Webb.cm.utexas.edu

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Cancer drug discovery by repurposing: teaching new tricks to old dogs Subash C. Gupta1, Bokyung Sung1, Sahdeo Prasad1, Lauren J. Webb2, and Bharat B. Aggarwal1 1 Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 2 Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, TX 78712, USA Progressively increasing failure rates, high cost, poor oncology drugs entering Phase I clinical trials are ultimately bioavailability, poor safety, limited efficacy, and a approved [1]. These failure rates underscore the need for lengthy design and testing process associated with can- alternative efforts for drug development [2]. Furthermore, cer drug development have necessitated alternative most of the currently available cancer drugs are highly approaches to drug discovery. Exploring established expensive, provide minimal increase in the overall survival, non-cancer drugs for anticancer activity provides an and are associated with numerous side effects [3].
opportunity rapidly to advance therapeutic strategies There has been much discussion on the overall steps into clinical trials. The impetus for development of can- involved and the future of the drug discovery process [4].
cer therapeutics from non-cancer drugs stems from the Drug development requires an average of 13 years of fact that different diseases share common molecular research and an investment of US$1.8 billion to bring a pathways and targets in the cell. Common molecular single drug from the bench to a patient's bedside [5] origins of diverse diseases have been discovered (Figure 1). Drug development, in addition to design and through advancements in genomics, proteomics, and production, comprises examining the efficacy, toxicity, and informatics technologies, as well as through the devel- pharmacokinetic and pharmacodynamic profiles of the opment of analytical tools that allow researchers simul- drug by cell- and animal-based studies. The next step in taneously to screen large numbers of existing drugs drug development is testing the safety and efficacy in against a particular disease target. Thus, drugs originally human subjects by clinical trials that normally comprise identified as antitussive, sedative, analgesic, antipyretic, four phases. In general, if the drug is found efficacious in antiarthritic, anesthetic, antidiabetic, muscle relaxant, Phase III trials, it receives FDA approval. Most drugs, immunosuppressant, antibiotic, antiepileptic, cardio- however, fail to receive FDA approval, even when they protective, antihypertensive, erectile function enhanc- exhibit safety in Phase I trials; according to one study, this ing, or angina relieving are being repurposed for failure is primarily due to a lack of efficacy in Phase II cancer. This review describes the repurposing of these trials [6]. Success rates for Phase II trials have decreased drugs for cancer treatment.
from 28% in 2006–2007 to 18% in 2008–2009 [7]. It has been suggested that most drugs fail because they did not effectively target the disease for which they were intended Despite the tremendous resources being invested in cancer [6]. However, because of the common molecular origins of prevention and treatment, cancer remains one of the leading diverse diseases, it is estimated that approximately 90% of causes of mortality worldwide. During the past decade, new approved drugs possess secondary indications and can be technologies such as structure-based drug discovery have used for other purposes [8]. Researchers and clinicians been created, hundreds of biotechnology companies have have adopted numerous strategies to reduce the cost been launched, research expenditure by the US National and time involved in cancer drug development. One such Institutes of Health has increased by more than two-fold, strategy is to evaluate established non-cancer drugs that and pharmaceutical industries have doubled their R&D have already been approved for noncancerous diseases, spending. This investment, however, has not resulted in whose targets have already been discovered and for which proportionate quantities of new and novel anticancer drugs.
reliable biomarkers indicative of success already exist.
Some of the common anticancer drugs approved by the FDA This approach, alternatively called ‘new uses for old drugs', and their molecular targets are shown in Table 1. These ‘drug repositioning', ‘drug repurposing', ‘drug re-profiling', drugs may be classified into two basic categories: non-tar- ‘therapeutic switching', or ‘indication switching', has geted and targeted. Only one of every 5000–10,000 prospec- gained considerable attention over the past decade tive anticancer agents receives FDA approval and only 5% of [9,10]. The major advantage of this approach is that the pharmacokinetic, pharmacodynamic, and toxicity profiles Corresponding author: Aggarwal, B.B. ([email protected]).
of drugs are in general well known because of the preclini- Keywords: cancer drugs; drug repurposing; inflammation; NF-kB; STAT3.
cal and Phase I studies. Thus, these drugs could be rapidly 0165-6147/$ – see front matter .
translated into Phase II and III clinical studies and the Trends in Pharmacological Sciences September 2013, Vol. 34, No. 9 Author's personal copy
Trends in Pharmacological Sciences September 2013, Vol. 34, No. 9 Table 1. Common anticancer drugs approved by the FDA and their molecular targetsa CLL, Hodgkin lymphoma, NHL ALL, Hodgkin lymphoma, NHL, rhabdomyosarcoma, Wilms' tumor Breast, head and neck, Hodgkin lymphoma, lung ALL, AML, CML, meningeal leukemia Cervical, Hodgkin lymphoma, lung, MPE, NHL, testicular, vulva Hodgkin lymphoma, metastatic melanoma Tamoxifen citrate Estrogen receptor # Lung, mesothelioma, ovarian Breast, lung, lymphoma, osteosarcoma, ovarian, testicular ALL, breast, GTD, Hodgkin lymphoma, osteosarcoma Ewing sarcoma, lung, testicular Breast, gastric, head and neck, lung, prostate Breast, lung, ovarian, pancreatic Topoisomerase I # Denileukin diftitox Cutaneous T cell lymphoma ALL, AML, CML, meningeal leukemia ALL, AML, bone, bladder, breast, gastric, Hodgkin lymphoma, neuroblastoma, NHL, ovarian, thyroid, Wilms' tumor Cutaneous T cell lymphoma Retinoid X receptor " Gemtuzumab ozagamicin Leuprolide acetate Anaplastic astrocytoma, glioblastoma multiforme CML, gastrointestinal Breast, colorectal Ibritumomab tiuxetan Basal cell carcinoma, breast, colorectal, gastric, pancreatic Mantle cell lymphoma, MM Tositumomab and 131I Colorectal, glioblastoma, lung, renal Colorectal, head and neck Myelodysplastic syndrome Sorafenib tosylate PDGFR #, VEGFR #, CD117 # MM, myelodysplastic syndrome PDGFR #, BCR-ABL #, Src # Gastrointestinal, renal Cutaneous T cell lymphoma Myelodysplastic syndrome Author's personal copy
Trends in Pharmacological Sciences September 2013, Vol. 34, No. 9 Table 1 (Continued ) Lapatinib ditosylate PDGFR #, BCR-ABL #, CD117 # Cervical, lung, ovarian Topoisomerase I # CLL, Hodgkin lymphoma, lung, MM, NHL Renal, astrocytoma Cutaneous T cell lymphoma Mesothelioma, lung Peripheral T cell lymphoma Eribulin mesylate aAbbreviations: ALK,, anaplastic lymphoma kinase; ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; BCR-ABL, breakpoint cluster region gene on chromosome 22 and Abelson murine leukemia viral oncogene homolog; BRAF, v-raf murine sarcoma viral oncogene homolog B1; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CTLA 4, cytotoxic T-lymphocyte-associated antigen 4; EGFR, epidermal growth factor receptor; GnRH, gonadotropin-releasing hormone; GTD, gestational trophoblastic disease; HER2, human epidermal receptor 2; JAK, Janus-associated kinase; MM, multiple myeloma; MPE, malignant pleural effusion; NHL, non-Hodgkin lymphoma; NSCLC, non-small cell lung cancer; NT, non-targeted; PDGFR, platelet-derived growth factor receptor; RANKL, receptor-activated NF-kB ligand; SERD, selective estrogen receptor downregulator; SERM, selective estrogen-receptor modulator; Src, sarcoma; VEGFR, vascular endothelial growth factor receptor; #, downregulation; ", upregulation.
associated cost could be significantly reduced. At a time the observation that almost all drugs used in human when the revenue of drug research is under extreme therapy possess more than one target and thus can produce pressure, pharmaceutical industries are re-evaluating off-target side effects in addition to their principal activity.
old drugs for new indications to maximize their return If these drugs interact with an off-target pathway with on investment. A more recent estimate indicates that, sufficient potency, there is a high likelihood that they could whereas 10% of new molecular entities make it to the be rapidly tested in patients. The second successful strate- market from Phase II clinical trials and 50% from Phase gy is based on the finding that many different diseases III, the rates for repurposed compounds are 25% and 65%, share common molecular pathways and targets in the cell.
respectively [11].
Thus, it is likely that the same drug can be therapeutic for Several strategies have been used effectively to identify more than one disease.
and implement current non-cancer drugs for cancer-relat- In the sections that follow, we review some of the most ed treatment [12]. The first successful strategy is based on common older drugs that have demonstrated anticancer New drug development
Phase 1
Phase 2
Phase 3
5∼7 years
1∼2 years
Rediscovery of old drugs
for new uses
TRENDS in Pharmacological Sciences Figure 1. Major steps and estimated time involved in the conventional drug development process, which involves basic research, drug design, testing of safety and efficacy with preclinical and clinical studies, and finally filing for FDA approval. The estimated time of drug development can be significantly reduced by repurposing old drugs.
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Trends in Pharmacological Sciences September 2013, Vol. 34, No. 9 Valproic acid
TRENDS in Pharmacological Sciences Figure 2. Chemical structure of common non-cancer drugs that exhibit anticancer activity.
activity, regardless of the fact that they were not originally myeloma [15]. This led to successful evaluation of thalido- intended for this use. We review drugs that were initially mide in a series of multicenter clinical trials and to final identified as antitussive, sedative, analgesic, antipyretic, FDA approval of the drug for treatment of multiple myelo- antiarthritic, anesthetic, antidiabetic, muscle relaxant, ma. Recent studies have demonstrated the efficacy of immunosuppressant, antibiotic, antiepileptic, or cardio- thalidomide against several malignancies, including mye- protective and drugs designed for hypertension, erectile lodysplastic syndrome[16], myelodysplasia [17], and acute dysfunction, and angina. These drugs fall into two different myeloid leukemia [18].
categories: (i) drugs that were approved for other uses but Research over the past decade has indicated that tha- whose biological activities are known well enough that lidomide, although initially evaluated because of its poten- they are logically selected for anticancer activities (thalid- tial antiangiogenic effects, can modulate numerous cancer- omide, aspirin, valproic acid [VPA], celecoxib, leflunomide, associated cell signaling pathways. Work from our labora- wortmannin, minocycline, vesnarinone, statins, metfor- tory and others has demonstrated that, through inhibition min, thiocolchicoside, rapamycin, methotrexate, bispho- of IkB kinase (IKK), thalidomide inhibits the activation of sphonates); and (ii) agents identified from a set of nuclear factor kappa light chain enhancer of activated B approved drugs arbitrarily chosen to examine their speci- cells (NF-kB), which has been linked closely to inflamma- ficity for defined cancer targets (nitroxoline, noscapine).
tion and the survival, proliferation, invasion, and metas- Some of these drugs with palliative benefits can also tasis of tumors [19,20]. Further elucidation of the exhibit anticancer activities. These drugs are chemically molecular mechanism indicated that the inhibition of diverse (Figure 2) and can hit numerous targets in tumor NF-kB activation was due to suppression of inhibitor of development (Table 2). The diverse cancer targets of these NF-kB (IkBa) degradation in tumor cells.
drugs and the molecular mechanisms by which they exert anticancer activities are discussed in this review.
Aspirin (acetylsalicylic acid), one of the non-steroidal anti- Repurposed non-cancer drugs inflammatory drugs (NSAIDs), has been used as an anal- gesic to relieve pain, as an antipyretic to reduce fever, and Thalidomide, a derivative of glutamic acid, was originally to prevent heart attack and stroke. The first indication for developed in the 1950s as a sedative hypnotic for the the possible role of aspirin in cancer therapy dates back treatment of nausea during pregnancy. However, the drug more than four decades, when Gasic and colleagues dem- was withdrawn from the market in 1961 because of its onstrated that platelet reduction by neuraminidase ad- teratogenic effects. Numerous mechanisms were proposed ministration in tumor-bearing mice was associated with a for the teratogenic effects of thalidomide, including anti- 50% reduction in lung metastases [21]. In a subsequent angiogenic [13] and oxidative DNA-damaging activities study, the group reported a significant reduction in the [14]. Singhal and colleagues demonstrated that, because number of metastases in tumor-bearing mice by aspirin.
of its antiangiogenic activities, thalidomide as a single Furthermore, inhibition of platelet formation was pro- agent can be used for treating patients with refractory posed as the mechanism of action of aspirin. A recent Author's personal copy
Trends in Pharmacological Sciences September 2013, Vol. 34, No. 9 Table 2. Non-cancer drugs and their mechanism of action for non-cancer and cancer activitiesa Original indication (mechanism) New anticancer indication (mechanism) Antiemetic in pregnancy (TNF-a #) Multiple myeloma (NF-kB #, STAT3 #) Analgesic, antipyretic (COX-1 #, COX-2 #) Colorectal cancer (COX-2 #, NF-kB #, AP-1 #) Antiepileptic (GABA ") Leukemia, solid tumors (HDACI #, HDACII #, NF-kB #, IL-6 #) Osteoarthritis, rheumatoid arthritis (COX-2 #) Colorectal cancer, lung cancer (COX-2 #, NF-kB #) Myocardial infarction (HMG-CoA reductase #) Prostate cancer, leukemia (NF-kB #, HMG-CoA reductase #) Diabetes mellitus (AMPK "a) Breast, adenocarcinoma, prostate, colorectal (AMPK "a, NF-kB #, Immunosuppressant (mTOR #) Colorectal cancer, lymphoma, leukemia (NF-kB #, IL-6 #, IKK #) Acute leukemia (DHFR #) Osteosarcoma, breast cancer, Hodgkin lymphoma (NF-kB #, TNF-a #) Anti-bone resorption (osteoclast #) Multiple myeloma, prostate cancer, breast cancer (CXCR-4 #, MMPs #, IL-6 #, Bcl-2 #, Bax ", FOXO3a "a) Rheumatoid arthritis (DHODH #) Prostate cancer (PDGFR #, EGFR #, FGFR #, NF-kB #) Leukemia (NF-kB #, AP-1 #) Ovarian cancer, glioma (MMPs #) Oral cancer, leukemia, lymphoma (NF-kB #, IL-8 #, VEGF #, AP-1 #) Muscle relaxant (GABA #) Leukemia, multiple myeloma (NF-kB #) Bladder, breast cancer (MetAP-2 #) Antitussive, antimalarial, analgesic (bradykinin #) Multiple cancer types (NF-kB #, HIF-1a #, Bcl-2 #, p21 ", p53 ", AIF ") aAbbreviations: AIF, apoptosis-inducing factor; Bax, Bcl-2-associated X protein; CXCR-4, CXC chemokine receptor-4; DHFR, dihydrofolate reductase; DHODH, dihydroor- otate dehydrogenase; FGFR, fibroblast growth factor receptor; FOXO, forkhead homeobox type O; GABA, g-aminobutyric acid; HIF-1a, hypoxia-inducible factor-1a; MCP-1, monocyte chemoattractant protein-1; MetAP, methionine aminopeptidase; MMP, matrix metalloproteinase; "a, activation; #, downregulation; ", upregulation.
study indicated that a daily dose of 75 mg of aspirin can as cell proliferation, cell-cycle regulation, and apoptosis.
produce significant beneficial effects against common can- Possibly due to its actions as an HDAC inhibitor, VPA has cers such as gastrointestinal, esophageal, pancreatic, been shown to inhibit the survival, invasion, angiogenesis, brain, and lung [22]. In another study [23], daily intake and metastasis of cancer cells [30]. This HDAC inhibitor of 75 mg of aspirin for 1–5 years was associated with has also been shown to suppress cytokine production and to decreased risk of colorectal cancer.
modulate inflammatory pathways in cancer cells. For in- Preclinical studies have demonstrated the inhibitory stance, production of interleukin (IL)-6 and TNF-a was effects of aspirin on cyclooxygenase (COX)-1 and COX-2, suppressed in human monocytic leukemia cells and in with the drug exhibiting higher preference for COX-1 [24].
human glioma cells by VPA treatment [31]. In prostate Aspirin has also been shown to inhibit NF-kB activation cancer cells, suppression in IL-6 production was mediated [25], thus illustrating its anticancer activities in a COX- through inhibition of NF-kB activity [32]. VPA has been independent pathway. Furthermore, aspirin has been shown to increase the acetylation of signal transducers and shown to modulate the production of inflammatory cyto- activators of transcription protein (STAT) 1, which permits kines, to inhibit the activity of activator protein (AP)-1 (a binding of STAT1 to NF-kB and reduces NF-kB activity in transcription factor closely associated with proliferation of human melanoma cell lines [33]. Whether VPA modulates tumor cells) [26], and to modulate numerous molecules inflammatory pathways in cancer patients has not been linked with tumorigenesis, such as b-catenin, wnt, and demonstrated. VPA has been evaluated for safety and tumor necrosis factor (TNF) [27].
efficacy in numerous clinical trials for different leukemias In summary, these epidemiological and preclinical stud- and solid tumors either alone or in combination with other ies suggest the potent anticancer activities of aspirin.
agents [34]. Some of these trials have advanced to Phase II However, aspirin intake is associated with gastrointestinal for recurrent glioblastoma, advanced thyroid cancers, and renal toxicities and thus aspirin cannot be adminis- acute myelogenous leukemia, relapsed/refractory leuke- tered chronically. Further research is needed to identify mias, non-small and small-cell lung cancers, B cell lym- safer NSAIDs with minimal gastrointestinal and renal phoma, breast cancer, melanoma, prostate cancer, and these studies suggest VPA as a promising drug to fight cancer, either alone or in combination with other agents. It Depakine (valproic acid, VPA), a short-chain fatty acid, is is expected that the completion of these clinical trials will used for the treatment of convulsions and migraines. The place this HDAC inhibitor at the forefront of anticancer drug was first identified as exhibiting anticancer activities in human leukemia cells because of its structural similari- ty with another anticonvulsant that has anticancer activi- ties, 1-methyl-1-cyclohexanecarboxylic acid (MCCA) [28].
Celecoxib is a NSAID that helps to relieve the pain and In subsequent years, VPA was shown to inhibit histone inflammation associated with rheumatoid arthritis (RA) deacetylase (HDAC) [29]. Altered expression and muta- and osteoarthritis. Originally approved by the FDA in tions of genes that encode HDACs have been implicated in 1998, the drug has been shown to interact selectively tumor growth because they can induce the aberrant tran- with and inhibit COX-2, a well-known inflammatory scription of genes regulating crucial cellular functions such cancer target. Celecoxib has also been shown to exhibit Author's personal copy
Trends in Pharmacological Sciences September 2013, Vol. 34, No. 9 chemopreventive activities against numerous cancer the range recommended for patients with coronary heart types because of its COX-2 inhibitory activities. Animal disease. A population-based case-control study was studies have supported the antitumor activities of cel- designed to assess the efficacy of statin use in patients ecoxib [35]. Some COX-2-independent targets of this drug with adenocarcinoma of the colon or rectum [42]. The use of are NF-kB, AKT8 virus oncogene cellular homolog (AKT), statins was not associated with reduced risk of colorectal glycogen synthase kinase (GSK) 3b, b-catenin, and cell cancer. The risk of stage IV cancer was, however, signifi- survival proteins of the inhibitor of apoptosis protein cantly lower among statin users than among non-users. In (IAP) and the B cell lymphoma (Bcl)-2 families [36].
another study, 5 years of long-term statin therapy was not In patients with familial adenomatous polyposis, 6 associated with significant reduction in colorectal cancer months of twice-daily treatment with 400 mg of celecoxib risk [43]. Further clinical studies are thus required to was found to produce a significant reduction in the number demonstrate the efficacy of statins in cancer patients.
of colorectal polyps [37]. On the basis of results from a National Cancer Institute-sponsored Phase II trial, the drug was approved by the FDA for the prevention of polyps Metformin has been widely used for more than 30 years in in patients with familial adenomatous polyposis (FAP) in the treatment of type 2 diabetes. At the molecular level, December 1999 [37]. However, the recommended dose for metformin has been shown to activate AMP-activated the prevention of FAP (800 mg/day) is higher than that for protein kinase (AMPK), a key regulator of cellular metab- patients with osteoarthritis (200 mg/day) or RA (200– olism. The fact that mammalian target of rapamycin 400 mg/day). The putative gastrointestinal, renal, and (mTOR), a master gene involved in cancer cell survival, cardiotoxic effects associated with this drug are one of is negatively regulated by AMPK has led many researchers its major drawbacks and, therefore, caution is required to evaluate the efficacy of metformin in patients treated while taking this NSAID as an anticancer drug alone or in with this drug [44]. Studies indicate that metformin can also reduce mTOR signaling independent of AMPK by Additionally, short-term COX-2 inhibition by celecoxib inhibiting Ras-related GTPase (Rag)-mediated activation was associated with antitumor activity in primary breast of mTOR [45]. Extensive preclinical and clinical studies cancer tissue in a recent study. The drug exhibited anti- over the past decade have demonstrated the antitumor proliferative activities as reflected by a reduction of Ki-67- properties of this drug.
positive cells. It was concluded that COX-2 inhibition In patients with diabetes and at the dose of metformin should be considered as a treatment strategy for further used by these patients (250–500 mg/day), the drug has clinical testing in primary breast cancer.
been shown to reduce the risk of cancer. A large prospective study [46] indicated that the incidence of gastroenterologi- cal cancer in patients with diabetes was reduced by a daily Statins are a group of cholesterol-lowering agents that dose of metformin (500 mg/day). A recent systematic re- inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG- view and meta-analysis indicated that metformin was CoA) reductase, a rate-limiting enzyme in the cholesterol associated with a substantially lower risk of all-cancer biosynthesis pathway. Statins are used to lower the en- mortality and incidence in patients with diabetes [47]. A dogenous synthesis of cholesterol in patients at high risk of relationship between long-term use of metformin and de- myocardial infarction. Owing to their HMG-CoA reductase creased risk of breast cancer in women with type 2 diabetes inhibitory activities, statins reduce the concentration of was demonstrated in an observational study [48]. Further- downstream byproducts including mevalonate and farne- more, diabetes patients with breast cancer receiving met- syl and geranylgeranyl pyrophosphate. Because tumor formin and neoadjuvant chemotherapy had a higher cells depend heavily on sustained availability of these pathological complete response rate than did patients with molecules, statins represent promising cancer therapeu- diabetes not receiving metformin [49]. The therapeutic tics. One of our studies showed that simvastatin can potential of metformin in prostate, breast, endometrial, potentiate TNF-induced apoptosis through downregula- and pancreatic cancers is currently being evaluated in tion of NF-kB-regulated antiapoptotic gene products in several clinical trials, some of which have advanced to chronic myeloid leukemia cells [38]. In a subsequent study, Phase III (e.g., NCT01101438, NCT01864096).
we found that of the six statins, only the natural statins (simvastatin, mevastatin, lovastatin, and pravastatin), and not the synthetic statins (fluvastatin and atorvasta- Rapamycin (sirolimus) is a lipophilic macrolide and an tin), were able to inhibit TNF-induced NF-kB activation in allosteric inhibitor of the mTOR pathway that was ap- chronic myeloid leukemia cells [39]. The antitumor activi- proved as an immunosuppressant in 1999 for the preven- ties of statins are supported by studies in animal tumor tion of allograft rejection. Because mTOR is frequently models in which statins have been found to reduce the upregulated in many tumor types [50], rapamycin has incidence and growth of tumors [40].
been heavily investigated for its anticancer properties.
Observational studies in humans support the chemo- However, the immunosuppressant nature of rapamycin preventive effect of statins, showing significant reduction makes it somewhat paradoxical. In one study, the drug in the overall risk of cancer. In a case-control study, use of suppressed colony formation of leukemic progenitor cells in statins, in particular simvastatin (!40 mg/day for 2–5 patients with acute myeloid leukemia [51]. The drug has years), was associated with a significantly reduced inci- also been shown to be efficacious in patients with imatinib- dence of colorectal cancer [41]. These doses are well within resistant chronic myelogenous leukemia [52]. Patients Author's personal copy
Trends in Pharmacological Sciences September 2013, Vol. 34, No. 9 showed a positive response and a decrease in vascular evident from another recent study [62]. Zoledronic acid endothelial growth factor (VEGF) mRNA levels in circu- was found effective in preventing or delaying skeleton- lating leukemic cells. The side effects during rapamycin related events in patients with advanced cancer metastasis treatment were mild in most patients.
to bone or myeloma. Bisphosphonates, alone or as adju- Interest in the anticancer activities of rapamycin has vants, were also found efficacious in preventing bone me- stimulated researchers to develop new semisynthetic rapa- tastases and overall progression of disease in patients with mycin analogs (rapalogs) such as everolimus, temsiroli- breast cancer [63], prostate cancer [64], and osteosarcoma mus, and deforolimus (ridaforolimus) with high specificity, better solubility, and minimal adverse effects[53]. Temsir- Zoledronic acid is now approved for the treatment of olimus was approved for the treatment of renal cell carci- metastatic bone disease [66]. However, the recommended noma by the FDA and the European Medicines Agency in doses for treating bone metastases are much higher than those required for the treatment of postmenopausal osteo- porosis. Furthermore, the adverse effects associated with these drugs, such as renal toxicity, osteonecrosis of the jaw, Methotrexate is a folic acid analog that inhibits dihydro- and gastrointestinal problems, deserve attention.
folate reductase, an enzyme needed for DNA synthesis, repair, and cellular replication. In the early 1950s, when Other non-cancer drugs methotrexate was first proposed as a treatment for leuke- In addition to the drugs discussed above, numerous other mia, its dihydrofolate reductase inhibitory effects were non-cancer drugs have demonstrated anticancer activities.
shown to contribute to its antitumor activities [54]. Studies Leflunomide is an immunomodulatory drug often used as a in subsequent years proved the antitumor efficacy of this first-choice disease-modifying antirheumatic drug [67]. In drug in a wide range of malignancies, including breast, addition to its inhibitory effects on dihydroorotate dehy- ovarian, bladder and head and neck cancers [55]. In 1988, drogenase, the drug has been shown to be a potent inhibi- the drug was approved by the FDA for the treatment of tor of tyrosine kinases, epidermal growth factor receptor, osteosarcoma, breast cancer, acute lymphoblastic leuke- and fibroblast growth factor receptor [68]. Because activa- mia, and Hodgkin lymphoma.
tion of these kinases is often associated with various forms Methotrexate has also been found to target inflamma- of cancer, leflunomide represents a potentially important tory pathways. In our own laboratory, the drug was found cancer therapeutic.
to suppress NF-kB activation through the release of aden- Wortmannin is a fungal metabolite that was originally osine in cancer cells. The drug decreases the production of reported for its anti-inflammatory activity. It is an irre- TNF-a and chemokines and exhibits antiangiogenic prop- versible inhibitor of phosphoinositide 3-kinase (PI3K) that erties that may also contribute to its anti-inflammatory forms a covalent bond in the ATP-binding cleft of the profile [56].
kinase [69]. The PI3K pathway is frequently activated and is involved in the pathogenesis of numerous cancer types. Because of the inhibitory effects of wortmannin on Bisphosphonates are a class of drugs most commonly the PI3K pathway, this fungal metabolite could play a role prescribed to treat osteoporosis (bone destruction). These in future cancer therapeutics.
drugs have been widely used to prevent bone loss and to Minocycline is a lipophilic semisynthetic derivative of reduce the risk of skeletal complications because of their the tetracycline group of antibiotics originally prescribed proven efficacy in inhibiting osteoclast-mediated bone for the treatment of severe acne and approved by the FDA resorption [57]. Because of anti-bone-resorptive effects, in 1971. Recent studies have demonstrated that minocy- bisphosphonates are now being used to ameliorate can- cline has anticancer activities against ovarian cancer, cer-related bone loss in patients. Bisphosphonates inhibit glioma, and numerous other cancer types [70].
farnesyldiphosphate synthase in the mevalonate pathway Vesnarinone, a synthetic quinolinone derivative with and thereby prevent protein prenylation of small GTPase inotropic effects, was originally developed to treat cardiac signaling proteins required for osteoclast function [58].
failure. Because of its antiproliferative, differentiation- Numerous bisphosphonates have been developed over inducing, and apoptosis-inducing properties, the drug the years, including etidronate, clodronate, tiludronate, has exhibited activities against several human malignan- pamidronate, alendronate, ibandronate, risedronate, and cies, including leukemia and several solid tumors [71].
zoledronic acid.
Thiocolchicoside is a semisynthetic drug derived from Preclinical and clinical studies have shown that bispho- colchicoside that has been used for more than 35 years as sphonates possess various antitumor effects in numerous an analgesic, a muscle relaxant, and a treatment for cancer types, including multiple myeloma, breast cancer, numerous orthopedic, traumatic, and rheumatological con- prostate cancer, and osteosarcoma [59]. The efficacy of ditions [72]. Studies over the past decade have indicated bisphosphonates in ameliorating cancer-related bone loss the anticancer potential of this drug [73–75]. Mechanisti- in patients with metastatic bone disease and multiple cally, thiocolchicoside has been shown to inhibit the NF-kB myeloma has been well established [60]. In a recent, large signaling pathway in cancer cells [73]. We found that the randomized clinical trial involving 1970 multiple myeloma drug inhibited the phosphorylation, ubiquitination, and patients, zoledronic acid was found to suppress bone loss degradation of the IkBa subunit of NF-kB that was linked [61]. The benefits of zoledronic acid in improving overall with suppression of IKK activation and p65 nuclear trans- survival rates of patients with multiple myeloma were location [73]. However, further studies using animal Author's personal copy
Trends in Pharmacological Sciences September 2013, Vol. 34, No. 9 models and human studies are needed to prove the anti- Considering the fact that the hurdles associated with cancer potential of this fascinating muscle relaxant.
Phase II and III trials have not changed over the years and Nitroxoline is an antibiotic that is used to treat urinary that these trials are the most expensive in drug develop- tract infections. In an attempt to identify potent anticancer ment, it is unknown whether repurposing failed Phase II or agents from a library of 175,000 chemical compounds, approved drugs would save money and time. However, nitroxoline was recently found to possess potent antiangio- there are many places along the drug development process genic activity [76]. The anticancer activity of nitroxoline where the strategy of repurposing an old drug for a new was shown by another recent study [77]. Among six differ- anticancer indication could save time and expense. The ent compounds tested, nitroxoline was one of the potent period of preclinical and Phase I testing is extensive. Drugs agents against lymphoma, leukemia, and pancreatic can- that successfully complete this testing are approved for cer cells [77].
Phase II testing. If drugs fail in a Phase II trial, this is Noscapine is a natural non-opiate alkaloid known to usually because they did not effectively treat the disease possess antitussive (cough suppressant), antimalarial, and for which they were intended. However, because these analgesic properties. Studies over the past 5 years have drugs modulate various targets in the preclinical models demonstrated the anticancer activities of this drug [78,79].
and had passed Phase I toxicity testing in humans, it is The most common mechanisms implicated in the antican- possible that these drugs could still be effective but needs cer activities of noscapine include inhibition in microtubule testing against the right disease, such as cancer. Some of assembly [80], suppression of the expression of hypoxia- the drugs discussed in this review, such as wortmannin inducible factor-1a [78] and Bcl-2 [81], induction of the and thiocolchicoside, have shown activity only in preclini- expression of p21 and p53 [82], and activation of c-Jun cal studies. Whether these observations will translate into NH2-terminal kinase [83]. Clinical data on the anticancer the clinic remains to be seen. If they are unsuccessful, we activities of noscapine are limited, however.
believe that, through careful analysis of the observations, it might be possible to use their chemical structures or Perspective and future directions targets to develop new anticancer drugs. We believe that During the past decade, interest in finding new uses for exploring the utility of a known drug with known molecu- old drugs has grown among clinicians and researchers.
lar targets and biological effects has less risk of failure than In this review, we have discussed several defined drugs does developing a new molecule with untested biological and two drug classes (statins and bisphosphonates) that effects. This line of thought was probably the basis for the have shown anticancer activities and palliative benefits following statement made by James Black, pharmacologist in cancer patients. Only a few of these drugs (thalido- and winner of the 1988 Nobel Prize in Physiology or mide, celecoxib, methotrexate, and zoledronic acid) have Medicine: ‘the most fruitful basis for the discovery of a been approved for cancer patients, however. The ratio- new drug is to start with an old drug' [84]. In most cases, it nale for evaluating the anticancer activity of most of is uncertain whether drug doses, formulations, and routes these non-cancer-approved drugs came from previous of administration similar to those used for the original knowledge of their biological activities on cancer targets indication are needed for a new anticancer indication. If and the fact that they have passed significant numbers the new drug doses are not readily achievable in humans, of toxicity tests and thus have known safety. The further modifications of the original structure might be possibilities of failure for reasons of adverse toxicology needed to achieve the pharmacokinetic and pharmacody- are minimal.
namic profiles suitable for new oncology indications.
Although drug repurposing should significantly reduce Furthermore, the approved drugs are surrounded by reg- the money and time associated with new cancer drug ulatory standards and intellectual property issues that development, there are numerous points that deserve could impede commercialization for new anticancer indi- attention. The approved non-cancer drugs cannot be tested cation. Given the demonstrated successes of the bedside-to- blindly in cancer patients without valid mechanistic in- bench approach highlighted in this review, we believe that sight into their possible efficacy. Only a few non-cancer each of these challenges deserves further extensive re- drugs (e.g., thalidomide) have progressed straight to can- search throughout the drug discovery community.
cer patients. Identification of similar drugs would obvious- ly be immensely valuable. Because in most cases the real Concluding remarks mechanism of action of drugs in the human body is un- In summary, starting with an existing old drug with a known, it may be worth examining the efficacy of approved known clinical history can significantly reduce the time and abandoned drugs with defined biological activities and cost associated with the development of new drugs for (e.g., thiocolchicoside, nitroxoline) directly in cancer the prevention and treatment of cancer. We hope that drug patients. When considering drugs for repurposing, we repurposing will play a high-impact role in developing new recommend extra care in selecting only those abandoned cancer drug therapies and bringing these therapies rapidly drugs whose non-cancer activities have been demonstrated to patients who are in great need of medicine to cure this using reliable end points and that have properly defined deadly disease. Drug repurposing offers an opportunity to pharmacokinetic and pharmacodynamic data. The drugs significantly advance basic understanding throughout the discussed in this review have been approved for other drug design process and to establish novel collaborations purposes, have well-defined pharmacokinetic and pharma- between academic and industry scientists. Indeed, such codynamic properties, and have well-characterized cancer collaborative approaches are already under way. For in- stance, the National Institutes of Health, via its National Author's personal copy
Trends in Pharmacological Sciences September 2013, Vol. 34, No. 9 Center for Advancing Translational Sciences, has collabo- 20 Keifer, J.A. et al. (2001) Inhibition of NF-kappa B activity by rated with eight companies to test 58 abandoned drugs for thalidomide through suppression of IkappaB kinase activity. J. Biol.
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