Cancer drug discovery by repurposing: teaching new tricks to old dogs

How to improve R&D productivity: the pharmaceutical industry's grand challenge

Paul, S. M., Mytelka, D. S., Dunwiddie, C. T., Persinger, C. C., Munos, B. H., Lindborg, S. R., & Schacht, A. L. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3078 · Cited by 3,566

Antitumor Activity of Thalidomide in Refractory Multiple Myeloma

Singhal, S., Mehta, J., Desikan, R., Ayers, D., Roberson, P., Eddlemon, P., Munshi, N., Anaissie, E., Wilson, C., Dhodapkar, M., et al. (1999) · New England Journal of Medicine · doi:10.1056/nejm199911183412102 · Cited by 2,575

The Effect of Celecoxib, a Cyclooxygenase-2 Inhibitor, in Familial Adenomatous Polyposis

Steinbach, G., Lynch, P. M., Phillips, R. K. S., Wallace, M. H., Hawk, E., Gordon, G. B., Wakabayashi, N., Saunders, B., Shen, Y., Fujimura, T., et al. (2000) · New England Journal of Medicine · doi:10.1056/nejm200006293422603 · Cited by 2,526

Thalidomide is an inhibitor of angiogenesis.

D'Amato, R. J., Loughnan, M. S., Flynn, E., & Folkman, J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.9.4082 · Cited by 2,454

Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition

Simmons, D. L., Botting, R. M., & Hla, T. (2004) · Pharmacological Reviews · doi:10.1124/pr.56.3.3 · Cited by 1,693

Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials

Rothwell, P. M., Fowkes, F. G. R., Belch, J. F., Ogawa, H., Warlow, C. P., & Meade, T. W. (2011) · The Lancet · doi:10.1016/s0140-6736(10)62110-1 · Cited by 1,497

Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma

Henry, D. H., Costa, L., Goldwasser, F., Hirsh, V., Hungria, V., Prausova, J., Scagliotti, G. V., Sleeboom, H., Spencer, A., Vadhan-Raj, S., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.31.3304 · Cited by 1,263

Anti-inflammatory Agents: Present and Future

Dinarello, C. A. (2010) · Cell · doi:10.1016/j.cell.2010.02.043 · Cited by 1,095

Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer

Gnant, M., Mlineritsch, B., Schippinger, W., Luschin-Ebengreuth, G., Pöstlberger, S., Menzel, C., Jakesz, R., Seifert, M., Hubalek, M., Bjelic-Radisic, V., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0806285 · Cited by 1,025

Rapamycin passes the torch: a new generation of mTOR inhibitors

Benjamin, D., Colombi, M., Moroni, C., & Hall, M. N. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3531 · Cited by 989

Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner

Kalender, A., Selvaraj, A., Kim, S. Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B. E., Bardeesy, N., Dennis, P., Schlager, J. J., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.014 · Cited by 889

Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer

Jiralerspong, S., Palla, S. L., Giordano, S. H., Meric-Bernstam, F., Liedtke, C., Barnett, C. M., Hsu, L., Hung, M.-C., Hortobagyi, G. N., & Gonzalez-Angulo, A. M. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.19.6410 · Cited by 880

Phase II failures: 2008–2010

Arrowsmith, J. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3439 · Cited by 622

First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial

Morgan, G. J., Davies, F. E., Gregory, W. M., Cocks, K., Bell, S. E., Szubert, A. J., Navarro-Coy, N., Drayson, M. T., Owen, R. G., Feyler, S., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)62051-x · Cited by 575

Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis

Noto, H., Goto, A., Tsujimoto, T., & Noda, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033411 · Cited by 566

Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity

Parman, T., Wiley, M. J., & Wells, P. G. (1999) · Nature Medicine · doi:10.1038/8466 · Cited by 495

Inhibition of NF-κB Activity by Thalidomide through Suppression of IκB Kinase Activity

Keifer, J. A., Guttridge, D. C., Ashburner, B. P., & Jr.Baldwin, A. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100938200 · Cited by 478

Long-Term Metformin Use Is Associated With Decreased Risk of Breast Cancer

Bodmer, M., Meier, C., Krähenbühl, S., Jick, S. S., & Meier, C. R. (2010) · Diabetes Care · doi:10.2337/dc09-1791 · Cited by 466

Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals

Lee, M.-S., Hsu, C.-C., Wahlqvist, M. L., Tsai, H.-N., Chang, Y.-H., & Huang, Y.-C. (2011) · BMC Cancer · doi:10.1186/1471-2407-11-20 · Cited by 380

Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells

Ye, K., Ke, Y., Keshava, N., Shanks, J., Kapp, J. A., Tekmal, R. R., Petros, J., & Joshi, H. C. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.4.1601 · Cited by 341

Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-κB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation

Takada, Y., Bhardwaj, A., Potdar, P., & Aggarwal, B. B. (2004) · Oncogene · doi:10.1038/sj.onc.1208169 · Cited by 310

Metformin: Multi-faceted protection against cancer

Del Barco, S., Vazquez-Martin, A., Cufí, S., Oliveras-Ferraros, C., Bosch-Barrera, J., Joven, J., Martin-Castillo, B., & Menendez, J. A. (2011) · Oncotarget · doi:10.18632/oncotarget.387 · Cited by 302

Antileukemic activity of rapamycin in acute myeloid leukemia

Récher, C., Beyne-Rauzy, O., Demur, C., Chicanne, G., Dos Santos, C., Mas, V. M.-D., Benzaquen, D., Laurent, G., Huguet, F., & Payrastre, B. (2005) · Blood · doi:10.1182/blood-2004-06-2494 · Cited by 296

Effect of aspirin and NSAIDs on risk and survival from colorectal cancer

Din, F. V. N., Theodoratou, E., Farrington, S. M., Tenesa, A., Barnetson, R. A., Cetnarskyj, R., Stark, L., Porteous, M. E., Campbell, H., & Dunlop, M. G. (2010) · Gut · doi:10.1136/gut.2009.203000 · Cited by 284

Aspirin, salicylates, and cancer

Elwood, P. C., Gallagher, A. M., Duthie, G. G., Mur, L. A., & Morgan, G. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60243-9 · Cited by 282

Best Practices in Cancer Nanotechnology: Perspective from NCI Nanotechnology Alliance

Zamboni, W. C., Torchilin, V., Patri, A. K., Hrkach, J., Stern, S., Lee, R., Nel, A., Panaro, N. J., & Grodzinski, P. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2938 · Cited by 275

Drugging the PI3 Kinome: From Chemical Tools to Drugs in the Clinic

Workman, P., Clarke, P. A., Raynaud, F. I., & van Montfort, R. L. M. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4355 · Cited by 264

Repurposing with a Difference

Boguski, M. S., Mandl, K. D., & Sukhatme, V. P. (2009) · Science · doi:10.1126/science.1169920 · Cited by 220

Acetylation of Stat1 modulates NF-κB activity

Krämer, O. H., Baus, D., Knauer, S. K., Stein, S., Jäger, E., Stauber, R. H., Grez, M., Pfitzner, E., & Heinzel, T. (2006) · Genes & Development · doi:10.1101/gad.364306 · Cited by 219

Sodium valproate inhibits production of TNF-α and IL-6 and activation of NF-κB

Ichiyama, T., Okada, K., Lipton, J. M., Matsubara, T., Hayashi, T., & Furukawa, S. (2000) · Brain Research · doi:10.1016/s0006-8993(99)02439-7 · Cited by 196

Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis‐associated colon cancer in mice

Cho, S., Kim, J. S., Kim, J. M., Lee, J. Y., Jung, H. C., & Song, I. S. (2008) · International Journal of Cancer · doi:10.1002/ijc.23593 · Cited by 195

Targeting apoptosis pathways by Celecoxib in cancer

Jendrossek, V. (2013) · Cancer Letters · doi:10.1016/j.canlet.2011.01.012 · Cited by 194

Long-Term Silicone Central Venous Catheters Impregnated With Minocycline and Rifampin Decrease Rates of Catheter-Related Bloodstream Infection in Cancer Patients: A Prospective Randomized Clinical Trial

Hanna, H., Benjamin, R., Chatzinikolaou, I., Alakech, B., Richardson, D., Mansfield, P., Dvorak, T., Munsell, M. F., Darouiche, R., Kantarjian, H., et al. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.04.124 · Cited by 191

Addition of pamidronate to chemotherapy for the treatment of osteosarcoma

Meyers, P. A., Healey, J. H., Chou, A. J., Wexler, L. H., Merola, P. R., Morris, C. D., Laquaglia, M. P., Kellick, M. G., Abramson, S. J., & Gorlick, R. (2011) · Cancer · doi:10.1002/cncr.25744 · Cited by 178

Thalidomide Suppresses NF-κB Activation Induced by TNF and H2O2, But Not That Activated by Ceramide, Lipopolysaccharides, or Phorbol Ester

Majumdar, S., Lamothe, B., & Aggarwal, B. B. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.6.2644 · Cited by 160

Nitroxoline (8-hydroxy-5-nitroquinoline) is more a potent anti-cancer agent than clioquinol (5-chloro-7-iodo-8-quinoline)

Jiang, H., Taggart, J. E., Zhang, X., Benbrook, D. M., Lind, S. E., & Ding, W. (2011) · Cancer Letters · doi:10.1016/j.canlet.2011.06.032 · Cited by 147

Capturing the Unexpected Benefits of Medical Research

Gelijns, A. C., Rosenberg, N., & Moskowitz, A. J. (1998) · New England Journal of Medicine · doi:10.1056/nejm199809033391010 · Cited by 146

Paclitaxel-resistant Human Ovarian Cancer Cells Undergo c-Jun NH2-terminal Kinase-mediated Apoptosis in Response to Noscapine

Zhou, J., Gupta, K. K., Yao, J. L., Ye, K., Panda, D., Giannakakou, P., & Joshi, H. C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203927200 · Cited by 139

ANTI-METASTATIC EFFECT OF ASPIRIN

Gasic, G. J., Gasic, T. B., & Murphy, S. (1972) · The Lancet · doi:10.1016/s0140-6736(72)92581-0 · Cited by 137

A multi-institutional phase ii study of SU101, a platelet-derived growth factor receptor inhibitor, for patients with hormone-refractory prostate cancer.

Ko, Y. J., Small, E. J., Kabbinavar, F. F., et al. (2001) · PubMed · Cited by 136

The Nobel Chronicles

Raju, T. N. K. (2000) · The Lancet · doi:10.1016/s0140-6736(05)74775-9 · Cited by 133

Metformin Treatment Exerts Antiinvasive and Antimetastatic Effects in Human Endometrial Carcinoma Cells

Tan, B. K., Adya, R., Chen, J., Lehnert, H., Cassia, L. J. S., & Randeva, H. S. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-1803 · Cited by 129

Statin Use and Risk of Colorectal Cancer

Coogan, P. F., Smith, J., & Rosenberg, L. A. (2007) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djk003 · Cited by 122

Effect of Nitroxoline on Angiogenesis and Growth of Human Bladder Cancer

Shim, J. S., Matsui, Y., Bhat, S., Nacev, B. A., Xu, J., Bhang, H.-E. C., Dhara, S., Han, K. C., Chong, C. R., Pomper, M. G., et al. (2010) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djq457 · Cited by 115

Reversal of chemoresistance and enhancement of apoptosis by statins through down-regulation of the NF-κB pathway

Ahn, K. S., Sethi, G., & Aggarwal, B. B. (2007) · Biochemical Pharmacology · doi:10.1016/j.bcp.2007.10.010 · Cited by 114

Biologically Targeted Cancer Therapy and Marginal Benefits: Are We Making Too Much of Too Little or Are We Achieving Too Little by Giving Too Much?

Fojo, T., & Parkinson, D. R. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1277 · Cited by 110

Simvastatin Potentiates TNF-α-Induced Apoptosis through the Down-Regulation of NF-κB-Dependent Antiapoptotic Gene Products: Role of IκBα Kinase and TGF-β-Activated Kinase-1

Ahn, K. S., Sethi, G., & Aggarwal, B. B. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.4.2507 · Cited by 107

Noscapine, a Benzylisoquinoline Alkaloid, Sensitizes Leukemic Cells to Chemotherapeutic Agents and Cytokines by Modulating the NF-κB Signaling Pathway

Sung, B., Ahn, K. S., & Aggarwal, B. B. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4230 · Cited by 89

Drug repurposing programmes get lift off

Mullard, A. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3776 · Cited by 86

p53 and p21 Determine the Sensitivity of Noscapine-Induced Apoptosis in Colon Cancer Cells

Aneja, R., Ghaleb, A. M., Zhou, J., Yang, V. W., & Joshi, H. C. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4282 · Cited by 79

Single-agent lenalidomide induces complete remission of acute myeloid leukemia in patients with isolated trisomy 13

Fehniger, T. A., Byrd, J. C., Marcucci, G., Abboud, C. N., Kefauver, C. A., Payton, J. E., Vij, R., & Blum, W. G. (2008) · Blood · doi:10.1182/blood-2008-04-152678 · Cited by 77

Drug Repurposing and the Medicinal Chemist

Aubé, J. (2012) · ACS Medicinal Chemistry Letters · doi:10.1021/ml300114c · Cited by 74

Evaluation of antileukaemic effects of rapamycin in patients with imatinib‐resistant chronic myeloid leukaemia

Sillaber, C., Mayerhofer, M., Böhm, A., Vales, A., Gruze, A., Aichberger, K. J., Esterbauer, H., Pfeilstöcker, M., Sperr, W. R., Pickl, W. F., et al. (2007) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.2007.01892.x · Cited by 71

Leflunomide: A Drug with a Potential Beyond Rheumatology

Teschner, S., & Burst, V. R. (2010) · Immunotherapy · doi:10.2217/imt.10.52 · Cited by 69

Thiocolchicoside Exhibits Anticancer Effects through Downregulation of NF-κB Pathway and Its Regulated Gene Products Linked to Inflammation and Cancer

Reuter, S., Prasad, S., Phromnoi, K., Ravindran, J., Sung, B., Yadav, V. R., Kannappan, R., Chaturvedi, M. M., & Aggarwal, B. B. (2010) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-10-0037 · Cited by 67

Chemically modified non-antimicrobial tetracyclines are multifunctional drugs against advanced cancers☆

Lokeshwar, B. L. (2010) · Pharmacological Research · doi:10.1016/j.phrs.2010.11.003 · Cited by 62

Bisphosphonate Therapeutics in Bone Disease: The Hard and Soft Data on Osteoclast Inhibition

Drake, M. T., & Cremers, S. C. L. M. (2010) · Molecular Interventions · doi:10.1124/mi.10.3.5 · Cited by 61

Inhibition by anticonvulsants of prostate-specific antigen and interleukin-6 secretion by human prostate cancer cells.

Abdul, M., & Hoosein, N. M. (2001) · PubMed · Cited by 58

Chronic statin therapy and the risk of colorectal cancer

Yang, Y., Hennessy, S., PROPERT, K. J., Hwang, W., Sarkar, M., & Lewis, J. D. (2008) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.1599 · Cited by 55

Noscapine inhibits hypoxia-mediated HIF-1α expression andangiogenesis in vitro: a novel function for an old drug

Newcomb, E. W., Lukyanov, Y., Schnee, T., Ali, M., Li, L., & Zagzag, D. (2006) · International Journal of Oncology · doi:10.3892/ijo.28.5.1121 · Cited by 53

Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma

Gu, S., Tian, Y., Chlenski, A., Salwen, H. R., Lu, Z., Raj, J. U., & Yang, Q. (2012) · Anti-Cancer Drugs · doi:10.1097/cad.0b013e32835739dd · Cited by 49

Progress in the treatment of bone metastases in cancer patients

Mackiewicz-Wysocka, M., Pankowska, M. M., & Wysocki, P. J. (2012) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2012.679928 · Cited by 49

Clinical activity of mammalian target of rapamycin inhibitors in solid tumors

Alvarado, Y., Mita, M. M., Vemulapalli, S., Mahalingam, D., & Mita, A. C. (2011) · Targeted Oncology · doi:10.1007/s11523-011-0178-5 · Cited by 42

Bisphosphonates and Cancer: What Opportunities from Nanotechnology?

Rosa, G. D., Misso, G., Salzano, G., & Caraglia, M. (2013) · Journal of Drug Delivery · doi:10.1155/2013/637976 · Cited by 39

Statin use is associated with a reduced incidence of colorectal cancer: a colonoscopy-controlled case–control study

Broughton, T., Sington, J., & Beales, I. (2012) · BMC Gastroenterology · doi:10.1186/1471-230x-12-36 · Cited by 36

The efficacy of topical thiocolchicoside (Muscoril) in the treatment of acute cervical myofascial pain syndrome: a single-blind, randomized, prospective, phase IV clinical study.

Ketenci, A., Basat, H., & Esmaeilzadeh, S. (2009) · PubMed · Cited by 33

Inhibition of ultraviolet C irradiation-induced AP-1 activity by aspirin is through inhibition of JNKs but not erks or P38 MAP kinase.

Ma, W. Y., Huang, C., & Dong, Z. (1998) · International Journal of Oncology · doi:10.3892/ijo.12.3.565 · Cited by 32

Bisphosphonates as antimyeloma drugs

Modi, N., & Lentzsch, S. (2011) · Leukemia · doi:10.1038/leu.2011.282 · Cited by 31

Antitumor effects of bisphosphonates: from the laboratory to the clinic

Berenson, J. R. (2011) · Current Opinion in Supportive and Palliative Care · doi:10.1097/spc.0b013e328349dc17 · Cited by 28

Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug

Reuter, S., Gupta, S. C., Phromnoi, K., & Aggarwal, B. B. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01702.x · Cited by 24

A combination of thalidomide and arsenic trioxide is effective and well tolerated in patients with myelodysplastic syndromes

Wei, W., Zhou, F., Zhang, Y., Guo, L., Shi, H., & Hou, J. (2012) · Leukemia Research · doi:10.1016/j.leukres.2011.12.023 · Cited by 19

Interest of the association azacitidine–lenalidomide as frontline therapy in high-risk myelodysplasia or acute myeloid leukemia with complex karyotype

Scherman, E., Malak, S., Pérot, C., Gorin, N. C., Rubio, M., & Isnard, F. (2011) · Leukemia · doi:10.1038/leu.2011.284 · Cited by 18

Four Lessons from Global Health Drug Discovery: Medicine for an Ailing Industry?

Elliott, R. L. (2012) · ACS Medicinal Chemistry Letters · doi:10.1021/ml3002105 · Cited by 14

Enhancement of anti-tumor activity by low-dose combination of the recombinant urokinase kringle domain and celecoxib in a glioma model

Kim, C. K., Joe, Y. A., Lee, S., Kim, E., Eunju, O., Kim, H.-K., Oh, B. J., Hong, S. H., & Hong, Y.-K. (2009) · Cancer Letters · doi:10.1016/j.canlet.2009.07.008 · Cited by 11

Anticancer Conjugates and Cocktails Based on Methotrexate and Nucleoside Synergism

Vortherms, A. R., Dang, H. N., & Doyle, R. P. (2009) · Clinical medicine Oncology · doi:10.4137/cmo.s2113 · Cited by 7

Bioelectric signaling: Reprogrammable circuits underlying embryogenesis, regeneration, and cancer

Levin, M. (2021) · Cell · doi:10.1016/j.cell.2021.02.034 · Cited by 505

Potential of long non‐coding RNAs in cancer patients: From biomarkers to therapeutic targets

Chandra Gupta, S., & Nandan Tripathi, Y. (2017) · International Journal of Cancer · doi:10.1002/ijc.30546 · Cited by 527

Statins: a repurposed drug to fight cancer

Jiang, W., Hu, J.-W., He, X.-R., Jin, W.-L., & He, X.-Y. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02041-2 · Cited by 417

Drug repurposing in cancer

Sleire, L., Førde, H. E., Netland, I. A., Leiss, L., Skeie, B. S., & Enger, P. Ø. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.07.013 · Cited by 329

A systematic analysis of FDA-approved anticancer drugs

Sun, J., Wei, Q., Zhou, Y., Wang, J., Liu, Q., & Xu, H. (2017) · BMC Systems Biology · doi:10.1186/s12918-017-0464-7 · Cited by 322