Cancer wars: natural products strike back Christine Basmadjian1,2, Qian Zhao1,2, Embarek Bentouhami3, Amel Djehal1,3, Canan G. Nebigil4, Roger A…. [600187]

REVIEW ARTICLE
published: 01 May 2014
doi: 10.3389/fchem.2014.00020
Cancer wars: natural products strike back
Christine Basmadjian1,2, Qian Zhao1,2, Embarek Bentouhami3, Amel Djehal1,3, Canan G. Nebigil4,
Roger A. Johnson5,M a r i aS e r o v a2, Armand de Gramont2, Sandrine Faivre2,6, Eric Raymond2,6and
Laurent G. Désaubry1*
1Therapeutic Innovation Laboratory, UMR7200, CNRS/University of Strasbourg, Illkirch, France
2AAREC Filia Research, Clichy, France
3L.C.I.M.N Laboratory, Department of Process Engineering, Faculty of Technology, University Ferhat Abbas, Sétif, Algeria
4Biotechnology and Cell Signaling Laboratory, UMR 7242, CNRS/ University of Strasbourg, Illkirch, France
5Department of Physiology and Biophysics, State University of New Y ork, Stony Brook, NY , USA
6Department of Medical Oncology, Beaujon University Hospital, INSERM U728/AP-HP , Clichy, France
Edited by:
Asier Unciti-Broceta, The University
of Edinburgh, UK
Reviewed by:
Luis Álvarez De Cienfuegos
Rodríguez, University of Granada,
Spain
Francisco Franco-Montalbán,
University of Granada, Spain
*Correspondence:
Laurent G. Désaubry, Therapeutic
Innovation Laboratory (UMR 7200),
Faculté de Pharmacie, 7 4 Route du
Rhin, 67 401 Illkirch, France
e-mail: [anonimizat] products have historically been a mainstay source of anticancer drugs, but in
the 90’s they fell out of favor in pharmaceutical companies with the emergence of
targeted therapies, which rely on antibodies or small synthetic molecules identified by
high throughput screening. Although targeted therapies greatly improved the treatment
of a few cancers, the benefit has remained disappointing for many solid tumors, which
revitalized the interest in natural products. With the approval of rapamycin in 2007 , 12 novel
natural product derivatives have been brought to market. The present review describes the
discovery and development of these new anticancer drugs and highlights the peculiarities
of natural product and new trends in this exciting field of drug discovery.
Keywords: natural products, cancer, drug discovery, pharmacognosy, molecular targets, privileged structures
INTRODUCTION
Recent analyses of tooth plaques showed that ∼50,000 years ago
Neanderthals already used medicinal plants to treat their ailments
(Hardy et al., 2012 ). Currently, more than half of humanity does
not have access to modern medicine and relies on traditional
treatments ( Cordell and Colvard, 2012 ). A recent analysis of the
strategies used in the discovery of new medicines showed that
36% of the first-in-class small-molecules approved by U.S. Food
and Drug Administration (FDA) between 1999 and 2008 were
natural products or natural products derivatives ( Swinney and
Anthony, 2011 ).
Natural products are small-molecule secondary metabolites
that contribute to organism survival. These substances display
considerable structural diversity and “privileged scaffolds,” i.e.,
molecular architectures that are tailored to protein binding, as
first coined by Evans in the late 1980s ( Evans et al., 1988 ). Indeed
natural products have evolved to bind biological targets and elicit
biological effects as chemical weapons or to convey information
from one organism to another. Steroid derivatives are often not
considered as natural products because their design is not based
on a research in pharmacognosy, however we subjectively decided
to include them here due to their importance in drug discovery.
The synthesis of aspirin by Charles Gerhard at Strasbourg
faculty of pharmacy in 1853 paved the road for the medici-
nal chemistry of natural products ( Gerhardt, 1853 ). In 1964,
actinomycin became the first natural product approved for an
indication in oncology. Other natural products based medicines
such as anthracyclines, vinca alkaloids, epipodophyllotoxin lig-
nans, camptothecin derivatives, and taxoids that were launched
before 1997, are still an essential part of the armament for treating
cancers.From 1997 to 2007 no new natural product was approved
for the treatment of cancer ( Bailly, 2009 ). With the imminent
achievement of the genome project, the head of a pharmaceuti-
cal company declared that natural products were outdated. Their
development was greatly reduced and many big pharmaceutical
companies closed their departments of natural product chem-
istry ( Bailly, 2009 ). The future was targeted therapies, which
uses fully synthetic molecules or antibodies to target specific
proteins in tumor growth and progression. In some forms of
leukemia, gastrointestinal, prostate or breast cancers, targeted
therapies greatly delayed tumor progression, and/or improved the
life expectancy of the patients. Some tumors with specific onco-
genic addictions (for example fusion proteins leading to ALK
expression in lung cancer or Bcr-Abl in chronic myeloid leukemia,
KIT expression or mutations in GIST or EGFR mutation in lung
cancer, HER2 amplification in breast cancer or MET overex-
pression in liver tumors) greatly benefited from targeted agents.
However, the vast majority of common tumors were found to
be not dependent of a single “targetable” oncogenic activation.
For instance altogether ALK activations and EGFR mutations
account for less than 10% of lung adenocarcinoma and while
those targeted agents are more efficient than chemotherapy in
oncogenic tumors, antitumor effects are limited to few months.
Importantly, most tumors were shown to activate multiple signal-
ing pathway redundancies and adaptive mechanisms that either
render tumors primarily resistant to targeted drugs or facili-
tate acquired resistance to cell signaling inhibition after only few
months of treatments. As a result, the expected progression-free
survival benefit from targeted therapy is often less than 6-months.
For those later forming complex but rather frequent tumors,
chemotherapy alone remains the cornerstone of treatment with
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Basmadjian et al. Anticancer natural products
some limited add-on benefits by use of monoclonal antibodies in
a limited proportion of patients. Combinations of several targetedagents have also been proposed to counteract potential adaptivemechanisms although one should notice that combining targetedagent together was more often associated with unacceptable tox-icity than great clinical synergy. Then there is the additionalinfluence of cost-to-benefit concerns. The financial cost of suchtargeted therapies, to patients or health insurance entities, canbe considered enormous, e.g., thousands to tens of thousands ofeuros per day of extended life. However, the net financial benefitto pharmaceutical companies of those agents that are given onlyfor few months (or years) in only a small proportion of patientsin niche indications may lead to restricted investment by pharma-ceutical industries; blockbuster indications usually provide higherrevenues.
These drawbacks are at the origin of the re-emergence of
natural products in oncology. Since 2007, with the approval ofrapamycin and derivatives of it, 12 natural product derivativeshave been approved for the treatment of cancers ( Ta b l e 1 ).
Recently Stuart Schreiber, Paul Clemons and coworkers at the
Broad Institute in Boston performed a bioinformatics analysis ofnatural product targets and demonstrated that natural productsstatically tend to target proteins with a high number of protein–protein interactions that are particularly essential to an organism(Dan ˇcík et al., 2010 ). This observation is consistent with the com-
mon role played by natural products as chemical weapons againstpredators or competitors.
Henkel et al. at Bayer AG in Germany offered a statistical
analysis of the structural differences between natural productsand fully synthetic drugs ( Henkel et al., 1999 ). Compared with
fully synthetic drugs, natural product tend to have more chi-ral centers, more oxygen atoms, less nitrogen atoms, and morevaried ring systems. Complementary analyses of structural fea-tures of natural products have been reviewed ( Lee and Schneider,
2001; Ortholand and Ganesan, 2004; Ganesan, 2008; Grabowskiet al., 2008 ). A consequence of this structural complexity is that
natural products tend to be more selective toward their tar-gets than fully synthetic drugs, and consequently rarely displayoff-target—induced iatrogenicity.
Moreover, complex natural products tend to act through only
one class of molecular target, even though there are some excep-tions. Indeed, taxanes are known to target β-tubulin and interfere
with microtubule dynamics; however they also bind to Bcl-2 toblock its anti-apoptotic activity. Both β-tubulin and Bcl-2 interact
with the orphan nuclear receptor Nur77 (NGFI-B, TR3, NR4A1).Ferlini et al. showed that in fact taxanes mimic the domainof Nur77 involved in the interaction with β-tubulin and Bcl-
2(Ferlini et al., 2009 ). Another example concerns flavaglines,
an emerging family of natural compounds found in medicinalplants of South-East Asia, which display potent anticancer effectsthrough their direct effects on the scaffold proteins prohibitinsand the initiation factor of translation eIF4a ( Basmadjian et al.,
2013; Thuaud et al., 2013 ).
Modifying the structure of a drug may change the nature
of its molecular target. A striking example concerns the notso rational development of the anticancer medicines etoposideand teniposide ( Figure 1 ). Considering that cardiac glycosidesdisplay enhanced pharmacological properties compared to the
cognate aglycone, Sandoz scientists hypothesized that conjugat-ing podophyllotoxin to a glucose moiety could improve theactivity of this cytotoxic agent that binds tubulin and inhibitsassembly of the mitotic spindle. Fortunately, this glycoconju-gate named etoposide displayed a promising anticancer activitywith reduced adverse effects compared with podophyllotoxin.Surprisingly, etoposide did not affect tubulin polymerization butinhibited another very important target in oncology: DNA topoi-somerase II. This story illustrates well the importance in drugdiscovery of serendipity, which was likened to “looking for aneedle in a haystack and discovering the farmer’s daughter” byProfessor Pierre Potier, inventor of the anticancer drug taxotere(Zard, 2012 ).
Another non-rational issue regarding the SAR of derivatives of
natural compounds concerns the relationship between the chem-ical structure of a drug and its therapeutic indication. Indeed,transforming the structure of a drug may modify the nature ofthe targeted cancer. This is well established for vinca alkaloids for
instance ( Ta b l e 2 ). If we could understand the influence of the
molecular structure of a drug with its optimal therapeutic indi-cation, then we might be able to adapt known medicines to treatcancers that are reluctant to current therapies.
In spite of the major achievements in systems biology and
translational medicine over the last decade, there is still, at best,a presumptive relationship between the efficacy of a drug inpreclinical assays and the likelihood of its value in clinic.
RAPALOGUES: TEMSIROLIMUS®AND EVEROLIMUS®
In 1975, researchers at Ayerst Laboratories (Canada) reported theisolation of rapamycin as a secondary metabolite from a strain ofStreptomyces hygroscopicus based on its antifungal activity ( Sehgal
et al., 1975; Vezina et al., 1975 ). Its name comes from Rapa
Nui (Easter Island) where its producer strain had been collectedfrom a soil sample. Its richly adorned macrocyclic structure wasfully elucidated a few years later ( Swindells et al., 1978; Findlay
and Radics, 1980; McAlpine et al., 1991 ). Rapamycin did not
attract so much attention until the discovery in 1987 of the struc-turally related immunosuppressant FK506 ( Kino et al., 1987a,b ).
Rapamycin was eventually developed without further structuralmodifications as the oral immunosuppressant drug sirolimus. Itwas approved for prevention of rejection in organ transplantationin 1999 ( Calne et al., 1989; Kahan et al., 1991; Watson et al., 1999;
Calne, 2003 ).
Determining the mode of action of rapamycin unraveled one
of the most important signaling pathways in cell biology, whichillustrates another important asp ect of the pharmacology of nat-
ural products. Indeed a common caveat of developing an originalnatural product toward clinical application is the requirement toidentify its molecular target and understand its mode of action(Krysiak and Breinbauer, 2012 ). However, when the target is
identified, it may lead to major breakthroughs in cell biology(Pucheault, 2008 ). Gratefully, current technologies render this
task increasingly easier ( Ares et al., 2013 ).
In 1991, Michael Hall et al. identified the molecular target
of rapamycin in a gene complementation assay in yeast andnamed it TOR for “Target Of Rapamycin” ( Hietman et al., 1991 ).
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Basmadjian et al. Anticancer natural products
T able 1 | Novel anticancer medicines based on natural products.
Name (trade name), structure Y ear of approval, company Therapeutic indication, mode of action
Temsirolimus (Torisel®): R=R1
Everolimus (Afinitor®), R=R22007 , Wyeth Treatment of renal cell carcinoma (RCC), inhibition of mTOR
2009, Novartis Treatment of advanced kidney cancer, inhibition of mTOR
Ixabepilone (Ixempra®) 2007 , Bristol-Myers Squibb Treatment of aggressive metastatic or locally advanced breast cancer no
longer responding to currently available chemotherapies, stabilization ofmicrotubules
Vinflunine (Javlor®) 2009, Pierre Fabre Treatment of bladder cancer, inhibition of tubulin polymerization
Romidepsin (Istodax®) 2009, Celgene Treatment of cutaneous T -cell lymphoma (CTCL), inhibition of the
isoforms 1 and 2 of histone deacetylases
Trabectedin =ecteinascidin 7 43 (Y ondelis®) 2009, Zeltia and Johnson
and JohnsonTreatment of advanced soft tissue sarcoma and ovarian cancer, induction
of DNA damage
(Continued)
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Basmadjian et al. Anticancer natural products
T able 1 | Continued
Name (trade name), structure Y ear of approval, company Therapeutic indication, mode of action
Cabazitaxel (Jevtana®) 2010, Sanofi-Aventis Treatment of hormone-refractory metastatic prostate cancer,
microtubule stabilization
Abiraterone acetate (Zytiga®) 2011, Janssen Treatment of castration-resistant prostate cancer, inhibition of 17
α-hydroxylase/C17 , 20 lyase (CYP17A1)
Eribulin mesylate (Halaven®) 2011, Eisai Co. Treatment of metastatic breast cancer, inhibition of microtubule
dynamics
Homoharringtonine, Omacetaxinemepesuccinate (Synribo
®)2012, Teva Chronic myelogenous leukemia (CML), inhibition of protein synthesis
Carfilzomib (Kyprolis®) 2012, Onyx Treatment of multiple myeloma, inhibition of proteasome
Ingenol mebutate (Picato®) 2012, LEO Pharma Actinic keratosis, activation of PKC δ
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Basmadjian et al. Anticancer natural products
Three years later, Stuart Shreiber et al. identified its mammalian
homolog referred to today as the kinase mTOR (mammalianTOR) ( Brown et al., 1994 ). The mode of action of rapamycin is
unique: it binds to two proteins at the same time, mTOR andthe immunophilin FKBP-12, to form a ternary complex devoidof any kinase activity. mTOR plays a central role integratingsignals from growth factors, nutrients, stress, and hormones toregulate metabolism, proliferation, cell growth, and apoptosis.However, the exact mechanisms of action of rapamycin deriva-tives, called rapalogues, remain only moderately understood.Some recent evidence indicates that rapalogues may primarilydisplay their anticancer effects through an inhibition of angio-genesis in patients ( Faivre and Raymond, 2008 ). This hypothesis
would explain why rapologues are particularly effective in hyper-vascularized tumors.
Currently, two rapalogues, temsirolimus, and everolimus, have
been developed for the treatment of renal, breast, and pancreascancers, astrocytoma, and mantle cell lymphoma. These drugs
FIGURE 1 | Structures of podophyllotoxin, etoposide, and teniposide.differ in their formulation, application, and dosing schemes,thereby yielding varying bioavailabilities. They are all prepared bysemi-synthesis.
IXABEPILONE (IXEMPRA®)
Drugs that target microtubules, such as taxoids and vinca alka-
loids, continue to represent an important class of chemotherapeu-tic agents ( Jordan and Wilson, 2004 ). Over the last two decades
other classes of naturally occurring nontaxoid compounds, theepothilones ( Gerth et al., 1996; Höfle et al., 1996 ), discoder-
molides ( Gunasekera et al., 1990 ), eleutherobins ( Lindel et al.,
1997 ), and laulimalides ( Mooberry et al., 1999 ) that stabilize
microtubule assemblies similarly to taxol, have been identified(Figure 2 ). Based upon extensive structure-activity data, a com-
mon pharmacophore for these different classes of compounds hasbeen proposed ( Ojima et al., 1999 ).
Not only is epothilone B more cytotoxic than taxol, but
it is also much less sensitive toward the development ofmultidrug-resistance, a major concern in the clinic ( Horwitz,
1994; Bollag et al., 1995; Kirikae et al., 1996 ). This impres-
sive pharmacological profile coupled with the challenge of itstotal synthesis has attracted the attention of some of the mostwell-known organic chemists in the world, including SamuelDanishefsky ( Balog et al., 1996; Su et al., 1997 ), followed by
Nicolaou ( Nicolaou et al., 1997; Y ang et al., 1997 ), Schinzer
(Schinzer et al., 1997 ), Mulzer ( Mulzer et al., 2000 )a n dC a r r e i r a
(Bode and Carreira, 2001 ).
Early investigations indicated that natural epothilones dis-
play poor metabolic stability and unfavorable pharmacokineticproperties ( Lee et al., 2000 ). Several synthetic and semi-synthetic
analogs were then examined and evaluated in preclinical stud-ies. Eventually, isosteric replacement of the lactone by a lac-tam afforded ixabepilone (also known as azaepothilone B) ( Lee
et al., 2008 ). Not only is this drug not susceptible to hydroly-
sis by esterases, conferring metabolic stability, but it also displaysimproved water solubility, which greatly alleviate galenic prob-lems associated with hypersensitivity reaction in patients.
T able 2 | Structures and therapeutic indications of vinca alkaloids.
Name n QR1R2R3R4R5Therapeutic indication
Vinblastine 2 OH H Et OAc Me OMe Lymphomas, germ cell tumors, breast, head and neck cancer and testicular
cancers
Vinorelbine 1 Q =R1=∅(alkene) Et OAc Me OMe Osteosarcoma, breast, and non-small cell lung cancers
Vincristine 2 OH H Et OAc CHO OMe Acute lymphoblastic leukemia, rhabdomyosarcoma, neuroblastoma,
lymphomas, and nephroblastoma
Vindesine 2 OH H Et OH Me NH 2 Melanoma, lung, breast and uterine cancers, leukemia and lymphoma
Vinflunine 1 H H CF 2Me OAc Me OMe Bladder cancer
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Basmadjian et al. Anticancer natural products
FIGURE 2 | Chemical structures of representative natural compounds that stabilize microtubule assemblies.
In 2007, the FDA (but not its European equivalent, European
Medicines Agency or EMA) approved ixabepilone for the treat-ment of aggressive metastatic or locally advanced breast cancerno longer responding to currently available chemotherapies.
VINFLUNINE (JAVLOR®)
Vinca alkaloids were the first chemotherapeutic agents that tar-
get microtubules. The first member of this class, vinblastine, wasisolated in 1958 ( Noble et al., 1959 ). Latter, some derivatives, vin-
cristine, vinorelbine, and finally avelbine, were developed to treathematological and solid malignancies in both adult and pediatricpatients ( Ta b l e 1 ).Vinca alkaloids block the polymerization of
tubulin molecules into microtubules to prevent the formation ofthe mitotic spindle.In the course of their study on the reactivity of functionalized
molecules in superacid media, Jacquesy and collaborators foundthat the treatment of vinorelbine with a combination of HF andSbF
5gave a difluoro analog, later called vinflunine ( Scheme 1 )
(Fahy et al., 1997 ). Importantly, this new compound displayed
an enhanced bioavailability compared to other vinca alka-
loids. Indeed, its terminal half-life was calculated to be about40 h and the terminal half-life for its active metabolite (4- O-
deacetylvinflunine) was reported to be 4–6 days in several phase Itrials ( Bennouna et al., 2003, 2005; Johnson et al., 2006 ).
Resistance to vinflunine develops more slowly than with other
vinca alkaloids. In addition, vinflunine in vitro neurotoxicity is
lower than that of vincristine or vinorelbine ( Etiévant et al., 1998,
2001; Estève et al., 2006 ). Further development by Pierre Fabre
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Basmadjian et al. Anticancer natural products
SCHEME 1 | Synthesis of vinflunine from vinorelbine ( Fahy et al., 1997 ).
and Bristol Myers Squibb laboratories ended with the approval of
vinflunine for the treatment of bladder cancer by the EuropeanMedicines Agency (EMA) in 2009.
ROMIDEPSIN (ISTODAX®)
The cyclic depsi-pentapeptide romidepsin, also called FR901228,FK228, or NSC 630176, was isolated and identified by Ueda andcolleagues at Fujisawa Pharmaceutical in Japan through a screen-ing program of fermentation products able to revert the trans-formed morphology of a Ha-ras NIH3T3 cells to normal ( Ueda
et al., 1994 ). Indeed Ha-ras is an oncogene involved in tumorigen-
esis and consequently represents an important target in oncology.Importantly, romidespsin displayed potent antitumor activitiesagainst A549 and MCF-7 tumors in xenografted mice. Theseresults attracted the attention of NCI scientists who continuedto explore its anticancer properties under a Cooperative Researchand Development Agreement with Fujisawa Corporation (nowAstellas).
When romidepsin was discovered, histone deacetylases
(HDAC) were emerging as important targets for the treatmentof cancer ( Thaler and Mercurio, 2014 ). Screening of micro-
bial metabolites for their effects on transcription showed thatromidepsin behaves similarly to trichostatin A, a known HDACinhibitor ( Nakajima et al., 1998 ). Romidepsin acts as a prodrug,
which is reduced in cells to its active form by glutathione, yield-ing a monocyclic dithiol that preferentially inhibits the isoformsHDAC1 and HDAC2 ( Furumai et al., 2002 ).
In 2002, when it became established that romidepsin
holds a promising therapeutic potential, Fujisawa Corporationbegan clinical trials. Romidepsin was licensed to GloucesterPharmaceuticals in 2004 (latter acquired by Celgene Co)and was approved by the FDA in 2009 for the treat-
ment of cutaneous T-cell lymphoma. The preclinical and clin-ical development has been described in an excellent review(Vandermolen et al., 2011 ).
ECTEINASCIDIN 743 =TRABECTEDIN (YONDELIS®)
In 1969, unidentified alkaloids from the Caribbean tunicate
Ecteinascidia turbinate were shown to display some anticancer
activities, but the structure of these complex alkaloids could notbe determined because of their natural scarcity and the limita-tion of analytical chemistry at that time ( Sigel et al., 1970 ). In
1990, Rinehart et al. from the University of Illinois at Urbana-Champaign elucidated the structure and reported the cytotoxi-city of these tetrahydroisoquinoline alkaloids, the ecteinascidins(Rinehart et al., 1990 ). These compounds displayed greater in
vitro and in vivo antitumor activity than those reported for
the structurally related microbial metabolites saframycins andsafracins.
Ecteinascidin 743, also called trabectedin and ET-743, was
then selected for preclinical development based on its exceptionalin vitro cytotoxicity. Pommier et al. at NCI demonstrated that this
drug binds in the minor groove of DNA and alkylates the exo-cyclic amino group at position 2 of guanine in GC-rich regions(Scheme 2 )(Pommier et al., 1996 ).
Ecteinascidin 743 was shown to block the DNA excision repair
system ( Takebayashi et al., 2001; Zewail-Foote et al., 2001 ), to
cross-link DNA with topoisomerase I ( Martinez et al., 1999;
Takebayashi et al., 1999; Zewail-Foote and Hurley, 1999 ), and
also to inhibit the binding of DNA to some transcription fac-tors ( Bonfanti et al., 1999; Jin et al., 2000; Minuzzo et al.,
2000 ). However, the cascade of events that links DNA damage
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Basmadjian et al. Anticancer natural products
SCHEME 2 | DNA Alkylation by ecteinascidin 743.
to the resulting antitumor activity is far from being understood
(D’Incalci and Galmarini, 2010 ).
When ecteinascidin 743 was licensed to PharmaMar; this com-
pany launched a very challenging program of aquaculture toproduce sufficient quantities of tunicate biomass to feed clinicaltrials program. After several years of intensive development, thecumulative total biomass reached some 250 metric tons. However,isolation of ecteinascidin 743 required complex and costly stepsof purification with final yields less than 1 g/ton ( Cuevas and
Francesch, 2009 ). Several total syntheses have been reported, but
they cannot be translated into industrial production ( Corey et al.,
1996; Endo et al., 2002; Chen et al., 2006; Zheng et al., 2006;Fishlock and Williams, 2008; Imai et al., 2012; Kawagishi et al.,2013 ). Eventually, this supply problem was solved by use of a
complex semi-synthesis from cyanosafracin B, which is avail-able in kilogram quantities by fermentation ( Cuevas et al., 2000;
Menchaca et al., 2003 ).
Preclinical studies did not reveal that soft tissue sarcoma is
more sensitive to ecteinascidin 743 than other solid tumors.This response was unveiled first during phase I clinical trialsand confirmed in phase II ( Taamma et al., 2001; Villalona-
Calero et al., 2002; D’Incalci and Jimeno, 2003 ). This drug was
approved under the name of Y ondelis in 2007 in the EuropeanUnion for the treatment of patients with advanced soft tis-sue sarcoma. This compound was the first anticancer medicineof marine origin to be approved. It was followed by eribu-lin (vide infra), validating the concept that marine naturalproducts should be considered important contenders in drugdiscovery.
CABAZITAXEL (JEVTANA®)
The taxane anticancer drug cabazitaxel is a semi-synthetic deriva-tive of the natural taxoid 10-deacetylbaccatin III. It was approvedin 2010 by the FDA, in combination with prednisone, forthe treatment of patients with hormone-refractory metastaticprostate cancer who had already been administered a treatmentcontaining the taxane docetaxel ( Galsky et al., 2010 ). In 2013,
Vrignaud et al. showed that in vitro , cabazitaxel stabilized micro-
tubules as effectively as docetaxel but was also 10 times morepotent than docetaxel in chemotherapy-resistant tumor cells.They also noted that cabazitaxel was active in docetaxal-resistanttumors ( Vrignaud et al., 2013 ). In addition, cabazitaxel pene-
trates the blood-brain barrier. Cabazitaxel was approved 20 yearsafter taxol, illustrating that there is still room to improve wellestablished anticancer medicines.
ABIRATERONE ACETATE (ZYTIGA®)
Abiraterone acetate is an oral inhibitor of androgen synthesis usedsince 2011 for the treatment of castration-resistant prostate can-cer. Previous treatments of prostatic cancers prevented androgenproduction by the testes, but not by the adrenals. Abirateroneacetate is rapidly hydrolyzed in vivo to abiraterone, which is a
selective, irreversible inhibitor of cytochrome P450 17 α(CYP17),
an enzyme that catalyzes the conversion of pregnenolone andprogesterone into DHEA or androstenedione, two precursors oftestosterone. This drug was originally designed and synthesizedby Jarman et al. at the Institute of Cancer Research in Sutton (UK)based on the hypothesis that the nitrogen lone pair of a pyridylmoiety linked to the steroid skeleton would coordinate with theiron atom of the heme cofactor in the active site of CYP17 ( Potter
et al., 1995; Jarman et al., 1998 ).
The inhibition of CYP17 by abiraterone acetate blocks andro-
gen biosynthesis and significantly improves the therapy ofcastration-resistant prostate cancer, which remains a challenge totreat ( Rehman and Rosenberg, 2012 ). Unfortunately, this CYP17
inhibition also decreases glucocorticoid and increases mineralo-corticoid production, which results in the main source of adverseeffects.
Since the invention of abiraterone, different steroids bear-
ing a heteroaromatic substituent on the D ring continued to bedeveloped as CYP17 inhibitors. Among those, galeterone (TOK-001 or VN/124-1) recently entered clinical trials for the treat-ment of chemotherapy-naive, castration-resistant prostate cancer(Figure 3 )(Vasaitis and Njar, 2010 ). Interestingly, this drug not
only inhibits CYP17, but is also an androgen receptor antagonist(Handratta et al., 2005 ).
ERIBULIN MESYLATE (HALAVEN®)
In1985 ,Uemura et al. isolated and identified norhalichon-
drin A from the marine sponge Halichondria okadai based
on its potent in vitro toxicity ( Uemura et al., 1985 ). Related
polyether macrolides, including halichondrin B ( Hirata and
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Basmadjian et al. Anticancer natural products
FIGURE 3 | Structure of galeterone.
Uemura, 1986 ) were identified in the following years ( Qi and
Ma, 2011 ). T ests with NCI’s 60-cell line screen suggested that
halichondrin B affects tubulin polymerization. Further studiesshowed that this drug displays subtle differences in mechanism ofaction from those of other known antimitotics targeting tubulin.Although halichondrin B displayed promising activity, its preclin-ical investigation has been hampered by its scarcity from naturalsources.
Due to its complexity, the total synthesis of halichondrin
B was considered as an attractive objective by Kishi et al. atHarvard University. This team achieved this formidable chal-lenge in 1992 ( Aicher et al., 1992 ). Further collaborative studies
from this group and Eisai Co. ultimately led to the develop-ment of the simplified and pharmaceutically improved analogeribulin ( Jackson et al., 2009 ). Although it is less complex than
natural halichondrins, eribulin contains 19 stereogenic centers,two exocyclic olefins, seven polyoxygenated pyrans and tetrahy-drofurans, a 22-membered macrolactone ring, and a 36 carbonbackbone. With its 35 steps, eribulin synthesis extended thelimit of feasibility for industrial production. Indeed, eribulin isthe single most complex molecule synthesized at an industrialscale and represents an awe-inspiring testimony to the currentpower of organic synthesis. Eribulin was approved by FDA in2010 to treat patients with metastatic breast cancer who havereceived at least two prior chemotherapy regimens for late-stagedisease.
HOMOHARRINGTONINE =OMACETAXINE MEPESUCCINATE
(CEFLATONIN®)
T oxic seeds of the conifer Cephalotaxus harringtonia K. Koch
varharringtonia belong to the traditional Chinese pharmacopeia.
In observance with Mao Tse-tung’s judgment that Chinesemedicine and pharmacology represent a national treasure thatneeds to be valorized, Chinese investigators established that thetotal alkaloids from C ephalotaxus fortunei Hook.f possesses anti-
tumor activity in preliminary clinical trials ( Group, 1976 ). In the
same period, National Cancer Institute (NCI) scientists foundthat Cephalotaxus harringtonia seed extracts displayed signifi-
cant in vivo activity against L-1210 and P-388 leukemia tumors
in mice. Powell et al. from the U.S. Department of Agricultureisolated and identified the structure of cytotoxic Cephalotaxus
alkaloids: harringtonine, isoharringtonine, homoharringtonine,a n dd e o x y h a r r i n g t o n i n e( Powell et al., 1970 )(Figure 4 ). These
compounds are esters of cephalotaxine, an inactive alkaloid firstisolated by Paudler et al. in 1963 at Ohio University ( Paudler et al.,
1963 ). Homoharringtonine was found to be the most effective inFIGURE 4 | Structures of cytotoxic Cephalotaxus alkaloids.
prolonging survival of P388 leukemic mice ( Powell et al., 1972 ).
Clinical trials performed in China demonstrated the efficacy ofthis agent against acute myeloid leukemia (AML), myelodys-plastic syndrome (MDS), acute promyelocytic leukemia (APL),polycythemia vera, and central nervous system (CNS) leukemia(Kantarjian et al., 2013 ).
Homoharringtonine inhibits protein synthesis ( Huang, 1975 ).
More specifically, it blocks the aminoacyl-tRNA binding to freeribosomes and monosomes, but not to polyribosomes ( Fresno
et al., 1977 ). Tang et al. demonstrated that decreased expression
of the antiapoptotic factor myeloid cell leukemia-1 (Mcl-1) is akey event in this antileukemic mechanism of action ( Tang et al.,
2006 ).
In 1998, a T exan biotech company developed the semisynthetic
form of homoharringtonine, designated “omacetaxine mepesuc-cinate” (Synribo®), and provided a reliable source supply forclinical investigations by ChemGenex and the M.D. AndersonCancer Center ( Robin et al., 1999 ).
This preparation of homoharringtonine [Omacetaxine mepe-
succinate (Synribo®)] has been granted orphan drug status inEurope and the U.S. to treat chronic myelogenous leukemia(CML). It was approved by the US FDA in October 2012 forthe treatment of adult patients with CML after failure of twoor more tyrosine kinase inhibitors (for a review on its clini-cal development, see Kantarjian et al., 2013 ). It is interesting
to note that these approvals occurred more than 40 years afterthe initial discovery of this compound. Even though omacetax-ine has a narrow indication in the U.S. and Europe, it hasbeen part of standard acute myeloid leukemia (AML) ther-apy in China, which begs for extending its use for additionalindications.
CARFILZOMIB (KYPROLIS®)
In 1992, Bristol-Myers Squibb scientists from T okyo reported thestructure of epoxomicin, a microbial tetrapeptide appended withan electrophilic epoxy ketone group. This compound displayedpotent in vivo antitumor activity against murine B16 melanoma
tumors. However, because the mechanism of action could notbe established, its investigation was abandoned, thereby lead-ing to the publication of the initial discovery. Eventually, BMSclosed the research center in T okyo. It was a common practice
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Basmadjian et al. Anticancer natural products
during that period for big pharmaceutical companies to close
their departments of natural product chemistry.
In 1999, the potent anticancer activity of epoxomicin attracted
the attention of Craig Crews at Y ale University, who designedthe first synthesis of epoxomicin. In the course of this endeavor,he established the absolute configuration of the epoxide stere-ocenter and synthesized also a biotinylated probe, which wasused to identify the proteasome as the molecular target of epox-omicin. The proteasome is a multiprotein complex that degradesunneeded or damaged proteins by proteolysis. Importantly,epoxomicin does not display any cross-inhibition with pro-teases, which is a major problem encountered with other anti-cancer proteasome inhibitors, such as bortezomib (Velcade®).The source of this selectivity was elucidated by a crystallo-graphic approach ( Groll et al., 2000 ). The crystal structure
of the proteasome bound to epoxomicin revealed the for-mation of a morpholino ring between the amino terminalthreonine of the proteasome and the electrophilic moiety ofepoxomicin, probably through the mechanism displayed inScheme 3 .
The specificity of epoxomicin toward proteasome prompted
Crews to associate with Caltech professor Raymond Deshaies toestablish a start-up company, Proteolix, dedicated to the develop-ment of a clinical candidate. During this process, they identifiedYU-101, which had better inhibitory activity than bortezomib(Figure 5 ). Addition of a morpholine moiety to YU-101 improved
its solubility, thereby creating carfilzomib, which rapidly enteredPhase I and II clinical trials. Importantly, the peripheral neu-ropathy that was observed with bortezomib did not occur withcarfilzomib. In 2009, Onyx Pharmaceuticals acquired Proteolixand this compound was approved for the treatment of multiplemyeloma in 2012.
INGENOL MEBUTATE (PICATO®)
Phorbol diesters, such as 12- O-tetradecanoylphorbol-13-acetate
(TPA), rank among the most potent tumor promoters iden-tified so far ( Figure 6 )(Nishizuka, 1984 ). These compounds
induce tumor formation by activating protein kinase C (PKC).Interestingly, a natural compound extracted from Euphorbia
peplus plants, Ingenol mebutate, also activates PKC but with a dif-
ferent pharmacological profile. Indeed, this compound inducesthe death of precancerous skin lesions induced by sunlight, calledactinic keratosis.
The sap of Euphorbia peplus (known commonly as petty
spurge) is commonly used as an alternative therapy for skindiseases in Australia ( Weedon and Chick, 1976 ). In 1998, its effi-
cacy was established for the self-treatment of skin cancers andactinic keratosis ( Green and Beardmore, 1988 ).
Ingenol mebutate was first identified in 1980 by Evans et al.
from the National Research Center in Cairo (Egypt) ( Sayed et al.,
1980 ). These authors demonstrated also that this compound
is cytotoxic to cancer cells. For more than 20 years, ingenolmebutate remained poorly investigated, until 2004, when thelab of Peter Blumberg at NCI showed that it activates PKC iso-forms, but with a different pharmacological profile than thatof TPA. Importantly, the activation of protein kinase C delta(PKC δ) was shown to promote the production and release of
inflammatory cytokines contributing to the elimination of actinickeratosis.
At the same time, Eric Raymond in Clichy (France) showed
that ingenol mebutate-induced activation of PKC δand reduced
e x p r e s s i o no fP K C αlead to an activation of Ras/Raf/MAPK, an
inhibition of the phosphatidylinositol 3-kinase/AKT signalingpathways, and ultimately to apoptosis of cancer cells ( Benhadji
et al., 2008; Serova et al., 2008; Ghoul et al., 2009 ).
After few years of preclinical investigations, ingenol mebu-
tate entered clinical trials ( Siller et al., 2009 ) and was eventually
approved by FDA and EMA in 2012 for the topical treatment ofactinic keratosis. This compound is produced by extraction fromthe petty spurge plant in low yield (1 g of pure compound/800 kgof plant). T o improve the production of this molecule, JakobFelding of LEO pharma associated with Phil Baran from ScrippsInstitute to develop an elegant synthesis of ingenol in only 14steps from inexpensive ( +)-3-carene ( Jørgensen et al., 2013 ). This
synthesis has been rapidly scaled-up to kilogram levels ( Ritter,
2013 ).
CONJUGATION OF NATURAL PRODUCTS TO ANTIBODIES OR
FOLIC ACID TO TARGET TUMORS
At the end of 19th century, Paul Ehrlich already considered
the conjugation of a toxin to a compound that selectively tar-gets a disease-causing organism to generate a “magic bullet”(“magische kugel ”) that would destroy the origin of the disease
without toxicity to healthy tissues in the body ( Ehrlich, 1897 ).
About 60 years later, Mathé et al. conjugated anti-tumor anti-bodies to the folic acid antagonist, methotrexate ( Loc et al.,
1958 ). Although the experiments in mice were encouraging,
this approach did not attract interest in the scientific commu-nity and returned to limbo for two decades, until 1975, whenGhose et al. demonstrated the efficacy of an anticancer alkylating
SCHEME 3 | Proposed mechanism of alkylation of the proteasome by epoxomicin.
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Basmadjian et al. Anticancer natural products
FIGURE 5 | Structures of epoxomicin, YU-101, carfilzomib.
FIGURE 6 | Structures of 12- O-tetradecanoylphorbol-13-acetate and ingenol mebutate.
agent, chloranbucil, conjugated to an antibody against a mouse
lymphoma ( Ghose et al., 1975 ). The advent of monoclonal anti-
bodies the same year definitely boosted this field of research(Kohler and Milstein, 1975 ). Since then, almost every cyto-
toxic agent has been conjugated to antibodies following variousstrategies.
After two decades of endeavor, low cytotoxicity, and lack of
specificity of antibodies for their targeted antigens, conjugateinstability, immunogenicity, and heterogeneous product charac-teristics were identified as important sources of failure in theclinic ( Scott et al., 2012; Ho and Chien, 2014 ). However, a sig-
nificant step forward was made with the use of extremely highlytoxic agents such as calicheamicin, maytansine, or auristatin(Figure 7 ). These drugs are so toxic that they cannot be used by
themselves without a targeting agent.
In 2000, four decades after Mathé’s pioneering work and one
century after Ehrlich’s dream, Wyeth received approval to com-mercialize Gemtuzumab ozogamicin (Mylotarg®) which resultsfrom the conjugation of a monoclonal antibody targeting CD33with a calicheamicin derivative. This drug was used for 10years against acute myelogenous leukemia, before being with-drawn in 2010, when it was demonstrated that it does notprovide any significant benefit over conventional cancer ther-apies. In 2011 and 2013, two other immunoconjugates weremarketed: brentuximab vedotin (Adcetris®) and trastuzumabemtansine (Kadcyla®). The first one targets the protein CD30,which is expressed in classical Hodgkin lymphoma and sys-temic anaplastic large cell lymphoma. This antibody is conjugated
to a fully synthetic analog of the antimitotic agent dolastatin
(Figure 7 ).Trastuzumab emtansine results of the conjugation of a mono-
clonal antibody targeting the receptor HER2 (a receptor tyrosine-kinase erbB-2), which is overexpressed mainly in some forms ofbreast and gastric cancers to the highly cytotoxic natural prod-uct maytansine. The development of this class of agents requiresa careful optimization of the monoclonal antibody, the cytotoxicpayload, and the chemical linker ( Ducry, 2012 ). The successful
introduction of immunoconjugates has validated this approachto treat cancers, and currently as many as 415 antibody–drugconjugates are under clinical evaluation.
In addition to antibodies, alternative tumor-selective ligands
have been conjugated to anticancer drugs. Based on observa-tions that cells internalize vitamins, such as folate, by receptor-mediated endocytosis, Leamon, and Low from Purdue Universitydemonstrated in 1991, that macromolecules conjugated to folicacid could be delivered into living cells ( Leamon and Low,
1991 ). Following this seminal observation, hundreds of publi-
cations have improved upon this approach, which is currentlybeing examined in clinical trials. The efficacy of this tech-nology lies on the overexpression of the folate receptor intumors, while it is quasi-absent in normal tissues. Very impor-tantly also, folic acid retains a high affinity to its receptorwhen it is conjugated via its γ-carboxyl ( Vlahov and Leamon,
2012 ).
Early attempts were limited by the release properties of the
conjugates. After two decades of intensive research, some guidingr u l e sw e r ei d e n t i fi e dt ol e a dc o m p o u n d st o w a r dc l i n i c s :
1. anticancer agents must display a high cytotoxicity (similar to
immunoconjugates);
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Basmadjian et al. Anticancer natural products
FIGURE 7 | Structures of marketed immunoconjugates.
2. enhanced hydrophilicity, to prevent passive diffusion into nor-
mal tissue;
3. an efficient cleavable linker system that releases the anticancer
drug at a reliable rate once inside the targeted cell;
4. a low molecular weight, to optimize the penetration into solid
tumor tissue with concomitant rapid systemic clearance.
Following these guidelines, five folic acid conjugates have reached
clinical trials, including the most advanced one, vintafolide(EC145), which is currently in a phase 3 trial in women with
cisplatin -resistant ovarian cancer.
In vintafolide, the highly cytotoxic vinblastine is con-
nected to the folate moiety trough a self-immolative linkerand a peptidic spacer ( Figure 8 ). T o provide the desired
hydrophilicity to the final drug-conjugate and prevent unspe-cific internalization, acidic, and basic amino acids such as
aspartic acid and arginine were introduced in the peptide-based
unit.
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Basmadjian et al. Anticancer natural products
FIGURE 8 | Structure of vintafolide and mechanism of release of the payload in the endosome.
The self-destructive linker system is based on a 1,2-elimination
mechanism by reduction of the disulfide bond between the cys-teine of the spacer and the linker, which occurs in the endosomethrough a not fully understood mechanism ( Figure 8 )(Y ang et al.,
2006 ).
TRADITIONAL HERBAL REMEDIES
In addition to purified molecules, traditional herbal remedies are
slowly emerging in modern Western medicine ( Basu, 2004 ). An
injectible form of an extract of the Chinese medicinal plant Semen
coicis called Kanglaite® (Kang-Lai-T e) has been used in China as
a lipid emulsion since the end of the 90’s for the treatment ofnon-small cell lung, liver, stomach, and breast cancers. It has beenmarketed also in the Russian Federation since 2003 and is thefirst traditional Chinese herbal remedy to enter into clinical tri-als in the US. As with many other traditional Chinese medicines,Kanglaite activity probably results from the combined actions ofmultiple pharmacologically active ingredients that have not beenyet identified ( Xu, 2011 ). Over the last decade, other botanical
drugs have entered clinical trials in the West to treat cancers orother ailments.
NANOPARTICLE DELIVERY OF ANTICANCER DRUGS
Tumor growth requires angiogenesis, i.e., the formation of newblood vessels. In contrast to normal angiogenesis, newly formedvessels in tumors display many structural and functional defects,which permit the leakage of macromolecules. This feature isreferred to as the “enhanced permeability and retention (EPR)effect.” Recent advances in the application of nanotechnology tomedicine enabled the approval of five nanoparticle chemother-apeutics for cancer ( Wang et al., 2012 ). Four liposomal for-
mulations have been approved for clinical use in oncology:pegylated liposomal doxorubicin (DOXIL®, Caelyx®), nonpegy-lated liposomal doxorubicin (Myocet®), and liposomal cytarabine(DepoCyte®) ( Hofheinz et al., 2005 ). Nab-paclitaxel (Abraxane®)
is an albumin bound approved for the treatment of breast can-cer and is undergoing clinical trials for other clinical indications.And finally, Genexol-PM is a polymeric micelle formulation ofpaclitaxel composed of block copolymers of PEG and poly-(D,L-
lactic acid) ( Kim et al., 2004 ).
Although nanomedicine is a new discipline, its translation
into clinics has been rapid. A novel generation of nanoparticlechemotherapeutics is under development and expected to greatlyimprove cancer treatments. These new formulations may alsooffer novel opportunities for established anticancer drugs ( Wang
et al., 2012 ).
MISSED OPPORTUNITIES AND HOW TO RESCUE THEM
In 2010, Bristol-Myers Squibb stopped the phase III clinical trial
of Tanespimycin, an inhibitor of heat shock protein 90, for thetreatment of multiple myeloma, probably because of the expi-ration of the patent in 2014. In addition to drug developmentsthat were terminated because of the shortness of patent life, thereare many interesting drugs that did not reach clinical trial or thatfailed in clinical trial because the conceptual tools to correctly per-form these assays were not available at that time. Indeed, “thereare no bad anticancer agents, only bad clinical trial designs” asstated by Von Hoff (1998) .
Flavaglines, such as rocaglamide, represent a striking example
of natural products that are enjoying reinvigorated investigationafter their original discovery by King et al. from the NationalDefense Medical Center of Taiwan ( King et al., 1985 ). The recent
identification of their molecular targets, the scaffold proteins pro-hibitins and the initiation factor of translation eIF4A, coupledwith a description in Science about the origin of their selective
cytotoxicity in cancer cells should promote further investiga-tions to unveil their therapeutic usefulness ( Basmadjian et al.,
2013; Santagata et al., 2013 ). However, clinical trials with these
compounds are unlikely unless some structurally original andpatentable analogs are identified. Indeed, clinical trials of non-patentable compounds are still scarce ( Roin, 2009; Cvek, 2012 ).
For instance, a non-profit company, the Institute for OneWorldHealth, developed in 2007 paromomycin, which is not patentable,as an effective treatment for visceral leishmaniasis. This wasaccomplished with financial support from the Bill and MelindaGates Foundation, the Special Program for Research and Training
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Basmadjian et al. Anticancer natural products
SCHEME 4 | Combination of biotechnology and organic synthesis for the synthesis of ansamitocin derivatives ( T aft et al., 2008 ).
in Tropical Diseases of the United Nations Development Program,
the World Bank, and the World Health Organization ( Sundar
et al., 2007 ). GlobalCures is another example of a non-profit
medical research organization, which aims to develop novel andcost-effective treatments for cancers ( Cvek, 2012 ). State agen-
cies, such as the National Center for Advancing Translational
Sciences are also deeply involved in the development of non-
profitable drugs. Only a radical change in public or internationalpolicy could support the further development of clinically usefulcompounds that are currently fated to be traded as generics.
BIOTECHNOLOGY-BASED GENERATION OF NOVEL NATURAL
PRODUCTS
Since the seminal synthesis of aspirin by Gerhardt (1853) ,a l l
the natural product derivatives were prepared by total synthesisor semi-synthesis. Alternate approaches are currently emergingbased on the progress in the deciphering of biosynthetic pathwaysand advances in biotechnologies. Currently, only a tiny fractionof microbes can be cultured with conventional approaches, yetuncultivated microorganisms represent an attractive source ofnovel natural products. It is now possible to isolate large frag-ments of microbial DNA directly from environmental samplesand to express them in an easily cultured microorganism. Thisapproach provides access to secondary metabolites that were orig-inally produced by inaccessible microorganisms. Additionally,the manipulation of these biosynthetic pathways can lead tonovel natural product derivatives. Metabolic engineering and syn-thetic biology are poised to revolutionize conventional chemicaland pharmaceutical manufacturing in the coming decade ( Ya d av
et al., 2012 ). Recently, methods and concepts of organic synthe-
sis have begun to be integrated to synthetic biology to generatenovel natural product derivatives. Such approaches that mergebiotechnology with organic synthesis are rapidly blooming andare expected to efficiently generate novel natural product analogsi nt h en e a rf u t u r e( Goss et al., 2012; Kirschning and Hahn, 2012 ).
A representative example of such an approach has been the useof an Actinosynnema pretiosum mutant that accepts 3-amino-4-
bromobenzoic acid as a substrate to prepare pharmacologicallyactive ansamitocin derivatives, which can then be transformed byclassical organic reactions ( Scheme 4 ;Taft et al., 2008 ).
CONCLUSION
The success of glivec and herceptin in the 90’s announced
the obsolescence of natural products in therapeutics. A decadelater, many cancer patients continue to die and pharmaceutical
companies have reconsidered their position on the potential ofnatural products in oncology. Indeed, for too many solid tumorsof advanced grades, the only therapeutic options remain exclu-sively palliative. There is therefore an urgent need to developoriginal medicines.
Some of newly developed agents induce a strong cytotox-
icity targeting conventional targets, DNA (for trabectedin) ormicrotubules (for ixabepilone, vinflunine, or eribulin), whileother target specific biochemical events such as steroid biosyn-thesis (abiraterone acetate), histone remodeling (for romidepsin),protein translation (homoharringtonine), or degradation (carfil-zomib). The case of rapamycin derivatives is atypical. These drugsare not cytotoxic, but can be considered as targeted therapy agentsdue to their inhibition of mTOR signaling.
In contrast with targeted therapeutics, which are designed for
a specific type of cancer, the development of natural productsis often more erratic and heavily relies on the skill of pharma-cologists to unravel their mechanism of action and clinicians toidentify the optimal indication in the clinic.
Over the last 15 years, natural products have been rehabil-
itated by pharmaceutical companies, even though some com-plementary approaches, such as molecular modeling based drugdesign are gaining in momentum. This latter methodology, whichwas pioneered by 2013 Nobel laureates, has successfully led toinnovative medicines. When it is possible to predict the 3Dstructure of proteins, then it will probably overshadow othermethods for identifying drug candidates. Until then, naturalproducts should continue to play a major role in drug dis-covery, especially in the treatment of cancers and infectiousdiseases.
ACKNOWLEDGMENTS
We are grateful to the “Association pour la Recherche sur leCancer” (ARC, grant numbers 3940 and SFI20111204054) forgenerous financial support. We also thank AAREC Filia Researchfor fellowships to Christine Basmadjian and Qian Zhao.
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Conflict of Interest Statement: The authors declare that the research was con-
ducted in the absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Received: 06 March 2014; accepted: 04 April 2014; published online: 01 May 2014.
Citation: Basmadjian C, Zhao Q, Bentouhami E, Djehal A, Nebigil CG, Johnson RA,
Serova M, de Gramont A, Faivre S, Raymond E and Désaubry LG (2014) Cancer wars:
natural products strike back. Front. Chem. 2:20. doi: 10.3389/fchem.2014.00020
This article was submitted to Medicinal and Pharmaceutical Chemistry, a section of
the journal Frontiers in Chemistry.
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