Ogni antibiotico è efficace in relazione a un determinato gruppo di microrganismi
comprare ciprofloxacina online in italiain caso di infezioni oculari vengono scelte gocce ed unguenti.
Webb.cm.utexas.edu
Author's personal copy
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.
Author's personal copy
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
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Source: http://webb.cm.utexas.edu/research/papers/Webb_TiPS_2013.pdf
1ASSAY TECHNOLOGIES Anuradha RoyDel Shankel Structural Biology Center, High Throughput Screening Laboratory, Lawrence, Kansas Gerald H. LushingtonMolecular Graphics and Modeling Laboratory, University of Kansas, Lawrence, Kansas; LiS Consulting, Lawrence, Kansas James McGee Quantitative Biology, Eli Lilly and Company, Indianapolis, Indiana
A MINI REVIEW Viridis BioPharma Pvt. Ltd. Viridis BioPharma Pvt. Ltd. "VITAMIN K2-7" A MINI REVIEW Had this review been written just 25 years ago, the metabolism of vitamin K would have been considered just in the context of its role in haemostasis. During the last 25 years there has been intensive research with the vitamin K and its analogues which has surfaced the role of vitamin K2-7 (natural) and K2-4 (synthetic) in the human physiology in multiple functions. The newly discovered functions extend throughout the body in the Ca metabolism giving rise to the label "Calcium Paradox" because Ca gets deposited in the vasculature instead of the required target bones. Vitamin K is an essential fat-soluble micronutrient which is needed for a unique posttranslational chemical modification in a small group of proteins with calcium-binding properties, collectively known as vitamin K – dependent proteins (VKD proteins) or Gla-proteins. This review is general as well as specific to K2-7 to bring out its importance amongst other vitamin K analogues. INTRODUCTION