T

he class of steroid-like compounds designated cardiac glycosides includes well-known drugs such as
digoxin, digitoxin, and ouabain. Their continued efficacy in treatment of congestive heart failure and
as anti-arrhythmic agents is well appreciated. Less well known, however, is the emerging role of this
category of compounds in the prevention and/or treatment of proliferative diseases such as cancer. New
findings within the past five years have revealed these compounds to be involved in complex cell-signal
transduction mechanisms, resulting in selective control of human tumor but not normal cellular prolif-
eration. As such, they represent a promising form of targeted cancer chemotherapy. New clinical studies
of their anticancer potential as single or adjuvant treatments may provide insight into these potentially
valuable therapeutic options. This review focuses on recent findings on cellular pharmacology of cardiac
glycosides as they relate to treatment of human cancer and attempts to explain why these agents have been
overlooked in the past.

Robert A. Newman1, Peiying Yang1, Alison D. Pawlus1,

and Keith I. Block2
1
Department of Experimental Therapeutics and Pharmaceutical Development Center,
University of Texas, M. D. Anderson Cancer Center, Houston, TX 77054;
2
Institute for Integrative Cancer Care, Evanston, IL 60201

36
 Cardiac Glycosides as Novel Cancer Therapeutic Agents

History of the Use of Cardiac Glycosides toad, known to contain multiple bufodeninolides (another type
for Cancer of cardiac glycoside), including bufalin (Figure 1) (5–7). The
potential use of cardenolide-like compounds for the treatment
The use of cardiac glycoside containing plants for medicinal of cancer, initially investigated forty years ago, was abandoned
purposes was first reported in ancient texts more than 1500 because of the toxicity of these compounds (8, 9). It was only
years ago. They have been used traditionally as arrow poisons, recently, however, that Scandinavian oncologists suggested that the
abortifacients, emetics, diuretics, and heart tonics. It is the latter apoptosis produced by digitalis in human tumor cells occurred at
pharmacologic activity that cardiac glycosides are most com- concentrations that could be achieved without toxicity in humans
monly associated with, and after 200 years, compounds such and, therefore, this agent might be useful for treatment of cancer
as digitalis and digoxin are still prescribed by Western doctors (10–12). In 1979, Stenkvist et al. (13) noted that the altered mor-
for control of congestive heart failure. Their use began after a phology of breast cancer cells from women treated with digitalis
meticulous analysis of a local herbalist’s formula in 1775 by the (who had undergone mastectomy). Women receiving digitalis had
English physician and scientist William Withering. He found that tumor cells with more benign characteristics than those tumor
a patient with “dropsy” (congestive heart failure) improved after cells in patients not receiving this cardiac glycoside. Moreover,
administration of an extract containing foxglove (Digitalis purpurea the cancer recurrence rate of women taking digitalis was lower,
L.) (1). Compounds extracted
from foxglove and oleander R=lactone ring
18
include cardenolides (Figure 17 O
12 H
Lactone Moiety
1), such as digitalis, digoxin, 19
11
H
13
16
O
9 14 15
O O
and oleandrin, which increase 2
1
10 8 Cardenolides R=
cardiac contractility and act 3 5 H 7
OH
4 6 H
as antiarrythmic agents to O O
H H
control atrial fibrillation (2, HO O
O H OH
3). The mechanism of their Steroid
Bufadienolides R=
HO Bufalin
action for the treatment of OH HO
H
congestive heart failure arises O O
from the inhibition of Na+,K+- Glycone
O O OH
ATPase, with a resulting HO
H H
increase in intracellular cal- HO H
cium concentrations. Cardiac H
H O
glycosides, however, have a H OH
narrow therapeutic index, H OH O O O
O OH
limiting their wider applica- O
O O HO
tion to the treatment of other HO H
Ouabain H
diseases, such as cancer. HO H
OCH3 Oleandrin OH
Despite their potential
to cause serious side effects, H OH

application of plant extracts O O

O O H
containing cardiac glycosides O O
HO
for the treatment of malignant OH Digitoxin
OH O
OH O
disease may extend back to
HO H
Arab physicians in the eighth O O
H
century (4). It is not just O
HO H
plants, however, that con- H
tribute to our appreciation of HN S OH H H OH
O
cardiac glycosides possibly O O
H OH O O H
having a role in cancer man-
O O
agement. An ancient Chinese O HO
OH OH Digioxin
OH
medicinal treatment of cancer OH
still in use today involves UNBS-1450 O
application of an extract of Figure 1. Structures of cardiac glycosides with antiproliferative activity. Representative cardenolide and bufadieno-
secretions of the Bufo bufo lide cardiac glycoside compounds are presented.

February 2008
Volume 8, Issue 1 37
 Review

Table 1. List of Plants and Animals with Cardiac Glycosides Having Antiproliferative Activities
Plant/Animal Species Cardiac Glycoside(s)
Apocynum cannabinum L. Apocannoside, cymarin
(Apocynaceae)
Asclepias curassavica L. Calotropin, 16α-acetoxycalotropin,
(Asclepiadaceae) 15β-hydroxycalotropin, calactin,
15β-hydroxycalactin, asclepin,
16α-hydroxyasclepin, uscharidin,
uscharin, uzarigenin
Beaumontia brevituba Digitoxigenin, oleandrigenin, digi-
Oliver (Apocynaceae) toxigenin, α-l-cymaroside, digitoxigenin
β-gentiobiosyl-α-l-cymaroside, Δ16-
digitoxigenin β-d-glucosyl-α-l-cymaroside
Bufo bufo gargarizans L. Bufalin, cinobufagin
Calotropis procera (Ait.) Calotropin, calactin, uscharin, voruscha-
R. Br. (Asclepiadaceae) rin, 2’’-oxovoruscharin
Cerbera odollam Gaertner 2′-O-Acetyl cerleaside A, 17α-neriifolin,
(Apocynaceae) 17β-neriifolin, cerberin
Coronilla varia L. Hyrcanoside
(Fabaceae)
Crossopetalum gau- Securigenin-3β-O-β-6-deoxyguloside,
meri (Loes.) Lundell 19-hydroxy-sarmentogenin-3β-O-β-6-
(Celastraceae) deoxyguloside, sarmentogenin-3β-O-
(α-allosyl-(1→4)-β-6-deoxyalloside),
securigenin-3β-O-(α-allosyl-(1→4)-β-6-
deoxyalloside)
Digitalis purpurea L. Digoxin, digitoxin, gitoxin
(Scrophulariaceae)
Digitalis lanata
(Scrophulariaceae)
Elaeodendron sp. Elaeodendrosides
Euonymus alata (Thunb.) Acovenosigenin A 3-O-α-l-
Sieb. (Celastraceae) ramnopyranoside, euonymoside A, euo-
nymusoside A
Euonymus sieboldianus Euonymoside A
Blume (Celastraceae)
Maquira calophylla (P.&E.) Maquiroside A
C.C. Berg (Moraceae)
Nerium oleander L. Oleander, oleandrin, cardenolide N-1,
(Apocynaceae) cardenolide N-4, 3β-O-(β-d-sarmentosyl)-
16β-acetoxy-14-hydroxy-5β,14β-card-
20-(22)-enolide, 16β-acetoxy-3β,14-
dihydroxy-5β,14β-card-20-(22)-enolide
In Vitro Cytotoxic Effect Reference
Human nasopharynx carcinoma (KB) (66)
Human lung carcinoma (A549), breast carcinomas (67)
(MCF-7 and MDA-MB-231), and hepatoma (HepG2)
Human breast carcinoma (BC1), colon carcinoma (68)
(Col2), fibrosarcoma (HT-1080), nasopharyngeal
carcinoma (KB), vinblastine-resistant KB (KB-V1), lung
carcinoma (Lu1), and melanoma (Mel2)
Prostate carcinomas (LNCaP, DU145, PC3), and (69, 70)
hepatoma (PLC/PRF/5)
Human non-small-cell lung carcinoma (A549), human (71, 72)
glioblastomas (Hs683 and U373), human colon
carcinomas (HCT-15 and LoVo), hepatoma (Huh7),
non-hepatoma (COS-1), and colorectal carcinoma
(COLO 320)
Human oral epidermoid carcinoma (KB), breast (73)
carcinoma (BC), and small-cell lung carcinoma
(NCI-H187)
Human lymphocytic leukemia (P-388) and (74)
nasopharynx carcinomas (9KB)
Human oral epidermoid carcinoma (KB) (75)
Human prostate carcinomas (LNCaP, DU145, PC3), (76, 77)
renal adenocarcinoma (TK-10), breast adenocarci-
noma (MCF-7), malignant melanoma (UACC-62),
and chronic myelogenous leukemia (K-562)
Human ovarian carcinoma (A2780) (78)
Human oral epidermoid (KB), promyelocytic (79)
lymphoma (HL-60), non-small-cell lung carcinoma
(A549), and cervical carcinoma (Hela)
Human lung carcinoma (A549) and ovarian (80)
adenocarcinoma (SK-OV- 3)
Human oral epidermoid carcinoma (KB) (81)
Human Jurkat leukaemia (T-cell), histiocytic lymphoma (82, 83)
(U-937), promyelocytic lymphoma (HL-60), cervical
carcinoma (Hela), breast carcinoma (MCF-7), pros-
tate carcinomas (LNCap, DU145, PC3), malignant
fibroblast (VA-13), and liver carcinoma (HepG2)

38
 Cardiac Glycosides as Novel Cancer Therapeutic Agents

Table 1. continued
Nierembergia aristata D. 17-epi-11α-hydroxy-6,7- Human breast carcinoma (BC1), fibrosarcoma (HT), (84)
Don (Solanaceae) dehydrostrophanthidin-3- lung cancer (LU1), melanoma (Mel2), colon carci-
O-β-boivinopyranoside; noma (Col2), oral epidermoid (KB), drug resistant KB
6,7-dehydrostrophanthidin- with and without vinblastine, epidermoid carcinoma
3-O-β-boivinopyranoside; (A-431), prostate carcinoma (LNCaP), hormone-
6,7-dehydrostrophanthidin-3-O-β- dependent breast carcinoma (ZR-75-1), and glioma
oleandropyranoside (U373)
Ornithogalum umbellatum Convallatoxin Human oral epidermoid carcinoma (KB) (85)
L. (Hyacinthaceae)
Pergularia tomentosa L. 3′-O-β-d-glucopyranosylcalactin, 12-dehy- Kaposi’s sarcoma (KS) (86)
(Asclepiadaceae) droxyghalakinoside, 6′-dehydroxygha-
lakinoside, ghalakinoside, calactin
Periploca graeca L. Periplocin isomers Human prostate carcinoma (PC-3) (87)
(Asclepiadaceae)
Rhodea japonica (Thunb.) Rhodexin A Human leukemia (K562) (88)
Roth. (Liliaceae)
Saussurea stella Maxim. 3-O-β-d-fucopyranosylstrophanthidin, Human gastric cancer (BGC-823) and hepatoma (89)
(Asteraceae) 3-O-β-d-quinovopyranosylperiplogenin, (Bel-7402)
3-O-β-d-glucopyranosyl-(1→4)-α-l-
rhamnopyranosylcannogenin, 3-O-β-d-
xylopyranosylperiplogenin, 3-O-β-d-
quinovopyranosylstrophanthidin,
3-O-β-d-xylopyranosylstrophanthidin,
3-O-β-d-fucopyranosylperiplogenin,
3-O-α-l-rhamnopyranosylcannogenol,
convallatoxin, 3-O-α-l-
rhamnpyranosylacovenosigenin A
Streblus asper Lour. Stebloside, mansonin Oral human epidermoid carcinoma (KB) (90)
(Moraceae)
Streptocaulon juven- Periplogenin digitoxoside, Human fibrosarcoma (HT-1080) (91)
tas (Lour.) Merr. Periplocymarin, digitoxigenin
(Asclepiadaceae) 3-O-(O-β-d-glucopyranosyl-(1→6)-
O-β-d-glucopyranosyl-(1→4)-β-d-
digitoxopyranoside, echujin, corchoru-
soside C
Streptocaulon griffithii 3-O-(β-glucopyranosyl)acovenosigenin A Human gastrointestinal cancer (HCG-27), lung carci- (92)
Hook.f. (Asclepiadaceae) noma (A549), breast carcinoma (MCF-7), and cervi-
cal carcinoma (HeLa)
Strophanthus gratus Ouabain Human prostate carcinomas (LNCaP, DU145, PC3) (76)
Thevetia ahouia (L.) A. Neriifolin, 3′-O-methylevomonoside, National Cancer Institute’s human disease oriented (93)
DC. (Apocynaceae) 2′-acetylneriifolin 60-cell line tumor screening panel
Thevetia peruviana Thevetin A and B, thevetoside Human hepatoma (SMMC-7721), gastric carcinoma (93)
(Pers.) K. Schum. (SGC-7901), and cervical carcinoma (HeLa)
(Apocynaceae)

Urginea maritime (L.) Proscillaridin A, scillaren A Human breast carcinoma (MCF-7) (94–96)
Baker (Liliaceae)

February 2008
Volume 8, Issue 1 39
 Review

suggesting an important beneficial anticancer effect of this cardiac
glycoside (14).
Within the past ten years, there has been a substantial
increase in the number of studies observing the effects of cardiac
glycosides on the growth of human malignant tumor cells. A
review of the literature indicates a surprising variety of plants and
even animals whose extracts and isolated cardiac glycoside com-
pounds have been cited for their antiproliferative effects (Table
1). The purpose of the present review, therefore, is to examine
the hypothesis already expressed by some (10, 14–20), that use of
selected cardiac glycosides may represent a worthwhile approach
toward control of malignant cell proliferation even despite their
narrow therapeutic index. This is all the more timely because
promising clinical trials of cardiac glycosides and extracts contain-
ing them have recently been initiated.

Table 2. Reported Mechanisms of Cardiac Glycoside–Mediated Inhibition of Tumor Cell Proliferation

Compound Proposed antiproliferative mechanism(s) Reference
Oleandrin Alteration of membrane fluidity (15, 35, 97, 100)
Decreased activation of nuclear transcription factors NF-κB, (19, 98)
JNK, and AP-1
Increased intracellular calcium (17, 50)
Increased expression of FasL (99)
Increased ROS production, oxidative injury, and mitochondrial injury (50, 51, 58)
Decreased phosphorylation of Akt (17, 36, 57)
Inhibition of cellular transport of tumor growth factors (FGF-2) (100)
Down regulation of IL-8 receptors (99)
Initiates Apo2L/TRAIL apoptosis via increased expression of death receptors 4 and 5 (18, 48)
Activation of calcineurin and nuclear transcription factor NF-AT (99)
Bufalin Increased activation of MAPKs (101–103)
Decreased cAMP content (5)
Inhibition of topoisomerases I and II (17, 104, 105)
Induction of differentiation in human myeloid leukemia (106, 107)
Downregulation of cyclin A, Bcl-2 and Bcl-xL; Increased expression of p21 and Bax (7, 104, 108)
Ouabain, Digitoxin Loss of mitochondrial membrane potential; increase Par-4 expression (17, 109)
Increased Ca2+ uptake (15, 16, 110, 111)
Acts as an estrogen receptor antagonist (15, 112)
Sustained ROS production (29, 31, 111)
Regulates expression of cell tight junctions and adhesion molecules (16, 17, 55)
Selective protein kinase C activation leading to differentiation (17, 113)
Increased activation of MAPKs (16, 113, 114)
Reduction in anti-apoptotic proteins Bcl-xL and Bcl-2 (114–116)
Increased cytochrome c release and caspase activation (28, 114, 116)
Inhibition of topoisomerase I (28, 61, 117, 118)
Block activation of the TNF-α/NF-κB signaling pathway (59, 119)
UNBS1450 Decreased heat shock protein (Hsp70) (59, 120)
Increased permeabilization of lyososomal membrane (120)
Block activation of the TNF-α/NF-κB signaling pathway (59)

NF-κB, Nuclear Factor-kappaB; JNK, c-Jun NH2-terminal kinase; AP-1, Activator Protein-1; FasL, Fas ligand; ROS, reactive oxygen species;
FGF-2, Fibroblast Growth Factor 2; IL-8, Interleukin-8; TNF-α, Tumor Necrosis Factor–α; TRAIL, (TNF)-related apoptosis-inducing ligand; NF-AT,
Nuclear Factor of Activated T cells; MAPKs, mitogen-activated protein kinases.

40
 Cardiac Glycosides as Novel Cancer Therapeutic Agents

Na+,K+-ATPase: Beyond Cell Membrane
Exchange of Na+ and K+
Na+,K+-ATPase, as an energy-transducing ion pump, has been
studied extensively since its discovery in 1957 (21). This enzyme
consists of two types of subunits, designated α and β, in addition
to a single-transmembrane-spanning protein, FXYD––named for
the conserved amino acids in its signature motif: (Phe-Xxx-Tyr-
Asp). The α subunit, responsible for binding of Mg2+, ATP, Na+, K+,
and cardiac glycosides, is considered the catalytic subunit of the
enzyme. The β subunit is a glycoprotein that seems to act as an
adhesion molecule that regulates gap junction proteins; is involved
in structural and functional maturation of the holoenzyme; facili-
tates transport of the α subunit to the plasma membrane and main-
tenance of the enzyme in the lateral membrane of epithelial cells
(15–17). The function of the FXYD protein involves regulation of
the enzyme function, thus adapting the kinetic properties of active
Na+ and K+ transport to the specific needs of different cells (22, 23).
Four α subunit variants, as well as three β, and seven FXYD sub-
unit variants have been identified (17). The well-established func-
tion of Na+,K+-ATPase is to use ATP as an energy source to drive
excess Na+ out of cells in exchange for K+, thereby maintaining an
essential ionic and osmotic
Apo2/TRAIL
balance. Binding of certain α Upregulation of death receptors
subunits by cardiac glycosides
DR4
DR5
inhibits ATP binding and dis-
rupts the ability of the enzyme
cinogen 1,2-dimethyldrazine (24). There have also been reports
of increased expression of particular subunits of Na+,K+-ATPase
in gastric (25) and bladder cancers (26). In addition, alterations
in overall Na+,K+-ATPase activity and relative subunit abundance
were observed in a highly invasive form of human renal carci-
noma cells (27), non-small cell lung cancer (28), and carcinoma
cell lines obtained from a number of other tissues (29). It would
appear, however, that simply looking at enzyme subunit content
or relative activity in malignant and non-malignant tissue may not
provide adequate insight into the role of this enzyme in cancer.
This can now be interpreted in the light of newly proposed conse-
quences of cardiac glycoside binding to Na+,K+-ATPase.
Proposed Mechanism(s) of
Cardiac Glycoside–Mediated
Antiproliferative Effects
An explanation of the role of Na+,K+-ATPase in complex cell
signaling pathways, many of which are of critical importance
to malignant cell proliferation, has been put forth by Xie and
colleagues (30–32). They have shown that binding of cardiac
glycosides (e.g., ouabain) to Na+,K+-ATPase triggers a complex
(J)
(A) Altered membrane
fluidty
Oleandrin,
bufalin,
TNF-A
C
av
eo
lin
digitoxin
TNFR

to perform this exchange in an FGF-2 (I)

FADD EGFR Export inhibited
efficient manner. This, in turn, Caspase (H)
B
results in an enhanced entry Activation B
TRADD Lysosomal membrane
Caveolin permeabilization
of calcium into cells, which, Apoptosis PLC A A RIP/TRAF2
IP
Apoptosis
(N)
in the event of failing cardiac ER/SC PI3K
3 Src
(F)
Ca 2+
(G) JNK
myofibrils, helps produce a Ras
ASK-1
Raf Cytochrome c release
more efficient myocardial con-
2+ NF-+B (M) LC3
traction and improves cardiac Ca
Akt (E) (K)
(B) i MEK
ROS
pump activity. PKC
Akt P (D)
Mitochondrial
Erk 1/2 Autophagy
What, then, is the evi- Apoptosis pErk 1/2
(L) Mitochondria
injury and
membrane condensation
dence supporting the hypoth- Nuclear
membrane
potential
AP-1 Gene activation
esis that Na+,K+-ATPase may differentiation
Bcl-XL, BcI-2
(C) topoisomerase I and IIa

be an important target for

cancer therapy? For the past
ten years, published stud-
ies have suggested a role for
Na+,K+-ATPase in regulation
of cell growth and expres-
sion of various genes beyond
that of ion transport. Davies
et al., for example, observed
altered Na+,K+-ATPase activ-
ity in premalignant mucosa
months before tumor devel-
opment induced by the car-
Figure 2. The Na+,K+-ATPase signalosome complex. The binding of selected cardiac glycosides (CGs)––such as ole-
andrin, bufalin, and digitoxin––to Na+,K+-ATPase results in complex but well-documented changes in cell signaling events.
The “signalosome” complex includes the enzyme, Na+,K+-ATPase as well as Src, phosphoinositide-3 kinase (PI3K), and
phospholipase C each of which, in turn, sets into action complex signaling events that can result in tumor cell death
through either apoptosis or autophagy-related mechanisms. Administration of CGs can (A) increase the (cell surface)
expression of death receptors (DR4, DR5) and activate caspase activity; (B) result in increased intracellular calcium con-
centrations, which, in turn, (C) decreases the expression of transcription factors such as Activator Protein-1 (AP-1). CG
treatment can also (D) inhibit activation (i.e., block the phosphorylation) of Akt, which normally blocks apoptosis; (E) inhibit
activation of the transcription factor Nuclear Factor-kappaB (NF-κB); (F) activate the Ras pathway, leading to increase
activity of Raf–MAPK pathway; (G) activate Src; (H) inhibit tumor necrosis factor (TNF)-mediated activation of NF-κB by
inhibiting the binding of tumor necrosis factor receptor 1–associated death domain protein (TRADD) to the cellular mem-
brane; (I) inhibit extracellular transport of tumor growth factors, such as fibroblast growth factor-2 (FGF-2); (J) alter mem-
brane fluidity which, in turn, may inhibit Fas-related signaling; (K) lead to the production of reactive oxygen species (ROS)
with subsequent injury to mitochondria; (L) produce a decrease in mitochondria membrane potential and a decrease in
quantity of anti-apoptotic proteins Bcl-XL and Bcl-2 and topoisomerases I and II; and (M) cause mitochondrial condensa-
tion and loss of function, that, in turn, can lead to autophagic processes and cell death (N). Adapted from (30).

February 2008
Volume 8, Issue 1 41
 Review
A 120
100
Percent of control cell growth
80
60 15.6 nM
40
5.6 nM
20
0 sustained ROS production with consequent mitochondrial injury;
0 100
B
Panc-02
BxPC3
A1
A3
B-Actin
Figure 3. Relative human and rodent tumor cell sensitivity to olean-
drin correlates with Na+,K+-ATPase subunit composition. A. Mouse
pancreatic cancer cells that lack expression of the α-3 subunit (Panc-02) are
non-responsive to oleandrin whereas human tumor cell lines MiaPaca and
Panc-1 (that contain high expression of α-3 relative to α-1) are extremely
responsive. The human pancreatic tumor cell line BXPC3 that contains a
very low level of the α-3 subunit, as per immunoblot analysis (B), is some-
what resistant to cytotoxic effects of oleandrin. These data suggest that it is
the lack of α3 in rodent tumor cell lines that explains their resistance to car-
diac glycosides. In addition, the data suggest that it is the relative α3:α1 ratio
correlates with human tumor cell sensitivity to lipid soluble cardiac glycosides
such as oleandrin.
signaling cascade that is initiated by interacting with neighboring
membrane proteins and organized cytosolic cascades of signaling
molecules. These signaling complexes send messages to intracellu-
lar organelles via the activation of the protein tyrosine kinase Src,
transactivation of epidermal growth factor receptor (EGFR) by Src,
activation of Ras and the p42/44 mitogen-activated protein kinases
[MAPKs, also termed extracellular-regulated protein kinases 1 and
2 (ERK1/2)], and increased generation of reactive oxygen species
(ROS) by mitochondria. Activation of these cellular pathways is
also linked with translocation of Na+,K+-ATPase, through endo-
cytosis, to the nucleus (17). In fact, Xie and colleagues (17, 30)
have referred to this as the Na+,K+-ATPase-Src-caveolin “signalo-
some” complex (Figure 2). The view of Na+,K+-ATPase as a simple
ion-exchange pump situated solely at the cell membrane is thus
outmoded. Further research on this enzyme, including its role in
regulation of cell proliferation and its inhibition through cardiac
glycosides, is clearly warranted.
The diverse mechanisms reported to specifically be involved
in cardiac glycoside-mediated control of malignant cell prolifera-
42
tion has been compiled (Table 2 and Figure 2), and there are
Panc-02
BxPC3 several excellent reviews on this subject (15–17). There are uni-
MiaPaca fying themes that link mechanisms involving the water-soluble
PANC-1
(ouabain) and relatively lipid-soluble (oleandrin, bufalin, and
digitoxin) cardiac glycosides, including activation of ERK1/2;
increased expression of the cell cycle inhibitor p21Cip1 and con-
210 nM
IC50 sequent inhibition of cell cycle progression (through decreased
expression of cyclin proteins); inhibition of transcription factors,
such as Nuclear Factor-kappaB (NF-κB) and Activator Protein-1
(AP-1); inhibition of Akt (a protein serine–threonine kinase) and
related critical components of the phosphoinositide-3 kinase
(PI3K) pathway; initiation of death receptor–mediated apoptosis;
200 300 400 500 600
Concentration (nM) and inhibition of topoisomerases and reduction in expression of
anti-apoptotic proteins, such as Bcl-xL and Bcl-2. Although the
known primary target of cardiac glycosides is Na+,K+-ATPase, not
MiaPaca
PANC-1
all of the reported mechanisms of antiproliferative action (Table 2)
are related to inhibition of this important enzyme. That is, cardiac
glycosides such as bufalin and oleandrin should be thought of as
pleiotropic or multi-mechanistic anticancer agents. Few, if any, of
these published reports on mechanism of action of cardiac glyco-
sides, however, address reasons for the well-established differential
in cardiac glycoside-mediated effects on human- vs rodent-derived
malignant cell lines.
Species-Dependent Sensitivity and Selective
Human Tumor Cell Response to Cardiac
Glycosides: Important Mechanistic Clues
An unusual attribute of compounds such as oleandrin, bufalin,
and digitoxin is that they are, on the one hand, almost completely
nontoxic to rodent (mouse, rat, and hamster)-derived tumor cell
lines but potently inhibit proliferation of monkey and human
tumor cell lines at nanomolar concentrations (33– 36). These
results have been confirmed across a wide spectrum of human
and rodent tumor cell lines, including those of hematologic and
solid tumor derivation. This species-dependent disparity in tumor
cell sensitivity to a proposed antitumor agent is unusual. It may, in
fact, have contributed to the conclusion in the 1970s that cardiac
glycosides were without efficacy because murine P388 and L1210
lymphocytic leukemia cell lines were, at the time, the only cell
lines available for anticancer drug development. The magnitude
of difference in response of murine as compared to human tumor
cell lines suggests that a fundamental difference in drug targeting
exists and, thus, serves as a probe or model for re-examination of
the pharmacologic role of this class of compounds in treatment of
human cancers.
Whereas the differences between human and murine
responses to cardiac glycosides are interesting and should be stud-
ied further, the differential effects of cardiac glycosieds on human
tumor vs normal cells are essential to their usefulness as a therapy.
Several published studies have confirmed the observation that car-
 Cardiac Glycosides as Novel Cancer Therapeutic Agents
diac glycosides have a selective effect on malignant but not normal
cell proliferation. For example, oleandrin suppresses the activation
of certain transcription factors and potentiates ceramide-induced
apoptosis in human tumor cells but not in normal, primary
human cells (19). In vitro observations that leukemia cells under-
go apoptosis in the presence of oleandrin and bufalin, but that
normal leukocytes do not, are also consistent with the hypothesis
of a potentially therapeutic, selective therapeutic effect of cardiac
glycosides on tumor growth (37–39). Not only do cardiac gly-
cosides appear to be more effective at inhibiting proliferation of
malignant cells than normal cells, but they also are more effective
at sensitizing tumor cells to irradiation, which would appear to
increase their potential utility in the clinic. Research reported by
several investigators (40–42) indicates that cardiac glycosides sen-
sitize human tumor but not normal cells to subsequent radiation
treatment. These data suggest that it may be possible to exploit
differences in the Na+,K+-ATPase pumps of normal as opposed to
tumor cells to improve the therapeutic index of radiation therapy.
Modern drug development seeks specific biochemical differ-
ences between malignant and normal cells that may be critical to
survival of cancer cells. One then attempts to develop selective
inhibitors to disrupt these pathways. Na+,K+-ATPase, however, is
a ubiquitous enzyme present in every mammalian cell. At first
appearance, therefore, it would appear to make Na+,K+-ATPase
an anticancer target of dubious value unless, of course, the target
were found to be fundamentally different in normal versus malig-
nant human cells or between rodent and mammalian cancer cells.
Our recent data suggest that, in fact, there is a difference in the
basic subunit composition of Na+,K+-ATPase that might explain
the differential species-dependent sensitivity to cardiac glycosides.
Although human tumor cells and tissues commonly express both
α1 and α3 subunits, all rodent tumor cell lines we have examined
to date only express the α1 subunit (Figure 3). Early reviews of
the biochemical properties of Na+,K+-ATPase suggested that cardi-
ac glycoside binding may be equal to all four α subunit isoforms;
however, more recent studies have shown a clear preferential
binding of cardenolides to the α3 form over that of the α1 or α2
isoforms (43–45). For example, O’Brien et al. (45) cite a 1000-fold
difference in binding of ouabain to the α3 isoform over that of
α1. Given the fact that rodent tumor cells possess the α1 subunit,
lack expression of α3, and are unresponsive to inhibition of prolif-
eration with cardiac glycosides, we suggest that the α3 subunit is
critical. The increased expression of α3 over α1 subunits has also
been noted in human colon colorectal cancer and colon adeno-
carcinoma cell lines (e.g., KM12-L4, T-84, HT-29, and WiDr),
whereas no significant expression of the α3 isoform protein was
noted in the normal kidney and renal tissues (46). Moreover,
human tumor cell lines with a low ratio of α3:α1 are relatively
resistant to growth inhibition with cardiac glycosides but those
tumor cell lines with high α3:α1 ratios are very sensitive (Figures
3 and 4). This finding, of course, also suggests that determination
of the relative α3:α1 ratio in tumor biopsy specimens may have
some prognostic value if that patient is to be subsequently treated
with a cardiac glycoside.
Mijatovic et al., on the other hand, suggest that, rather than
the α3 subunit, it is the α1 subunit of Na+,K+-ATPase that could
represent a novel anticancer target (47). They have shown that
human lung cancer cell lines overexpressing the α1 subunit were
sensitive to a few select cardenolides. They noted that the cardiac
glycosides produced a marked change in the actin cytoskeleton,
suggesting this abets tumor cell death. Whether it is altered
expression of α1, as suggested by Mijatovic et al., or an elevation
of α3, as indicated by our own work, or perhaps even a specific
ratio of α3:α1 that is most important as a predictor of cell sensi-
tivity, remains to be determined. More research, using human tis-
sues and not just cell lines, will no doubt shed light on the poten-
tial importance and perhaps even prognostic value of the enzyme
subunit composition within individual types of tumors.
It is significant that the relative composition of Na+,K+-ATPase
subunits may not be static within human tissues. The relative ratio
of α subunits within the enzyme may shift when tissues are trans-
formed from a benign to a malignant state. Sakai et al. (46) recent-
ly showed, for example, that a decrease in the α1 isoform and an
increase in the α3 subunit occurs in colon tissue when a normal
phenotype changes to a malignant one. If, as our data suggest, it
is the relative expression of α3 that is important for determining
sensitivity of a tissue to inhibition by cardiac glycosides then, in
essence, the report by Sakai et al. suggests that the tumor becomes
a more sensitive target than normal tissue to cardiac glycoside
therapy (46). Given the current as well as proposed clinical trials
of cardiac glycosides for treatment of cancer, specific determina-
tion of enzyme subunit composition in specific tissue types as
well as pathologic characterization may prove to be a timely tool
to help optimize the effectiveness of this class of potential cancer
therapeutic agents.
Cardiac Glycoside-Mediated Cancer Cell
Death: Autophagy and Apoptosis
Although it is clear that lipid-soluble cardiac glycosides (i.e.,
digitoxin, oleandrin, and bufalin) have a potent ability to pro-
duce human tumor cell death, the mechanisms by which this is
accomplished are still being defined. Apoptotic cell death medi-
ated by cardenolides has been demonstrated in a number of cell
lines. Sreenivasan et al., for example, have shown that oleandrin
produced an increase in expression of Fas and Tumor Necrosis
Factor Receptor 1 (TNFR1), resulting in potentiation of apoptosis
in tumor cells but not in normal primary cells, such as peripheral
blood mononuclear cells or neutrophils (48). Fas–Fas ligand and
TNF–TNFR1 death pathways are important mediators of apopto-
sis (49). Another recent report has shown that oleandrin, bufalin,
digoxin, and digitoxin initiate apoptosis induced by Apo2L/TNF-
related apoptosis-inducing ligand (TRAIL) in non-small-cell lung
cancer cells by increasing the expression of death receptors 4 and
February 2008
Volume 8, Issue 1 43
 Review
5 (18). Because Apo2L/TRAIL induces apoptosis in tumor cells
with little if any toxicity to normal cells, this cytokine is of great
interest to cancer researchers. The selective cardenolide activation
of death receptors may very well contribute to the observation
that compounds such as oleandrin are relatively selective in their
cytotoxic activity.
Oleandrin elicits caspase-associated apoptosis in human
prostate carcinoma cells (50). Interestingly, however, treatment of
human PANC-1 pancreatic cancer cells produces clear hallmarks
of autophagy, including formation of autophagosome bodies with
damaged mitochondria and expression of light chain-1 protein, an
early indicator of autophagosome formation (51). Frese et al. have
also suggested that the apoptotic potential of cardiac glycosides
depends on the cell type treated (18). Our data on the differential
effects of oleandrin on tumor cells, such as pancreatic vs prostate
tumor cells, as compared to oleandrin-treated normal human cells
concurs with this.
Cardiac Glycosides and Estrogen
Receptor Interaction
Selected cardiac glycosides may be of particular importance in the
treatment of human breast cancer. Chen et al. (15) have recently
suggested several reasons why cardenolides should be developed
as anti-breast cancer drugs. These include the facts that: 1) Na+,K+
-ATPase is a key player of cell adhesion and is involved in cancer
progression; 2) the enzyme serves as a versatile signal transducer
involving a number of hormones, including estrogens; and 3) the
aberrant expression and activity of this enzyme in breast cancer
implicates an etiologic or at least contributing role of Na+,K+-
ATPase in the development and progression of this malignant
disease. For example, there is now strong evidence that Na+,K+-
ATPase plays an important role in the assembly of tight junctions
(TJs) and cell adhesion (52–55). Chen et al. convincingly argue
that altered expression and malfunction of Na+,K+-ATPase may
lead to abnormal TJ structure and, thus, to altered cell adhesion
important in the progression of breast cancer. As mentioned pre-
viously, there are also strong data supporting the role of Na+,K+-
ATPase in a complex signalosome involved in transmitting mem-
brane signals to the nucleus.
A series of reports suggests that estrogen receptor (ER) ligands
(e.g., 17β-estradiol and estrogen-like molecules) can also serve as
ligands of Na+,K+-ATPase. Use of 17β-estradiol enhances Na+,K+-
ATPase activity (56) possibly through improvement of the interac-
tion of the enzyme with ATP as well as Na+ and K+ ions. Because
the interaction of 17β-estradiol with ERs serves as an important
determinant of breast cancer growth, and cardiac glycosides can
block this interaction, cardenolides could be considered effective
modulators of estradiol-dependent breast cancer proliferation.
44
Cardiac Glycosides and Cancer Prevention
Recent investigations of potent cardiac glycosides have focused on
their potential application to the treatment of established cancers;
however, at least one report has suggested that there may also be
a chemopreventive role for this class of agents. That is, Afaq et al.
have suggested that oleandrin might serve as an effective agent
for the prevention or treatment of skin cancer (57). Their research
investigated the topical application of oleandrin to CD-1 mice to
counteract the effects of TPA (12-0-tetradecanoylphorbol-13-ace-
tate), a widely used skin tumor promoter. The topical application
of TPA to mouse skin or its treatment in certain epidermal cells is
known to result in several biochemical alterations, changes in cel-
lular functions, and histological changes leading to dermal tumor
promotion. The data of Afaq et al. clearly show that application of
oleandrin to skin prior to TPA administration affords significant
inhibition of TPA-induced skin edema, hyperplasia, epidermal
ornithine decarboxylase (ODC) activity, and protein expression of
ODC and cyclooxygenase-2 (COX-2), classical markers of inflam-
mation and tumor promotion. Their data also show that topical
application of oleandrin prior to TPA inhibits activation of PI3K
and phosphorylation of Akt, activation of NF-κB, and degradation
and phosphorylation of the inhibitor of NF-κB α protein (IκBα).
These authors, therefore, recommend the use of chemopreven-
tive agents (i.e., oleandrin) in formulations such as emollients or
patches for the prevention or treatment of skin cancer (57). This
suggestion is all the more relevant when considered in light of our
own work which shows a potent ability of oleandrin to inhibit
human melanoma proliferation (58).
In Vivo Efficacy and Development of
Cardiac Glycosides for Clinical
Cancer Therapy
Rodent tumor cells fail to respond to cardiac glycosides in vitro.
Similarly, it has been very difficult to demonstrate an in vivo
response of syngeneic rodent tumors to administration of this class
of compounds. However, as shown in Figure 4, there is no ques-
tion that human tumor cell lines are extremely sensitive to treat-
ment with cardiac glycosides such as oleandrin and bufalin. Thus,
it is possible that human tumor xenografts would respond. Indeed,
this is exactly the case, as shown by several investigators. Han et
al. (7), for example, explored the response of a human hepatocel-
lular carcinoma cell line (BEL-7402) implanted orthotopically
(i.e., transplantation of cells or tissue into its normal anatomical
site) in liver tissue to intraperitoneal treatment with bufalin. They
found that this toad-derived cardiac glycoside produced significant
reductions in tumor volumes and a prolongation in life-span of
the animals. Importantly, no adverse morphological changes were
noted in myocardial, hepatic, or renal tissues. Another interesting
report involved use of the semi-synthetic cardenolide UNBS-1450
against orthotopically implanted human non-small-cell lung cancer
 Cardiac Glycosides as Novel Cancer Therapeutic Agents
BxPC3 PANC-1
ATPase-A3
Na,K-
Oleandrin
Figure 4. Relationship of expression of Na+,K+-ATPase α3 subunit and
binding of oleandrin to human pancreatic cancer cell membranes.
Cells were stained using a mitochondrial dye, Mitotracker, (red color) and a
nuclear Herscht dye (blue). Top row: Cells were also exposed to an antibody
to the α3 subunit of Na+,K+-ATPase (green color). Bottom row: Cells were
incubated with a fluorescent analog of oleandrin (green color). The presence
of green staining (top row) indicates the relative presence of the α3 subunit
which is more prevalent in the PANC-1 than the BXPC3 cells. There is a cor-
responding uptake of oleandrin (bottom row) only in those cells (PANC-1)
that express the α3 subunit.
(59). Chronic oral administration of this compound produced a
beneficial therapeutic effect against these orthotopically implanted
A549 tumor cells. Finally, digoxin inhibits human neuroblastoma
growth in vitro and significantly reduced the growth of human
neuroblastoma tumor in vivo in mice (60), whereby the antitumor
effect arose, at least in part, from an antiangiogenic effect because
digoxin was also found to be effective in the chicken chorioallanto-
ic membrane (CAM) assay. Thus, although limited, evidence exists
for antitumor activity against human tumor xenografts.
In this age of targeted therapeutics, however, where one
strives for selective effects within tumor cells so as to increase
effectiveness and also minimize toxicity to normal tissues, one
might reasonably question why cardiac glycosides with a known
narrow therapeutic index would ever be considered for clini-
cal development as an anticancer therapy. There is little doubt
that the potential for serious cardiovascular toxicity exists with
many, if not all cardiac glycosides, but the risks appear manage-
able because the effective concentrations (i.e., in the nanomolar
range) of these agents to control cancer-cell proliferation are well
below concentrations that produce cardiac toxicity (61). Because
the cardiovascular toxicities associated with this class of agents
are well documented, careful monitoring of plasma concentra-
tions may allow for the continued safe use of digitalis and related
compounds. Moreover, specific antibody-based treatments, such
as digoxin-specific Fab antibody fragments (Digibind; DigiTAb), as
well as an older treatment, activated charcoal, are available to res-
cue patients receiving accidental over-medication (62, 63).
The desirable goal of producing a synthetically derived car-
diac glycoside with potent ability to inhibit proliferation of human
tumors but without the potential to cause cardiac related toxicity,
unfortunately, has not yet been fully achieved. Investigators have
shown, however, that single cardenolides, or those derived from
various extracts of plants and animals (Table 1), represent potent
compounds with selective effects against human tumor cell lines
and xenografts. For example, UNBS-1450, a semisynthetic carde-
nolide derivative of a cardiac glycoside originally isolated from an
African plant (Calotropis procera), has shown promising activity
against human non-small cell lung carcinomas growing as xeno-
grafts in nude mice (59). UNBS-1450 can be safely administered
to mice in doses that are twenty-four times greater than that of
ouabain and twelves times greater than that of the parent com-
pound oxovoruscharin (64). With good activity against non-small
cell lung cancers in mice with metastases in the brain and liver,
UNBS-1450 is entering phase I clinical trials in Belgium (17).
To date, there is only a single plant extract, Anvirzel™,
derived from Nerium oleander, that has progressed through a
Phase I trial in the United States. Anvirzel is a hot-water extract
of oleander whose encouraging preclinical activity (65) led to a
successful investigational new drug application (IND) from the
FDA and to a Phase I clinical trial performed at the Cleveland
Clinic between 2000 and 2001. No objective responses were
noted which might be because the limited time of exposure to
the product and intramuscular route of administration limited
the total volume of extract that could be administered on a daily
basis. A longer time of exposure and a different route of admin-
istration may impact response. Also, no dose-limiting toxicities
were found. The product known as PBI-05204 was produced in
response to the need for a formulation and route of administration
suitable for adequately exploring the anticancer potential of an
oleander extract. PBI-05204 is a modified supercritical CO2 extract
of organically grown Nerium oleander that has been especially for-
mulated for oral administration to humans. An IND for evaluation
of PBI-05204 as a “botanical drug” was obtained from the FDA in
September, 2007, and a Phase I clinical trial in patients with solid
tumors has now been initiated at the University of Texas M.D.
Anderson Cancer Center. Given the expanding knowledge of the
multiple anticancer mechanisms for cardenolides, the outcome of
these early stage clinical trials of potent plant extracts, such as the
proposed botanical drug PBI-05204 and simpler single chemical
entities such as UNBS-1450, will be of great interest. The results
may hold the key as to whether this class of potent natural prod-
ucts is worthy of further development as primary and/or adjuvant
therapy for malignant diseases.
Conclusions
Our understanding of the spectrum of the pharmacologic activities
of cardiac glycosides has increased significantly since the discov-
ery of their effectiveness for treatment of congestive heart failure.
It is now recognized that certain cardiac glycosides are involved
in complex cell signal transduction mechanisms that may have
important consequences in their application to the prevention
and/or treatment of malignant diseases. Development of clinically
February 2008
Volume 8, Issue 1 45
 Review
targeted, antiproliferative cardiac glycosides could be helped by
systematic evaluations of several formulations and chemical vari-
ants. Furthermore, assays of the relative presence of α1 and α3
subunits in clinical samples, for example, may give some direction
for the assessment of which cancers might be most susceptible
to cardiac glycoside therapy. Further development of synthetic,
semi-synthetic, or naturally occurring cardiac glycosides, with
assessment of their toxicity and structure-activity relationships,
might expand the possibilities of finding a cardiac glycoside with
a wider therapeutic index. Because of concerns with toxicity of
internally used cardiac glycosides, topical formulations should
also be considered for skin cancer prevention and/or treatment.
Additionally, because chemotherapy has had limited benefits in
most advanced malignancies, cardiac glycosides could also be
investigated for possible adjuvant therapy. They may, for example,
be of benefit in early-stage disease as well as stand-alone therapy
for patients where conventional interventions are either not
applicable, because of patient tolerance, tumor cell sensitivity, or
where a patient has run out of conventional therapeutic options
altogether. Finally, consideration should be given to the use of
selected cardiac glycosides or natural extracts containing them as
adjuvant therapy for concomitant use with currently existing ther-
apies. Given that certain Na+,K+-ATPase subunits appear to make
unique targets that are selectively expressed in tumor as opposed
to normal tissue and that the potential for cardiac toxicity is not
shared by many other currently available cancer therapies, cardiac
glycosides should be considered as an therapeutic option for novel
combination therapy. doi:10.1124/mi.8.1.8
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 Cardiac Glycosides as Novel Cancer Therapeutic Agents

ATPase in human breast cancer cells. Molec. Pharmacol. 67, 929–936 (2005). Keith I. Block, MD, co-founded
111. Liu, J., Tian, J., Haas, M., Shapiro, J.I., Askari, A., and Xie, Z. Ouabain and is Medical/Scientific Director
interaction with cardiac Na+,K+-ATPase initiates signal cascades inde-
pendent of changes in intracellular Na+ and Ca2+ concentrations. J. Biol.
of the Block Center for Integrative
Chem. 275, 27838–27844 (2000). Cancer Treatment. He is a member
112. Contreras, R.G., Flores-Beni Tez, D., Flores-Maldonado, C., Larre, I., of the National Cancer Institute’s
Shoshani, L., and Cereijido, M. Na+,K+-ATPase and hormones: New roles Physician Data Query (PDQ)
for an old enzyme and an old inhibitor. Cell Mol. Biol. 52, 31–40 (2006).
Cancer CAM Editorial Board, the
113. Harwood, S. and Yaqoob, M.M. Ouabain-induced cell signaling. Front.
Biosci. 10, 2011–2017 (2005). editor-in-chief of the peer-reviewed
114. Kulikov, A., Eva, A., Kirch, U., Boldyrev, A., and Scheiner-Bobis, G. journal Integrative Cancer Therapies,
Ouabain activates signaling pathways associated with cell death in and a Clinical Assistant Professor
human neuroblastoma. Biochim. Biophys. Acta 1768, 1691–1702 (2007).
at the College of Medicine at the University of Illinois, Chicago.
115. Glibert, M. and Knox, S. Influence of Bcl-2 overexpression on Na+,K+-
ATPase pump activity: Correlation with radiation-induced programmed In collaboration with the University of Illinois and other univer-
cell death. J. Cell Physiol. 171, 299–304 (1997). sity facilities in the US and Israel, Dr. Block conducts research in
116. Lopez-Lazaro, M. Digitoxin as an anticancer agent with selectivity for nutrition and in the use of natural medicines in cancer treatment.
cancer cells: Possible mechanisms involved. Expert Opin. Ther. Targets
11, 1043–1053 (2007).
117. Johansson, S., Lindholm, P., Gullbo, J., Larsson, R., Bohlim, L., and
Peiying Yang, PhD, (Collaborator)
Claeson, P. Cytotoxicity of digitoxin and related cardiac glycosides in is an Assistant professor in the
human tumor cells. Anticancer Drugs 12, 475–483 (2001). Department of Experimental
118. Bielawski, K., Winnicka, K., and Bielawska, A. Inhibition of DNA topoi- Therapeutics. Dr. Yang’s research
somerase I and II and growth inhibition of breast cancer MCF-7 cells by oua-
bain, digoxin and proscillaridin A. Biol. Pharm. Bull. 29, 1493–1497 (2006). has focused on bioactive lipids
119. Yang, Q., Huang, W., Jozwik, C. et al. Cardiac glycosides inhibit TNF- and natural products in cancer
alpha/NF-κB signaling by blocking recruitment of TNF receptor-associat- development and prevention. She
ed death domain to the TNF receptor. Proc. Natl. Acad. Sci. U.S.A. 102,
developed a rapid, specific, and
9631–9636 (2005).
120. Mijatovic, T., Matthieu, V., Gaussin, J.F., DeNeve, N., Ribaucour, F.,
sensitive method for simultaneous-
VanQuaquebeke, E., Dumont, P., Darro, F., and Kiss, R. Cardenolide- ly determination of arachidonate
induced lysosomal membrane permeabiliazation demonstrates thera- metabolites in various biological matrices. Additionally, Dr. Yang
peutic benefits in experimental human non-small cell lung cancers.
Neoplasia 8, 402–412 (2006).
is interested in the effects of nutritional supplements, such as fish
oil, and Chinese herbal medicine.
Robert A. Newman, PhD,
received his undergraduate train- Alison Pawlus, RPh, PhD, com-
ing at the University of Rhode pleted her graduate training, in
Island and graduate training at the 2007, in Pharmacognosy at the
University of Connecticut, where University of Illinois at Chicago in
he obtained MS and PhD degrees the laboratory of Dr. A. Douglas
in pharmacology and toxicology. Kinghorn. She is a Postdoctoral
His postgraduate work was per- Fellow in the Department of
formed at the Medical School of Experimental Therapeutics at the
Georgia and at the University of University of Texas, M.D. Anderson
Vermont Medical School. After a sabbatical at Stanford University Cancer Center where she studies
in 1983, Dr. Newman joined the faculty of the University of Texas the use of natural products for cancer treatment and prevention.
M.D. Anderson Cancer Center. He is a Professor of Experimental
Therapeutics and holds the D.B. Land Professorship. Dr. Newman
also jointly runs the Pharmacology and Analytical Core lab for the
institution as well as co-directs the Pharmaceutical Development
Center that has introduced more than six compounds into the
clinic over the past seven years. He is the author of over 250 peer-
reviewed publications and several books. His current research
deals with the science of nutraceuticals and understanding how
these can be specifically applied for prevention and treatment of
inflammation and malignant disease. E-mail rnewman@mdander-
son.org; fax (713) 563-9093.

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