Current Medicinal Chemistry, 2011, 18, 1509-1514 1509 Exploring Old Drugs for the Treatment of Hematological Malignancies
F. Gan#,1,2, B. Cao#,1, D. Wu1, Z. Chen1, T. Hou*,3 and X. Mao*,1,4
1Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, China 2Department of Pharmacy, The First Hospital, Xianning University, Xianning, China 3Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, China 4Department of Pharmacology, School of Pharmacy, Soochow University, Suzhou, China Abstract: Drug discovery is costly and time-consuming, but it will become easier and simpler if a drug could be developed from an old one with well-documented investigations associated with pharmacology, pharmacokinetics, toxicology and clinical safety. In terms of hematological malignancies, several successful drugs have been discovered and developed from old ones such as arsenic trioxide for acute promyelocytic leukemia and thalidomide for multiple myeloma. In this review, we discussed the latest advancement in exploring old drugs for the treatment of hematological malignancies. Keywords: Drug repositioning, drug discovery, old drug, hematological malignancy. 1. INTRODUCTION
patent agreement, such as ampicillin; ii) those drugs withdrawn from the market due to its latent toxicity, such as thalidomide; iii)
Drug discovery is a complicated systemic engineering requiring
ancient drugs. This kind of drugs are traditional in most Eastern or
investment of capital, human resources, and various technology
African countries and have been used for hundreds of years or
expertise. More importantly, it requires strict adherence to regula-
longer but not scientifically developed in modern era; iv) to a cer-
tions on testing and manufacturing standards, thus, development of
tain extent, old drugs should also include those candidates aborted
a novel drug is time-consuming and costly. According to a recent
during the evaluation because of its efficacy or safety issues; v)
analysis of 68 approved drugs, it takes an average of 10 to 15 years
currently, most researchers also regard those on-patent drugs as old
and US$ 800 million to bring a single drug from bench to patient’s
drug resources because of its established safety evaluation and po-
bedside . By further analysis, the cost is steadily increased
tential application for new indications.
mainly due to the low successful rate and the high expenses in the safety evaluation and clinical trials. It would also expand the re-
3. OLD DRUGS ARE HOPES OF HEMATOLOGICAL MA-
sources for postmarketing safety surveillance to $29.3 million .
For fiscal year 2008, it would be nearly $400 million, accounting for more than 40% of FDA resources for drug regulation . To con-
Reviewing the history of the drug discovery, especially in the
trol the escalating high cost and increase the ebbing marketing rate
application of old drugs, one can find that most successful cases are
in the R & D of new drugs, scientists have incepted various strate-
found in hematological malignancies (Table 1), and these drugs
gies and developed advanced technologies, of which re-evaluation
include arsenic trioxide for acute promyelocytic leukemia (APL) [6,
of old drugs has emerged as the most rapid and most efficient way
7], dexamethasone and prednisolone for multiple myeloma (MM)
[3, 4]. As we have known that almost all drugs used in human ther-
[8, 9], and thalidomide for MM [10, 11], chronic lymphoid leuke-
apy possess more than one kind of acting targets and display major
mia (CLL)  and mantle cell lymphoma (MCL) . In addition,
and/or minor actions thus bringing one or several pharmacological
several other old drugs also display potential activity in the treat-
side effects in addition to their main activity . In some cases,
ment of leukemia and myeloma and have been currently evaluated
such “side” effects are therapeutic for other diseases. To extend
at preclinical or clinical settings (Table 1).
such old drugs, a new term “ Drug repositioning” or “Drug repur-posing” has emerged and new uses for old drugs has raised great
3.1. Arsenic Trioxide
interest among drug scientists and clinicians . Actually some old drugs have been developed for new indications, such as aspirin for
Arsenic trioxide has been used for the treatment of cancers and
stroke, sildenafil (Viagra) for erection dysfunction and
other disorders for more than 500 years in China . In Western
methotrexate for rheumatoid arthritis (Table 1). In this review, we
countries, arsenic derivatives were once used for syphilis treatment
discussed latest advancement in repositioning old drugs for hemato-
. However, arsenic exposure induces cardiovascular diseases,
logical malignancies and the discovery strategies.
developmental abnormalities, neurological and neurobehavioral disorders, diabetes, hearing loss, hematological disorders, and vari-
2. WHAT IS AN OLD DRUG?
ous types of cancers . Due to toxic side effects of long-term heroic-dose of oral arsenic in most patients, and with the advent of
Generally, an old drug should be “of age”, but latest concepts in
modern radiotherapy and chemotherapy, the arsenic treatment for
old drug repositioning indicate that an old drug sometimes is not
CML was abandoned in Western medicine. But in China, the study
very “old”. An old drug could be defined as the following catego-
on arsenic trioxide has never stopped. In 1971, they started a large
ries: i) off-patent drugs. These kinds of drugs have been used for a
scale clinical trial in more than 1000 cases of different types of
certain period and become generic and are not protected by the
cancers by i.v. administration of arsenic trioxide . Therapeutic
effects were observed in several cancer types, including CML, lym-
*Address correspondence to these authors at the Institute of Functional Nano & Soft
phoma, esophageal cancer, and particularly APL. The preliminary
Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional
result in APL was reported in 1992 . They found that a prepara-
Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China; Tel: +86
tion containing arsenic with a trace amount of mercury chloride was
(512) 65882039; Fax: +86 (512) 65882846; E-mail: [email protected]
Laboratory of Targeted Anti-leukemia Drug Discovery, Cyrus Tang Hematology
Center, Soochow University, 199 Ren Ai Road, Room703-507, Suzhou Industrial Park,
cal complete remission (CR) up to 84% without major toxic side
Suzhou, Jiangsu 215123, China; Tel: +86 (512) 65880877 ext 507; Fax: +86 (512)
effects . Moreover, 28% of the patients survived more than 10
65882123; E-mail: [email protected]
years [16, 17]. Following this study, a small scale clinical trial was
#These authors contributed equally to this study.
0929-8673/11 $58.00+.00 2011 Bentham Science Publishers Ltd. 1510 Current Medicinal Chemistry, 2011 Vol. 18, No. 10 Gan et al. Old Drugs Were Developed for Hematological Malignancies Drugs Original Indications* New Indications** Notes and refs.
Blood cancers, mainly for Acute Promyelocytic Leukemia
Leukemia, Mantle cell lymphoma, and Myeloma
Multiple Myeloma and other Plasma Cell Neoplasm
*indicates those diseases the drugs were originally designed for. **includes those indications approved by FDA or those potential applications.
held in USA, and 11 of the 12 patients studied achieved complete
genesis [32, 33]. Therefore thalidomide was immediately with-
remission after treatment that lasted from 12 to 39 days . Stud-
drawn from market in 1961. Research on thalidomide slowed down
ies on the mechanism of action indicated that arsenic trioxide pre-
in the 1960s, but never stopped. Several lines of mechanisms of
sents dual activities (induction of apoptosis and differentiation) on
teratogenesis were proposed including angiogenesis inhibition [32,
APL cells in vivo and in vitro . Apoptosis induced by arsenic
34], free radical-mediated oxidative DNA damage , and inhibi-
trioxide is associated with the insult of mitochondrial and the acti-
tion on IGF1 and FGF2 expression [34, 36]. All these molecular
vation of caspases. The differentiation of APL cells is closely re-
events are associated with cancer development. Thalidomide was
lated to the modulation of PML-RAR, the key protein in leu-
first tested as a single agent for the treatment of multiple myeloma
kemogenesis . Recent studies indicate thioredoxin reductase is a
in 1999 for its anti-angiogenesis activity , followed by a series
target of arsenic trioxide . Arsenic trioxide was approved by the
of successful multicenter clinical trials which ensured thalidomide
US FDA for acute promyelocytic leukemia  and is used as one
was approved by the FDA. Thalidomide analogues such as le-
nalidomide were also developed and are more powerful, but with fewer side effects . Thalidomide and lenalidomide are now used as a first line therapy for multiple myeloma. The discovery of tha-
lidomide was believed as a breakthrough in the therapy of multiple
Dexamethasone was first synthesized in late 1950s and imme-
myeloma in the last 30 years. Thalidomide has also been evaluated
diately became a new star in the corticosteroid family. In addition
in a number of other hematological disorders, including AML [38,
to its general application in the inflammatory and autoimmune dis-
39], myelofibrosis with myeloid metaplasia and MDS, and some
eases, dexamethasone is also used to protect patients from the side-
effects of chemotherapeutical agents. In 1972, one group found that cells of a cloned myeloma line from a Balb/c mouse bearing spe-
4. DISCOVERY STRATEGIES FOR DRUG REPOSITION-
cific cytoplasmic glucocorticoid receptors could be killed by dex-
amethasone . Further studies indicated that dexamethasone-induced myeloma cell death are associated with both apoptotic and
With the success of old drugs in the treatment of several dis-
autophagy signals . For example, dexamethasone induced cyto-
eases, scientists are becoming more and more interested in drug
chrome C-dependent and independent apoptosis  by changing
repositioning. Recently, several papers have been published in
the conformation of Bax and Bim . Recent studied indicated
highly-ranked journals to call for drug discovery from the old ones
that autophagy is a novel pathway induced by dexamethasone .
[3, 4, 41-43]. They not only called for the reformation in the law
The caspase inhibitor Z-VAD-fmk inhibited apoptosis but not auto-
system thus paving the road that allows old drugs used in valuable
phagy in Dexamethasone-treated cells . Following the first
new ways , but also developed new strategies for the reposition-
report, more and more investigations have demonstrated that dex-
ing of old drugs. Generally speaking, those strategies could be clas-
amethasone is very effective to myeloma cancer cells alone or in
combination with other drugs, such as doxorubicin, vincristine and even most recent drugs such as thalidomide and Bortezomib .
Dexamethasone is now the backbone in the prescription of multiple myeloma treatment. Recently, dexamethasone was introduced to the
Based on the mechanistic understanding, some physicians
would try their applications in some off-labeled diseases. Legally,
treatment of chronic lymphoid leukemia [29, 30] and relapsed lym-
off-label use is the practice of prescribing pharmaceuticals for an
phoma . Our recent study demonstrated that not only dex-amethasone and prednisolone, but all other glucocorticoids display
unapproved indication and it is empirical and sometimes leads to great discovery. The best example is the application of thalidomide
anti-myeloma activity for cells bearing c-maf and cyclin D2 .
in leprosy . As stated earlier in this paper, thalidomide was developed as a sleeping drug for morning sickness during preg-
nancy, and was withdrawn from the market in 1961 due to its tera-
Thalidomide was originally developed in the 1950s for the
togenicity. However, 3 years later, Dr. Jacob Sheskin, Professor at
treatment of pregnancy-associated morning sickness and was first
the Hebrew University of Jerusalem at Hadassah University Hospi-
marketed in 1957 as a "wonder drug" for insomnia, coughs, colds
tal, administered thalidomide to a critically ill patient with erythema
and headaches because its sedative-hypnotic effects. However,
nodosum leprosum in an attempt to relieve his pain in spite of the
thalidomide was soon found to be associated with malformation. In
ban. To his surprise, thalidomide was effective in control of the
the late 1950s and early 1960s, more than 10,000 children in 46
symptoms of this disorder. The result was followed by more favor-
countries were born with deformities such as phocomelia as a con-
able experiences and then by a clinical trial [44,45]. Mechanisti-
sequence of thalidomide use associated with its inhibition on angio-
cally, thalidomide cures leprosy by inhibiting tumor necrosis factor
Old Drugs for Blood Cancer Therapy Current Medicinal Chemistry, 2011 Vol. 18, No. 10 1511
alpha [46-48]. The FDA has since approved the drug's use in the
antagonists dichloroisoprenaline (DCI) and pronethalol  (Fig.
treatment of erythema nodosum leprosum. Thalomid, as the drug is
1a). DCI is a non-selective blocker for the 1-adrenergic and 2-
commercially known, sold over $300 million per year in United
adrenergic receptors, but it has low potency. Pronethalol was a
promising clinical candidate with similar structure to DCI but showed carcinogenicity in mice. However, the insertion of a
4.2. Exploration of the Side Activities
methoxy bridge into the arylethanolamine structure of pronethalol (Fig. 1a) will increase the potency of the compound and eliminate
Almost all drugs present one or more pharmacological side ef-
the carcinogenicity being found with pronethalol in animal models
fects because they can act on more than one target molecules or
. Similar efforts have brought newer and more selective beta-
organs. However, these side effects are possibly important in differ-
blockers (such as nebivolol) in the treatment of hypertension .
ent clinical settings and could lead to a therapeutic outcome to an-other disorder. The best example is the discovery of sildenafil. Sild-
Based on thalidomide, several derivatives were successfully
synthesized such as lenalidomide and pomalidomide (Fig. 1b). This
enafil was originally designed for the treatment of angina pectoris
secondary generation of thalidomide has been fully developed and
and hypertension. However, when it was applied for clinical trials for patients of angina, it displayed no positive return. In contrast,
displays more powerful therapeutic efficacy but less toxicity than thalidomide . Of them, lenalidomide was approved for clinic
continuous penile erection was noticed in patients. Then it was
earlier than thalidomide by FDA. In our exploration of clioquinol,
moved to the treatment of erection dysfunction (ED)  and achieved a great success. Thalidomide in the treatment of MM is
we designed and tested a series of clioquinol analogs and found that 5-amino-8-hydroxyquinoline (5AHQ, Fig. 1c) is more potent and
another good example. As we stated earlier, thalidomide is terato-
effective in inhibiting proteasomal activity than clioquinol. Further
genic by inhibiting VEGF signaling thus disrupting angiogenesis during the formation of limbs[30,31]. Angiogenesis is proposed as
studies suggested that 5AHQ overcomes bortezomib-resistance and induces cell apoptosis synergistically with bortezomib .
an important factor in myeloma development because increased bone marrow vascularity and angiogenesis-associated signals of IL-6, VEGF, FGFR are frequently seen in myeloma . Thus tha-
4.5. High Throughput Screening
lidomide was challenged for myeloma treatment in a clinical trial in
The above-discussed four strategies have led to the successful
1999 using its antiangiogenic activity . It turned out great re-
discovery of some drugs in the past decades. However, with the
mission after myeloma administration which finally led to the wide
advancement in the genomics, proteomics, and informatics technol-
application in myeloma. Currently, French Prestwick chemical
ogy, scientists are able to manipulate a large set of compounds si-
company developed a protocol called SOSA approach (Selective
multaneously to develop a novel drug from old ones. There are
Optimization of Side Activities) . The objective of SOSA is to
several collections of old drugs available from commercial and
proceed to a reversal of affinities, such that the identified side effect
public sectors, including (1) LoPac Library (Sigma-Aldrich), which
becomes the principal activity and vice versa. Prestwick has docu-
contains 1280 well-documented pharmacologically-active com-
mented an array of off-patent drugs for novel drug discovery. We
pounds (most of them are off-patent drugs); (2) Prestwick chemical
have screened this library and found several compounds for poten-
library from French Prestwick Chemical Co., which is composed of
1120 off-patent medicines (>85% are clinical pharmaceutics); (3) Spectrum Collection (MicroSource Discovery Systems, Inc.), con-
4.3. Development of Ancient or Traditional Drugs Using Mod-
taining 2000 biologically active and structurally diverse compounds
including known drugs; (4) NIH Brain Bioactive Compound Col-lection, a large collection of available medications including CNS
Ancient or traditional drugs are a great heritage of human be-
ings and have been long used in some countries. However, evalu-
or CNS-like active compounds. These libraries have paved a solid base for the identification of novel indications by means of high
ated under the modern standards, those old drugs are not safe
throughput screening which includes two basic strategies:
enough or don’t display high efficacy thus being abandoned. The best example is arsenic trioxide as stated earlier. Another example
Phenotype-based, or end-point, screening. In this strategy,
is harringtonine (HT). Harringtonine is a cephalotaxus alkaloid
an aliquot of each old drug is added to blood cancer cells of
from the evergreen tree Cephalotaxus harringtonia K. Koch var
interest. After a defined period of incubation, cell viability
harringtonia present in China . Seeds of this genus of conifers
is evaluated. Those drugs with ability to induce cancer cell
were part of the Traditional Chinese Medicine (TCM) since 1400s
but are toxic to humans . To improve its application, Chinese
Molecule-targeted screening. In this strategy, we first take
investigators applied modern analytic methods and isolated four
advantage of cancer genomics and proteomic advancements
alkaloids including homoharringtonine (HHT) which display sig-
and choose one or two molecules as the screening targets
nificant antitumour activity. Clinical trials were performed in the
for novel indications of old drugs. Most of blood cancer
U.S. using continuous infusion schedules of 3-7 mg/m2 daily for 5-
cells are featured with chromosomal aberrations, such as
7 days initially, and later lower dose schedules of 2.5 mg/m2 daily
translocation, deletion, and insertion, which lead to novel
for 7-14 days. Results in solid tumors were negative. However,
fusion genes or dysregulated genes. Best examples are the
encouraging results were reported in patients with AML, myelo-
BCR/ABL fusion gene due to the reciprocal translocation
dysplastic syndrome, APL, and CML . Currently, HHT has
denoted as t(9;22)(q34;q11) in chronic myelogenous leu-
been widely used for leukemia in China. And new semisynthetic
kemia and the PML/RAR fusion gene due to the transloca-
preparations and HHT derivatives that bypass multidrug resistance
tion denoted as t(15;17)(q22;q12) in acute promyelocytic
may improve the efficacy and toxicity profiles, and broaden the
leukemia. Drug discovery targeting these cancer-specific
genes will be molecular mechanism-oriented and, more im-portantly, because the molecules are usually cancer-
4.4. Structural Modification
specific, those drugs are less toxic and more effective in the treatment of blood cancer patients. We have applied this
Similar compounds with the same core structure theoretically
strategy to screen three small off-patent libraries and found
share the similar biological and pharmacological activity. The struc-tural modification can improve drug efficacy and decrease the tox-
that old drugs such as clioquinol  and cyproheptadine  show potential for the treatment of leukemia and mye-
icity of a lead candidate. Propranolol, the first successful non-
selective beta blocker, was derived from the early -adrenergic
1512 Current Medicinal Chemistry, 2011 Vol. 18, No. 10 Gan et al. Fig. (1). Drug discovery by structural modification. a, Propranolol was derived from the early -adrenergic antagonists dichloroisoprenaline (DCI) and pronethalol. The insertion of a methoxy bridge (*) into the arylethanolamine structure of pronethalol increases the potency of the compound and apparently eliminates the carcinogenicity found with pronethalol in animal models. b, More potent lenalidomide and pomalidomide are derived from thalidomide by adding amino group. c. 5-amino-8-hydroxyquinoline was developed from clioquinol by replacing the chloride with amino at position 5 and removing the io- dine. 5. OUR EXPERIENCE
breast and prostate cancer apoptosis in the presence of copper [65, 66]. In our effort to seek inhibitors of cyclin D2 transactivators, we
Multiple myeloma is an incurable plasma cell malignancy fea-
found that clioquinol could significantly decrease D-cyclins at both
tured with various chromosomal translocations and dysregulated
protein and mRNA levels. Mechanistically, Clioquinol-induced
genes such as D-cyclins and c-maf. At least one of the 3 cyclin Ds
cancer cell apoptosis is associated with its inhibition on proteaso-
(CCND1, CCND2 and CCND3) is dysregulated in any MM cells
mal activity [54, 66]. Further investigations suggested that clioqui-
. Cyclin D2, along with its transcription factor c-maf, was re-
nol alone can induce cell apoptosis of leukemia or myeloma cells
ported in more than 50% of MM cell lines and patient samples, and
and can delay tumor growth in leukemia cell xenografted mice,
is an indicator of poor prognosis [57, 58]. D-cyclins coordinate with
which is different from solid tumors such as breast and prostate
cyclin-dependent kinase 4 or 6 (CDK4/6) to phosphorylate the tu-
cancer xenografts . This kind of apoptosis induction is critical
mor suppressor pRb thus activating transcription factor E2F and
for the treatment because if clioquinol-induced cancer cell death is
enabling cell cycle progress to S phase from G1 phase . Thus
dependent on copper addition and it will add additional toxicity to
inhibition of cyclin D could arrest MM cells in G1 phase and in-
patients due to the accumulative toxicity of copper. Our clioquinol
duce cell apoptosis . Based on this hypothesis, we designed a
has been approved by Health Canada for clinical trial in the treat-
high throughput screening system using cyclin D2 promoter-driven
ment of refractory and/or relapse acute myelogenous leukemia.
firefly luciferase as a reporter and screened old drug libraries LO-PAC, Prestwick and Spectrum . Through this screen, we identi-
fied the off-patented drugs clioquinol  and cyproheptadine  as potential therapeutics for both myeloma and leukemia, and we
Cyproheptadine is a typical antihistamine/anticholinergic and
also found natural products such as pristimerin  and kinetin
antiserotonergic agent. It acts as a 5-HT2 receptor antagonist and
riboside  for the treatment of blood cancers.
also blocks calcium channels. Cyproheptadine is mostly used to treat allergic reactions such as hay fever and also used to treat
nightmares and manage serotonin syndrome and is also used to treat unintentional weight loss in patients with cancer , but it has
Clioquinol is an antifungal and antiprotozoal drug developed in
never been reported for its proapoptotic or anti-cancer activity. In
1930s and was very effective in anti-infective, intestinal
our efforts to look for the inhibitors of cyclin D transactivation by a
antiamebic, and vaginal trichomonacide and soon was marketed
high throughput screening, we found that cyproheptadine is able to
worldwide. However, clioquinol was suspected to be highly associ-
inhibit all 3 types of cyclin Ds in all the tested leukemia and mye-
ated with subacute myelo-optic neuropathy (SMON) between 1957
loma cell lines by inhibiting several transcription factors such as
and 1970 . It has thus been restricted or discontinued in some
AP-2 . Further studies indicated that cyproheptadine can shrink
countries. Recently, clioquinol was revitalized as a novel agent in
tumors of AML and myeloma xenografted mice models . Re-
the treatment of Alzhemier’s Disease  and Huntington’s Dis-
cent study indicated that cyproheptadine can also synergizes with
ease . In 2005, it was reported to be a potential drug to induce
Bortezomib in the treatment of mantal cell lymphoma by inhibiting
Old Drugs for Blood Cancer Therapy Current Medicinal Chemistry, 2011 Vol. 18, No. 10 1513
the histone deacetylase . This kind of potential therapeutic ac-
tivity in the treatment of malignant hematological diseases will be
Soignet, S.L.; Maslak, P.; Wang, Z.G.; Jhanwar, S.; Calleja, E.; Dardashti, L.J.; Corso, D.; DeBlasio, A.; Gabrilove, J.; Scheinberg, D.A.; Pandolfi, P.P.;
Warrell, R.P.Jr. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N. Engl. J. Med., 1998, 339, 1341-1348. 6. CONCLUSIONS
Zhu,J.; Chen, Z.; Lallemand-Breitenbach, V.; de The, H. How acute promye- locytic leukaemia revived arsenic. Nat. Rev. Cancer,2002, 2, 705-713.
Chen, Z.; Zhao, W.L.; Shen, Z.X.; Li, J.M.; Chen, S.J.; Zhu, J.; Lallemand-
Based on the above discussion and previous investigations, one
Breittenbach, V.; Zhou, J.; Guillemin, M.C.; Vitoux, D.; de Thé, H. Arsenic
can find that drug repositioning maximizes our use of existing
trioxide and acute promyelocytic leukemia: clinical and biological. Curr.
knowledge on old drugs or drug candidates. Starting from an exist-
Top. Microbiol. Immunol.,2007, 313, 129-144.
ing drug can bypass a large portion of the overall cost in the R & D
Lu, J.; Chew, E.H.; Holmgren, A. Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proc. Natl. Acad. Sci. U. S. A.,2007,
of drug discovery and will increase the marketing rate and shorten
the time in the development process. Thus, rather than chasing new
Cohen, M.H.; Hirschfeld, S.; Flamm, H.S.; Ibrahim, A.; Johnson, J.R.;
compounds, pharmaceutical companies are now pay more attention
O'Leary, J.J.; White, R.M.; Williams, G.A.; Pazdur, R. Drug approval sum-
in the existing products or old drugs. The most concern of drug
maries: arsenic trioxide, tamoxifen citrate, anastrazole, paclitaxel, bexaro- tene. Oncologist, 2001, 6, 4-11.
repositioning is the challenge of the intellectual property issues
Gehring, U.; Mohit, B.; Tomkins, G.M. Glucocorticoid action on hybrid
surrounding the original drug and from a commercial point of view
clones derived from cultured myeloma and lymphoma cell lines. Proc. Natl.
it may need extra caution when bringing such a drug to market.
Acad. Sci. U. S. A.,1972, 69, 3124-3127.
Grander, D.; Kharaziha, P.; Laane, E.; Pokrovskaja, K.; Panaretakis, T. Autophagy as the main means of cytotoxicity by glucocorticoids in hemato-
logical malignancies. Autophagy, 2009, 5, 1198-1200.
Chauhan, D.; Pandey, P.; Ogata, A.; Teoh, G.; Krett, N.; Halgren, R.; Rosen,
The authors thank Dr. Aaron D. Schimmer at Ontario Cancer
S.; Kufe, D.; Kharbanda, S.; Anderson, K. Cytochrome c-dependent and -
Institute, Princess Margaret Hospital, University Health Network,
independent induction of apoptosis in multiple myeloma cells. J. Biol.
Toronto, Canada, for his critical discussion. This project was sup-
Chem.,1997, 272, 29995-29997.
Lopez-Royuela, N.; Balsas, P.; Galan-Malo, P.; Anel, A.; Marzo, I.; Naval, J.
ported by Jiangsu Provincial Natural Science Foundation (Grant
Bim is the key mediator of glucocorticoid-induced apoptosis and of its poten-
No. BK2010218), by the National Basic Research Program (“973”
tiation by rapamycin in human myeloma cells. Biochim. Biophys. Acta.,
Program, Grants No. 2011CB933501, and 2011CB933503), by
Suzhou City Science and Technology Program (Social Develop-
Swerdlow, S.; McColl, K.; Rong, Y.; Lam, M.; Gupta, A.; Distelhorst, C.W. Apoptosis inhibition by Bcl-2 gives way to autophagy in glucocorticoid-
ment Project, Grant No. SS201033), and by National Natural Sci-
treated lymphocytes. Autophagy,2008, 4, 612-620.
ence Foundation of China (Grant No. 81071935), and by the Prior-
Kyle, R.A.; Rajkumar, S.V. Treatment of multiple myeloma: a comprehen-
ity Academic Program Development of Jiangsu Higher Education
sive review. Clin. Lymphoma Myeloma,2009, 9, 278-288.
Kaufman, M.; Limaye, S.A.; Driscoll, N.; Johnson, C.; Caramanica, A.; Lebowicz, Y.; Patel, D.; Kohn, N.; Rai, K. A combination of rituximab, cy-clophosphamide and dexamethasone effectively treats immune cytopenias of
chronic lymphocytic leukemia. Leuk. Lymphoma, 2009, 50, 892-899.
Lin, T.S.; Ruppert, A.S.; Johnson, A.J.; Fischer, B.; Heerema, N.A.; Andrit-
Rawlins, M.D. Cutting the cost of drug development. Nat. Rev. Drug Dis-
sos, L.A.; Blum, K.A.; Flynn, J.M.; Jones, J.A.; Hu, W.; Moran, M.E.;
cov.,2004, 3, 360-4.
Mitchell, S.M.; Smith, L.L.; Wagner, A.J.; Raymond, C.A.; Schaaf, L.J.;
McClellan, M. Drug safety reform at the FDA--pendulum swing or system-
Phelps, M.A.; Villalona-Calero, M.A.; Grever, M.R.; Byrd, J.C. Phase II
atic improvement. N. Engl. J. Med.,2007, 356, 1700-1702.
study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrat-
Aronson J.K. Old drugs--new uses. Br. J. Clin. Pharmacol., 2007, 64, 563-
ing high response rates in genetically high-risk disease. J. Clin. Oncol.,2009,
Chong, C.R.; Sullivan, D.J. Jr. New uses for old drugs. Nature,2007, 448,
Biagi, J.J.; Herbert, K.E.; Smith, C.; Abdi, E.; Leahy, M.; Falkson, C.; Wolf,
M.; Januszewicz, H.; Seymour, J.F.; Richards, K.; Matthews, J.P.; Dale, B.;
Wermuth, C.G. Selective optimization of side activities: another way for
Prince, H.M. A phase II study of dexamethasone, ifosfamide, cisplatin and
drug discovery. J. Med. Chem., 2004, 47, 1303-1314.
etoposide (DICE) as salvage chemotherapy for patients with relapsed and re-
Tallman, M.S. The expanding role of arsenic in acute promyelocytic leuke-
fractory lymphoma. Leuk. Lymphoma,2005, 46, 197-206.
mia. Semin. Hematol., 2008, 45,S25-S29.
D'Amato, R.J.; Loughnan, M.S.; Flynn, E.; Folkman, J. Thalidomide is an
Wang, Z. Y.; Chen, Z. Acute promyelocytic leukemia: from highly fatal to
inhibitor of angiogenesis. Proc. Natl. Acad. Sci. U. S. A., 1994, 91, 4082-
highly curable. Blood,2008,11,2505-2515.
Buzaid, A.C.; Durie, B.G. Management of refractory myeloma: a review. J.
Singhal, S.; Mehta, J.; Desikan, R.; Ayers, D.; Roberson, P.; Eddlemon, P.;
Clin. Oncol., 1988, 6, 889-905.
Munshi, N.; Anaissie, E.; Wilson, C.; Dhodapkar, M.; Zeddis, J.; Barlogie,
Alexanian, R.; Barlogie, B. New treatment strategies for multiple myeloma.
B. Antitumor activity of thalidomide in refractory multiple myeloma. N. Am. J. Hematol.,1990, 35, 194-198. Engl. J. Med., 1999, 341, 1565-1571.
Cavallo, F.; Boccadoro, M.; Palumbo, A. Review of thalidomide in the
Therapontos, C.; Erskine, L.; Gardner, E.R.; Figg, W.D.; Vargesson, N.
treatment of newly diagnosed multiple myeloma. Ther. Clin. Risk. Manag.,
Thalidomide induces limb defects by preventing angiogenic outgrowth dur-
2007, 3, 543-552.
ing early limb formation. Proc. Natl. Acad. Sci. U. S. A.,2009, 106, 8573-
Palumbo, A.; Facon, T.; Sonneveld, P.; Blade, J.; Offidani, M.; Gay, F.;
Moreau, P.; Waage, A.; Spencer, A.; Ludwig, H.; Boccadoro, M.; Harous-
Parman, T.; Wiley, M.J.; Wells, P.G. Free radical-mediated oxidative DNA
seau, J.L. Thalidomide for treatment of multiple myeloma: 10 years later.
damage in the mechanism of thalidomide teratogenicity. Nat. Med., 1999, 5, Blood, 2008, 111, 3968-3977.
Chanan-Khan, A.; Porter, C.W. Immunomodulating drugs for chronic lym-
Stephens, T.D.; Bunde, C.J.; Fillmore, B.J. Mechanism of action in thalido-
phocytic leukaemia. Lancet Oncol., 2006, 7, 480-488.
mide teratogenesis. Biochem. Pharmacol.,2000, 59, 1489-1499.
Goy, A. New directions in the treatment of mantle cell lymphoma: an over-
Chanan-Khan, A.A.; Cheson, B.D. Lenalidomide for the treatment of B-cell
view. Clin. Lymphoma Myeloma,2006, 7, Suppl 1: S24-32.
malignancies. J. Clin. Oncol.,2008, 26, 1544-1552.
Roboz, G.J. Arsenic and old lace: novel approaches in elderly patients with
Gore, S.D. New agents for the treatment of AML recent study findings. Clin.
acute myeloid leukemia. Semin. Hematol.,2008, 45, S22-24. Adv. Hematol. Oncol.,2008, 6, 6-8.
Tchounwou, P.B.; Centeno, J.A.; Patlolla, A.K. Arsenic toxicity, mutagene-
Fehniger, T.A.; Byrd, J.C.; Marcucci, G.; Abboud, C.N.; Kefauver, C.;
sis, and carcinogenesis--a health risk assessment and management approach.
Payton, J.E.; Vij, R.; Blum, W. Single-agent lenalidomide induces complete
Mol. Cell. Biochem.,2004, 255, 47-55.
remission of acute myeloid leukemia in patients with isolated trisomy 13.
Zhang, T.D.; Chen, G.Q.; Wang, Z.G.; Wang, Z.Y.; Chen, S.J.; Chen, Z.
Blood, 2009, 113, 1002-1005.
Arsenic trioxide, a therapeutic agent for APL. Oncogene,2001,20,7146-
Teo, S.K.; Stirling, D.I.; Zeldis, J.B. Thalidomide as a novel therapeutic
agent: new uses for an old product. Drug Discov. Today,2005, 10, 107-114.
Shen, Z.X.; Chen, G.Q.; Ni, J.H.; Li, X.S.; Xiong, S.M.; Qiu, Q.Y.; Zhu, J.;
McPhie, D.C. Old drugs, new uses: solving a Hatch-Waxman patent pre-
Tang, W.; Sun, G.L.; Yang, K.Q.; Chen, Y.; Zhou, L.; Fang, Z.W.; Wang,
dicament. Food Drug Law J.,2004, 59, 155-168.
Y.T.; Ma, J.; Zhang, P.; Zhang, T.D.; Chen, S.J.; Chen, Z.; Wang, Z.Y. Use
Berger, S.P. Old laws stop drugs being used in valuable new ways. Nature,
of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia
2007, 449, 972.
(APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood,
DiMasi, J.A.; Grabowski, H.G. Should the patent system for new medicines be abolished. Clin. Pharmacol. Ther., 2007, 82, 488-490. 1514 Current Medicinal Chemistry, 2011 Vol. 18, No. 10 Gan et al.
Walker, S.L.; Waters, M.F.; Lockwood, D.N. The role of thalidomide in the
art, A.K. Identification of kinetin riboside as a re pressor of CCND1 and
management of erythema nodosum leprosum. Lepr. Rev., 2007, 78, 197-215.
CCND2 with preclinical antimyeloma activity. J. Clin. Invest.,2008, 118,
Pearson, J.M.; Vedagiri, M. Treatment of moderately severe erythema nodo-
sum leprosum with thalidomide-a double-blind controlled trial. Lepr. Rev.,
Mao, X.; Schimmer, A.D. The toxicology of Clioquinol. Toxicol. Lett., 2008, 1969, 40, 111-116.
Santos, D.O.; Lorre, K.; de Boer, M.; Van Heuverswyn, H. Shedding of
Adlard, P.A.; Cherny, R.A.; Finkelstein, D.I.; Gautier, E.; Robb, E.; Cortes,
soluble receptor for tumor necrosis factor alpha induced by M. leprae or LPS
M.; Volitakis, I.; Liu, X.; Smith, J.P.; Perez, K.; Laughton, K.; Li, Q.X.;
from human mononuclear cells. Nihon Hansenbyo Gakkai Zasshi, 1999, 68,
Charman, S.A.; Nicolazzo, J.A.; Wilkins, S.; Deleva, K.; Lynch, T.; Kok, G.;
Ritchie, C.W.; Tanzi, R.E.; Cappai, R.; Masters, C.L.; Barnham, K.J.; Bush,
Tadesse, A.; Abebe, M.; Bizuneh, E.; Mulugeta, W.; Aseffa, A.; Shannon,
A.I. Rapid restoration of cognition in Alzheimer's transgenic mice with 8-
E.J. Effect of thalidomide on the expression of TNF-alpha m-RNA and syn-
hydroxy quinoline analogs is associated with decreased interstitial Abeta.
thesis of TNF-alpha in cells from leprosy patients with reversal reaction. Im-Neuron, 2008, 59, 43-55. munopharmacol. Immunotoxicol.,2006, 28, 431-441.
Nguyen, T.; Hamby, A.; Massa, S.M. Clioquinol down-regulates mutant
Shannon, E.; Noveck, R.; Sandoval, F.; Kamath, B. Thalidomide suppressed
huntingtin expression in vitro and mitigates pathology in a Huntington's dis-
IL-1beta while enhancing TNF-alpha and IL-10, when cells in whole blood
ease mouse model. Proc. Natl. Acad. Sci. U. S. A.,2005, 102, 11840-11845.
were stimulated with lipopolysaccharide. Immunopharmacol. Immunotoxi-
Daniel, K.G.; Chen, D.; Orlu, S.; Cui, Q.C.; Miller, F.R.; Dou, Q.P. Clioqui-
col.,2008, 30, 447-457.
nol and pyrrolidine dithiocarbamate complex with copper to form protea-
Li, W.W.; Hutnik, M.; Gehr, G. Antiangiogenesis in haematological malig-
some inhibitors and apoptosis inducers in human breast cancer cells. Breast
nancies. Br. J. Haematol.,2008, 143, 622-631. Cancer Res., 2005, 7, R897-R908.
Wermuth, C.G. Selective optimization of side activities: the SOSA approach.
Chen, D.; Cui, Q.C.; Yang, H.; Barrea, R.A.; Sarkar, F.H.; Sheng, S.; Yan,
Drug Discov. Today,2006, 11, 160-164.
B.; Reddy, G.P.; Dou, Q.P. Clioquinol, a therapeutic agent for Alzheimer's
Kantarjian, H.M.; Talpaz, M.; Santini, V.; Murgo, A.; Cheson, B.; O'Brien,
disease, has proteasome-inhibitory, androgen receptor-suppressing, apopto-
S.M. Homoharringtonine: history, current research, and future direction.
sis-inducing, and antitumor activities in human prostate cancer cells and
Cancer,2001, 92, 1591-1605.
xenografts. Cancer Res.,2007, 67, 1636-1644.
Barrett, A.M. Cardiac beta-adrenoceptor blockade: the quest for selectivity.
Mattox, T.W. Treatment of unintentional weight loss in patients with cancer.
J. Pharmacol., 1985, 16 Suppl 2, 95-108. Nutr. Clin. Pract.,2005, 20, 400-410.
Stewart, A.K. Novel therapies for relapsed myeloma. Hematology. Am. Soc.
Paoluzzi, L.; Scotto, L.; Marchi, E.; Seshan, V.E.; O'Connor, O.A. The anti-
Hematol. Educ. Program,2009, 578-586.
histaminic cyproheptadine synergizes the antineoplastic activity of borte-
Mao, X.; Li, X.; Sprangers, R.; Wang, X.; Venugopal, A.; Wood, T.; Zhang,
zomib in mantle cell lymphoma through its effects as a histone deacetylase
Y.; Kuntz, D.; Coe, E.; Stewart, A.K.; Roase, D.; Batey, R.A.; Kay, L.E.;
inhibitor. Br. J. Haematol., 2009, 146, 656-659.
Schimmer, A.D. Clioquinol inhibits the proteasome and displays preclinical
Li, X.; Wood, T.E.; Sprangers, R.; Jansen, G.; Franke, N.E.; Mao, X.; Wang,
activity in leukemia and myeloma. Leukemia,2009, 23, 585-590.
X.; Zhang, Y.; Verbrugge, S.E.; Adomat, H.; Li, Z.; Trudel, S.; Chen, C.; Re-
Mao, X.; Liang, S.B.; Hurren, R.; Gronda ,M.; Chow, S.; Xu, G.W.; Lee. K.;
liga, T.L.; Jamal, N.; Messner, H.; Cloos, J.; Rose, D.R.; Navon, A.; Guns,
Chow, S.; Liang, S.; Trudel, S.; Hedley, D.; Schimmer, A.D. Cyproheptadine
E.; Batey, R.A.; Kay, L.E.; Schimmer, A.D. J. Natl. Cancer Inst., 2010,
displays preclinical activity in myeloma and leukemia. Blood, 2008, 112,
Boolell, M.; Allen ,M.J.; Ballard, S.A.; Gepi-Attee,S.; Muirhead, G.J.; Nay-
Bergsagel, P.L.; Kuehl, W.M. Molecular pathogenesis and a consequent
lor, A.M.; Osterloh, I.H.; Gingell, C. Sildenafil: an orally active type 5 cyclic
classification of multiple myeloma. J. Clin. Oncol.,2005, 23, 6333-6338.
GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile
Hurt, E.M.; Wiestner, A.; Rosenwald, A.; Shaffer, A.L.; Campo, E.; Grogan,
dysfunction. Int. J. Impot. Res.,1996,8,47-52.
T.; Bergsagel, P.L.; Kuehl, W.M.; Staudt, L.M. Overexpression of c-maf is a
de Boer, R.A.; Voors, A.A.; van Veldhuisen, D.J. Nebivolol: third-generation
frequent oncogenic event in multiple myeloma that promotes proliferation
beta-blockade. Expert Opin. Pharmacother.,2007,8,1539-1550.
and pathological interactions with bone marrow stroma. Cancer Cell, 2004,
Eberhard, Y.; McDermott, S.P.; Wang, X.; Gronda, M.; Venugopal, A.;
Wood, T.E.; Hurren, R.; Datti, A.; Batey, R.A.; Wrana, J.; Antholine, W.E.;
Mao, X.; Stewart, A.K.; Hurren, R.; Datti, A.; Zhu, X.; Zhu, Y.; Shi, C.; Lee,
Dick, J.E.; Schimmer, A.D. Chelation of intracellular iron with the antifungal
K.; Tiedemann, R.; Eberhard, Y.; Trudel, S.; Liang, S.; Corey, S.; Gillis, L.;
agent ciclopirox olamine induces cell death in leukemia and myeloma cells.
Barber, D.L.; Wrana, J.; Ezzat, S.; Schimmer, A.D. A chemical biology
screen identifies glucocorticoids that regulate c-maf expression by increasing
Worldwide Clinical Trials Listings. Study of Fluphenazine in Relapsed or
its proteasomal degradation through up-regulation of ubiquitin. Blood,2007,
Relapsed-and-Refractory Multiple Myeloma. http://www.clinicaltrialssearch.
Vermeulen, K.; Van Bockstaele, D.R.; Berneman, Z.N. The cell cycle: a
Spagnuolo, P.A.; Hu, J.; Hurren, R.; Wang, X.; Gronda, M.; Sukhai, M.A.;
review of regulation, deregulation and therapeutic targets in cancer. Cell Pro-
Di Meo, A.; Boss, J.; Ashali, I.; Behesti Zavareh, R.; Fine, N.; Simpson,
lif., 2003, 36, 131-149.
C.D.; Sharmeen, S.; Rottapel, R.; Schimmer, A.D.The antihelmintic fluben-
Tiedemann, R.E.; Schmidt, J.; Keats, J.J.; Shi, C.X.; Zhu, Y.X.; Palmer, S.E.;
dazole inhibits microtubule function through a mechanism distinct from
Mao, X.; Schimmer, A.D.; Stewart, A.K. Identification of a potent natural
vinca-alkaloids and displays preclinical activity in leukemia and myeloma.
triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-
kappaB with antimyeloma activity in vitro and in vivo. Blood,2009, 113,
Tiedemann, R.E.; Mao, X.; Shi, C.X.; Zhu, Y.X.; Palmer, S.E.; Sebag, M.;
Marler, R.; Chesi, M.; Fonseca, R.; Bergsagel, P.L.; Schimmer, A.D.; Stew-
Received: December 15, 2010 Revised: March 05, 2011 Accepted: March 06, 2011
Title: Pandysautonomic Neuropathy Presents as Fatigue, Generalized Neuropathic Pain, and Dysphagia in a 15-Year-Old Female Author(s): Binh Phung, DO1; Travis Campbell, DO1; Shawna Duncan, DO1; Joseph Walter, MD2; Michael Chang, MD3; and David Siegler, MD4 Affiliation(s): 1 Oklahoma State University Department of Pediatrics, Tulsa, Oklahoma 2 Pediatric Pulmonology – The Children’s
wondrous divine intervention that led to Mordechai and Esther foiling the plot of Bigtan and Teresh to poison the king. Mordechai didn’t receive any reward for his heroism only after Haman was raised to great heights and then Hashem caused the king not to be able to sleep that night etc. In these events we clearly see the wonders of Hashem and that He is there thinking of us constantly, eve