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The COC Protocol™ and Blood Cancer

Summary

Evaluating complex scientific articles and technical literature can be a daunting task. Our search of the literature has retrieved over 60 articles which detail and discuss the potentially beneficial effects of the COC protocol medications in blood cancers, (i.e. leukaemia, lymphoma, and myeloma).

In summary, there are three key points to consider:

  • A large number of laboratory studies show that each of the COC protocol medications can
    directly attack and help disable or kill blood cancer cells.
  • Patients with blood cancer may benefit from taking the COC protocol alongside their
    standard treatments. Many studies show that the particular medications used in the COC
    protocol could help reduce resistance and improve the effectiveness of chemotherapy and other treatments.
  • This evidence is very encouraging and further studies are needed to determine exactly how,and who, the COC protocol medications may help. Our specialist clinicians can assist you in deciding whether you could benefit from taking the COC protocol. Contact the Care Oncology Clinic on 800-392-1353 or submit a form to Learn More.

 

 

 

 

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Statins

Statins have been widely prescribed for decades, and a large number of population studies (ie, studies which simply observe what happens to a defined group of people) 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), leukaemia (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 (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 leukaemia who did not want further induction therapy. The researchers found that the patient’s cells grown in the lab 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 authors reported that ‘this case illustrates the potential for lovastatin to provide a novel means of controlling leukemic cell growth in acute myeloid leukaemia 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). Lab 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 leukaemia were given increasing doses of pravastatin alongside a standard chemotherapy regimen had encouraging results, particularly in newly diagnosed patients with unfavourable 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 leukaemia 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 leukaemia 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 be to do with patient subset, 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 6 patients with refractory (ie 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).

Metformin

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 nondiabetic 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 lab 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 lab or taken from patients (Gu et al., 2015; 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).

Lab studies also suggest that metformin can benefit patients with leukaemia, both by directly acting on cancer cells, and by helping to lower high blood glucose levels, which are sometimes associated with treatment of leukaemia (Rosilio et al., 2014; Wang and Wetzler, 2015). This mode-of-action evidence shows that metformin can target, block growth, and destroy leukaemia 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 leukaemia (Sabnis et al., 2016; Velez et al., 2016; Yi et al., 2017).  These effects appear wide ranging across a number of different types of leukaemia; one study found that metformin was able to block oxygen uptake in 6 different types of leukaemia cell (Scotland et al., 2010).

Doxycycline

Lab studies from as far back as 1985 suggested that doxycycline could stop tumour growth and eradicate tumours in rats with leukaemia (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 target blood cancer cells in a myriad of different ways, over and above the traditional anti-bacterial and anti-inflammatory effects (Bahrami et al., 2012; Ferreri et al., 2006).

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 lab have now shown that doxycycline can directly damage, kill, or initiate processes which can lead to death (ie apoptosis) in a number of different types of cancer, including blood cancers (Alexander-Savino et al., 2016; Bahrami et al., 2012; Lamb et al., 2015; 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

Scientific interest in mebendazole as a potential anticancer treatment is relatively new, and is mostly based on promising mechanistic 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 leukaemia, 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 leukaemia (Matchett et al., 2016; Nygren et al., 2013). In one of these studies (Nygren et al., 2013), the leukaemia 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 leukaemia 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 leukaemia and myeloma cells in the lab (Spagnuolo et al., 2010).

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 LLC and its licensors.

Reading List

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.

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-KappaB 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. Leukemia & Lymphoma 58, 1130–1134.

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.

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. Hematological Oncology 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.

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., AmbesiImpiombato, 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. Biomarker Research 1, 33.

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.

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. JCO 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 Bcell lymphoma receiving rituximab plus CHOP therapy. Ann. 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 OcularAdnexal MALT Lymphoma: A Multicenter Prospective Trial. 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 Biomarkers Prev 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 PreClinical 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.

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.

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.

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.

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. Leukemia & 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.

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

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

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. Science Translational Medicine 10, eaaq1240.

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.

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. British Journal of Haematology 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. Leukemia & Lymphoma 40, 659–662.

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 Oncologica 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. JCO 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 & Disease 4, e518.

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., Cancer Letters, Cancer Letters. 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 Letters 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. JCO 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. European Journal of Haematology 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 & Disease 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 RituximabBased Chemo-Immunotherapy Improves The Clinical Outcome Of Diffuse Large B-Cell Lymphoma. Blood 122, 1825–1825.

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. Journal of Pharmacy Practice 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.

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. British Journal of 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. Journal of 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 Letters 356, 443–453.