination with Pravastatin for Relapsed Acute Myeloid Leukaemia. Br. J. Haematol. 167, 233–237.

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.

Alexander-Savino, C.V., Hayden, M.S., Richardson, C., Zhao, J., Poligone, B., Alexander-Savino, C.V., Hayden, M.S., Richardson, C., Zhao, J., and Poligone, B. (2016). Doxycycline is an NF-κB inhibitor that induces apoptotic cell death in malignant T-cells. Oncotarget 7, 75954–75967.

Alkhatib, Y., Rahman, Z.A., and Kuriakose, P. (2017). Clinical impact of metformin in diabetic diffuse large B-cell lymphoma patients: a case-control study. Leuk. Lymphoma 58, 1130–1134.

Andresen, V., and Gjertsen, B.T. (2019). Clinical Trials of Repurposing Medicines in Acute Myeloid Leukemia: Limitations and Possibilities in the Age of Precision Therapy. Cancer J. 25, 153.

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

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

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

van den Bogert, C., Dontje, B.H., and Kroon, A.M. (1985). The antitumour effect of doxycycline on a T-cell leukaemia in the rat. Leuk. Res. 9, 617–623.

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.

Brånvall, E., Eloranta, S., Ekberg, S., Birmann, B.M., and Smedby, K.E. Statin Use and Prognosis in 12,865 Non-Hodgkin Lymphoma Patients Treated in the Rituximab-Era. Hematol. Oncol. 35, 230–232.

Burke, L.P., and Kukoly, C.A. (2008). Statins induce lethal effects in acute myeloblastic leukemia [corrected] cells within 72 hours. Leuk. Lymphoma 49, 322–330.

Cerhan, J.R., Fredericksen, Z.S., Liebow, M., Kay, N.E., Witzig, T.E., Call, T.G., Dogan, A., Ristow, K.M., Wang, A.H., Slager, S.L., et al. (2007). Statin Use and Risk of Non-Hodgkin Lymphoma (NHL): Preliminary Results from the Mayo Clinic Case-Control Study. Blood 110, 2615–2615.

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.

Chiu, B.C.-H., Chen, J.-H., Yen, Y.-C., Calip, G.S., Chien, C.-R., Ahsan, H., Shih, Y.-C.T., and Cheng, K.-F. (2015). Long Term Statin Use and Risk of Multiple Myeloma Among 15.5 Million Taiwanese Adults: A Retrospective Cohort Study. Blood 126, 4198–4198.

Cho, S.-F., Yang, Y.-H., Liu, Y.-C., Hsiao, H.-H., Huang, C.-T., Wu, C.-H., Tsai, Y.-F., Wang, H.-C., and Liu, T.-C. (2015). Previous Exposure to Statin May Reduce the Risk of Subsequent Non-Hodgkin Lymphoma: A Nationwide Population-Based Case-Control Study. PLOS ONE 10, e0139289.

Chukkapalli, V., Gordon, L.I., Venugopal, P., Borgia, J.A., Karmali, R., Chukkapalli, V., Gordon, L.I., Venugopal, P., Borgia, J.A., and Karmali, R. (2018). Metabolic changes associated with metformin potentiates Bcl-2 inhibitor, Venetoclax, and CDK9 inhibitor, BAY1143572 and reduces viability of lymphoma cells. Oncotarget 9, 21166–21181.

Clutterbuck, R.D., Millar, B.C., Powles, R.L., Newman, A., Catovsky, D., Jarman, M., and Millar, J.L. (1998). Inhibitory effect of simvastatin on the proliferation of human myeloid leukaemia cells in severe combined immunodeficient (SCID) mice. Br. J. Haematol. 102, 522–527.

Codini, M., Cataldi, S., Lazzarini, A., Tasegian, A., Ceccarini, M.R., Floridi, A., Lazzarini, R., Ambesi-Impiombato, F.S., Curcio, F., Beccari, T., et al. (2016). Why high cholesterol levels help hematological malignancies: role of nuclear lipid microdomains. Lipids Health Dis. 15.

Crosbie, J., Magnussen, M., Dornbier, R., Iannone, A., and Steele, T.A. (2013). Statins inhibit proliferation and cytotoxicity of a human leukemic natural killer cell line. Biomark. Res. 1, 33.

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.

De Witt, M., Gamble, A., Hanson, D., Markowitz, D., Powell, C., Al Dimassi, S., Atlas, M., Boockvar, J., Ruggieri, R., and Symons, M. (2017). Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors. Mol. Med. 23, 50–56.

Dimitroulakos, J., Thai, S., Wasfy, G.H., Hedley, D.W., Minden, M.D., and Penn, L.Z. (2000). Lovastatin induces a pronounced differentiation response in acute myeloid leukemias. Leuk. Lymphoma 40, 167–178.

Dorjsuren, D., Adams, H., Metcalfe, D., and Palau, V. (2019). Finding Novel and Synergistic Cytotoxic Agents for the Treatment of Multiple Myeloma. Appalach. Stud. Res. Forum.

Duma, N., Vera Aguilera, J., Paludo, J., Wang, Y., Anagnostou, T., Fonder, A.L., Buadi, F., Kumar, S., Lacy, M., Hayman, S.R., et al. (2017). Impact of metformin use in the outcomes of multiple myeloma patients post stem cell transplant. J. Clin. Oncol. 35, 8034–8034.

Ennishi, D., Asai, H., Maeda, Y., Shinagawa, K., Ikeda, K., Yokoyama, M., Terui, Y., Takeuchi, K., Yoshino, T., Matsuo, K., et al. (2010). Statin-independent prognosis of patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 21, 1217–1221.

Epstein, M.M., Divine, G., Chao, C.R., Wells, K.E., Feigelson, H.S., Scholes, D., Roblin, D., Ulcickas Yood, M., Engel, L.S., Taylor, A., et al. (2017). Statin use and risk of multiple myeloma: An analysis from the cancer research network. Int. J. Cancer 141, 480–487.

Ferreri, A.J.M., Ponzoni, M., Guidoboni, M., Resti, A.G., Politi, L.S., Cortelazzo, S., Demeter, J., Zallio, F., Palmas, A., Muti, G., et al. (2006). Bacteria-Eradicating Therapy With Doxycycline in Ocular Adnexal MALT Lymphoma: A Multicenter Prospective Trial. JNCI J. Natl. Cancer Inst. 98, 1375–1382.

Fortuny, J., Sanjosé, S. de, Becker, N., Maynadié, M., Cocco, P.L., Staines, A., Foretova, L., Vornanen, M., Brennan, P., Nieters, A., et al. (2006). Statin Use and Risk of Lymphoid Neoplasms: Results from the European Case-Control Study EPILYMPH. Cancer Epidemiol. Prev. Biomark. 15, 921–925.

Gu, J.J., Zhang, Q., Mavis, C., Czuczman, M.S., and Hernandez-Ilizaliturri, F.J. (2015). Metformin Induces p53-Dependent Mitochondrial Stress in Therapy-Sensitive and -Resistant Lymphoma Pre-Clinical Model and Primary Patients Sample with B-Cell Non-Hodgkin Lymphoma (NHL). Blood 126, 4008–4008.

Hicks, A.M., Singh, A., Gu, J., Hare, R., Torka, P., Miller, A., and Hernandez-Ilizaliturri, F.J. (2017). Therapeutic Effects of Metformin in Follicular Lymphoma (FL) Treated with Rituximab in Combination with Bendamustine. Blood 130, 5152–5152.

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.

Hus, M., Grzasko, N., Szostek, M., Pluta, A., Helbig, G., Woszczyk, D., Adamczyk-Cioch, M., Jawniak, D., Legiec, W., Morawska, M., et al. (2011). Thalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage immunomodulatory therapy in patients with relapsed and refractory multiple myeloma. Ann. Hematol. 90, 1161–1166.

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.

Jagannathan, S., Abdel-Malek, M. a. Y., Malek, E., Vad, N., Latif, T., Anderson, K.C., and Driscoll, J.J. (2015). Pharmacologic screens reveal metformin that suppresses GRP78-dependent autophagy to enhance the anti-myeloma effect of bortezomib. Leukemia 29, 2184–2191.

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.

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.

Kirito, K. (2013). Metformin Exerts Anti-Leukemic Effects Via Direct Inhibition Of Oncogenic Kinase Activity In Leukemia Cells Derived From Myeloproliferative Neoplasms. Blood 122, 2853–2853.

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.

Koo, Y.X., Tan, D.S.W., Tan, I.B.H., Tai, D.W.M., Ha, T., Ong, W.S., Quek, R., Tao, M., and Lim, S.T. (2011). Effect of concomitant statin, metformin, or aspirin on rituximab treatment for diffuse large B-cell lymphoma. Leuk. Lymphoma 52, 1509–1516.

Kornblau, S.M., Banker, D.E., Stirewalt, D., Shen, D., Lemker, E., Verstovsek, S., Estrov, Z., Faderl, S., Cortes, J., Beran, M., et al. (2007). Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin + high-dose Ara-C: a phase 1 study. Blood 109, 2999–3006.

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

Kuzu, O.F., Noory, M.A., and Robertson, G.P. (2016). The role of cholesterol in cancer. Cancer Res. 76, 2063–2070.

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

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

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

Lee, J.S., Roberts, A., Juarez, D., Vo, T.-T.T., Bhatt, S., Herzog, L., Mallya, S., Bellin, R.J., Agarwal, S.K., Salem, A.H., et al. (2018). Statins enhance efficacy of venetoclax in blood cancers. Sci. Transl. Med. 10, eaaq1240.

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.

Li, H.Y., Appelbaum, F.R., Willman, C.L., Zager, R.A., and Banker, D.E. (2003). Cholesterol-modulating agents kill acute myeloid leukemia cells and sensitize them to therapeutics by blocking adaptive cholesterol responses. Blood 101, 3628–3634.

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.

Matar, P., Rozados, V.R., Binda, M.M., Roggero, E.A., Bonfil, R.D., and Scharovsky, O.G. (1999). Inhibitory effect of Lovastatin on spontaneous metastases derived from a rat lymphoma. Clin. Exp. Metastasis 17, 19–25.

Matchett, K., Grishagin, I., Kettyle, L., Gavory, G., Harrison, T., Mills, K., and Thompson, A. (2016). Mebendazole: A candidate FDA approved drug for repurposing in leukaemia. Br. J. Haematol. 173, 5–178.

Melenotte, C., and Raoult, D. (2017). Pro-apoptotic effect of doxycycline and hydroxychloroquine on B-cell lymphoma induced by C. burnetii. Oncotarget 9, 2726–2727.

Minden, M.D., Dimitroulakos, J., Nohynek, D., and Penn, L.Z. (2001). Lovastatin Induced Control of Blast Cell Growth in an Elderly Patient with Acute Myeloblastic Leukemia. Leuk. Lymphoma 40, 659–662.

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

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

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

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

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

Patel, P.P., Gu, J.J., Mavis, C., Czuczman, M.S., and Hernandez-Ilizaliturri, F.J. (2015). Metformin enhances the activity of rituximab in B-cell lymphoma pre-clinical models. J. Clin. Oncol. 33, e19513–e19513.

Pradelli, D., Soranna, D., Zambon, A., Catapano, A., Mancia, G., La Vecchia, C., and Corrao, G. (2015). Statins use and the risk of all and subtype hematological malignancies: a meta-analysis of observational studies. Cancer Med. 4, 770–780.

Pulvino, M., Chen, L., Oleksyn, D., Li, J., Compitello, G., Rossi, R., Spence, S., Balakrishnan, V., Jordan, C., Poligone, B., et al. (2015). Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline. Oncotarget 6, 14796–14813.

Qi, X.-F., Zheng, L., Lee, K.-J., Kim, D.-H., Kim, C.-S., Cai, D.-Q., Wu, Z., Qin, J.-W., Yu, Y.-H., and Kim, S.-K. (2013). HMG-CoA reductase inhibitors induce apoptosis of lymphoma cells by promoting ROS generation and regulating Akt, Erk and p38 signals via suppression of mevalonate pathway. Cell Death Dis. 4, e518.

Rizzieri, D., Paul, B., and Kang, Y. (2019). Metabolic alterations and the potential for targeting metabolic pathways in the treatment of multiple myeloma. J. Cancer Metastasis Treat. 5.

Rodríguez-Lirio, A., Pérez-Yarza, G., Fernández-Suárez, M.R., Alonso-Tejerina, E., Boyano, M.D., and Asumendi, A. (2015). Metformin Induces Cell Cycle Arrest and Apoptosis in Drug-Resistant Leukemia Cells.

Rosilio, C., Lounnas, N., Nebout, M., Imbert, V., Hagenbeek, T., Spits, H., Asnafi, V., Pontier-Bres, R., Reverso, J., Michiels, J.F., et al. (2013). The metabolic perturbators metformin, phenformin and AICAR interfere with the growth and survival of murine PTEN-deficient T cell lymphomas and human T-ALL/T-LL cancer cells. Cancer Lett. 336, 114–126.

Rosilio, C., Ben-Sahra, I., Bost, F., and Peyron, J.-F. (2014). Metformin: A metabolic disruptor and anti-diabetic drug to target human leukemia. Cancer Lett. 346, 188–196.

Sabnis, H.S., Bradley, H.L., Tripathi, S., Yu, W.-M., Tse, W., Qu, C.-K., and Bunting, K.D. (2016). Synergistic cell death in FLT3-ITD positive acute myeloid leukemia by combined treatment with metformin and 6-benzylthioinosine. Leuk. Res. 50, 132–140.

Sanfilippo, K.M., Keller, J., Gage, B.F., Luo, S., Wang, T.-F., Moskowitz, G., Gumbel, J., Blue, B., O’Brian, K., and Carson, K.R. (2016). Statins Are Associated With Reduced Mortality in Multiple Myeloma. J. Clin. Oncol. 34, 4008–4014.

Sassano, A., Katsoulidis, E., Antico, G., Altman, J.K., Redig, A.J., Minucci, S., Tallman, M.S., and Platanias, L.C. (2007). Suppressive Effects of Statins on Acute Promyelocytic Leukemia Cells. Cancer Res. 67, 4524–4532.

Schmidmaier, R., Baumann, P., Bumeder, I., Meinhardt, G., Straka, C., and Emmerich, B. (2007). First clinical experience with simvastatin to overcome drug resistance in refractory multiple myeloma. Eur. J. Haematol. 79, 240–243.

Scotland, S., Micklow, E., Wang, Z., Boutzen, H., Récher, C., Danet-Desnoyers, G., Selak, M., Carroll, M., and Sarry, J.-E. (2010). Metformin for Therapeutic Intervention In Acute Myeloid Leukemia. Blood 116, 4351–4351.

Shadman, M., Mawad, R., Dean, C., Chen, T.L., Shannon-Dorcy, K., Sandhu, V., Hendrie, P.C., Scott, B.L., Walter, R.B., Becker, P.S., et al. (2015). Idarubicin, cytarabine, and pravastatin as induction therapy for untreated acute myeloid leukemia and high-risk myelodysplastic syndrome. Am. J. Hematol. 90, 483–486.

Shi, W.-Y., Xiao, D., Wang, L., Dong, L.-H., Yan, Z.-X., Shen, Z.-X., Chen, S.-J., Chen, Y., and Zhao, W.-L. (2012). Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis. 3, e275.

Singh, A., Gu, J., Yanamadala, V., Czuczman, M.S., and Hernandez-Ilizaliturri, F.J. (2013). Metformin Lowers The Mitochondrial Potential Of Lymphoma Cells and Its Use During Front-Line Rituximab-Based Chemo-Immunotherapy Improves The Clinical Outcome Of Diffuse Large B-Cell Lymphoma. Blood 122, 1825–1825.

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.

Sondergaard, T.E., Pedersen, P.T., Andersen, T.L., Søe, K., Lund, T., Ostergaard, B., Garnero, P., Delaisse, J.-M., and Plesner, T. (2009). A phase II clinical trial does not show that high dose simvastatin has beneficial effect on markers of bone turnover in multiple myeloma. Hematol. Oncol. 27, 17–22.

Song, H., Fares, M., Maguire, K.R., Sidén, Å., and Potácová, Z. (2014). Cytotoxic Effects of Tetracycline Analogues (Doxycycline, Minocycline and COL-3) in Acute Myeloid Leukemia HL-60 Cells. PLoS ONE 9.

Spagnuolo, P.A., Hu, J., Hurren, R., Wang, X., Gronda, M., Sukhai, M.A., Di Meo, A., Boss, J., Ashali, I., Beheshti Zavareh, R., et al. (2010). The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma. Blood 115, 4824–4833.

van der Spek, E., Bloem, A.C., Sinnige, H.A., and Lokhorst, H. (2008). High dose Simvastatin does not reverse resistance to Vincristine, Adriamycin, and Dexamethasone (VAD) in Myeloma. Haematologica 92, e130-1.

Velez, J., Pan, R., Lee, J.T.C., Enciso, L., Suarez, M., Duque, J.E., Jaramillo, D., Lopez, C., Morales, L., Bornmann, W., et al. (2016). Biguanides sensitize leukemia cells to ABT-737-induced apoptosis by inhibiting mitochondrial electron transport. Oncotarget 7, 51435–51449.

Wallace, R., Anderson, M., Alqwasmi, A., Howard, B.V., Wu, C., Safford, M., Martin, L.W., Schlecht, N., Liu, S., Cetnar, J., et al. (2013). Prospective Analysis Of Statin Use and Risk Of Non-Hodgkin’s Lymphoma In The Women’s Health Initiative Cohort. Blood 122, 4279–4279.

Wang, E.S., and Wetzler, M. (2015). An Oncologist’s Perspective on Metformin Use and Acute Lymphoblastic Leukemia Outcomes. J. Pharm. Pract. 28, 46–47.

Wang, C., Xiang, R., Zhag, X., and Chen, Y. (2015). Doxycycline inhibits leukemic cell migration via inhibition of matrix metalloproteinases and phosphorylation of focal adhesion kinase. Mol. Med. Rep. 12, 3374–3380.

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, W., Merriman, K., Nabaah, A., Seval, N., Seval, D., Lin, H., Wang, M., Qazilbash, M.H., Baladandayuthapani, V., Berry, D., et al. (2014). The association of diabetes and anti-diabetic medications with clinical outcomes in multiple myeloma. Br. J. Cancer 111, 628–636.

Ye, X., Mneina, A., Johnston, J.B., and Mahmud, S.M. (2017). Associations between statin use and non-Hodgkin lymphoma (NHL) risk and survival: a meta-analysis. Hematol. Oncol. 35, 206–214.

Yi, X., Jia, W., Jin, Y., and Zhen, S. (2014). Statin Use Is Associated with Reduced Risk of Haematological Malignancies: Evidence from a Meta-Analysis. PLOS ONE 9, e87019.

Yi, Y., Gao, L., Wu, M., Ao, J., Zhang, C., Wang, X., Lin, M., Bergholz, J., Zhang, Y., and Xiao, Z.-X.J. (2017). Metformin Sensitizes Leukemia Cells to Vincristine via Activation of AMP-activated Protein Kinase. J. Cancer 8, 2636–2642.

Zi, F.-M., He, J.-S., Li, Y., Wu, C., Yang, L., Yang, Y., Wang, L.-J., He, D.-H., Zhao, Y., Wu, W.-J., et al. (2015). Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models. Cancer Lett. 356, 443–453.