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Current Topics in Medicinal Chemistry, 2013, 13, 2171-2183 2171

Mitochondria: A Promising Target for Anticancer Alkaloids

Flix A. Urra1,3,*, Miguel Crdova-Delgado1, Hernn Pessoa-Mahana1, Oney Ramrez-Rodrguez1,

Boris Weiss-Lpez2, Jorge Ferreira3 and Ramiro Araya-Maturana1,*

1
Department of Organic and Physical Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of
Chile, Santiago de Chile; 2Department of Chemistry, Faculty of Sciences, University of Chile, Santiago de Chile;
3
Laboratory of Bioenergetics and Cancer, Molecular and Clinical Pharmacology Program, ICBM, Faculty of Medicine,
University of Chile

Abstract: A great number of alkaloids exhibit high potential in cancer research. Some of them are anticancer drugs with
well-defined clinical uses, exerting their action on microtubules dynamics or DNA replication and topology. On the other
hand, mitochondria have been recognized as an essential organelle in the establishment of tumor characteristics, especially
the resistance to cell death, high proliferative capacity and adaptation to unfavorable cellular environment. Interestingly,
many alkaloids exert their anticancer activities affecting selectively some functions of the tumor mitochondria by 1)
modulating OXPHOS and ADP/ATP transport, 2) increasing ROS levels and mitochondrial potential dissipation by cross-
talk between endoplasmic reticulum (ER) and mitochondria, 3) inducing mitochondria-dependent apoptosis and auto-
phagy, 4) inhibiting mitochondrial metabolic pathways and 5) by alteration of the morphology and biogenesis of this or-
ganelle. These antecedents show the relevance of developing research about the effects of alkaloids on functions con-
trolled by tumor mitochondria, offering an attractive target for the design of new alkaloid derivatives, considering organ-
elle-specific delivery strategies. This review describes mitochondria as a central component in the anticancer action of a
set of alkaloids, in a way to illustrate the importance of this organelle in medicinal chemistry.
Keywords: Alkaloids, apoptosis, cancer cells, delivery, endoplasmic reticulum, mitochondria, targeting.

1. INTRODUCTION exploiting the pharmacological potential of this type of

Alkaloids are secondary metabolites isolated from sev-
eral source such as plants, bacteria, fungi, marine sponges
and slugs, arthropods, amphibians, birds and mammals, and
they show different biological activities [1, 2]. Alkaloids,
such as other natural products, exhibit a wide variety of
structural arrangements with many stereogenic centers, het-
eroatoms, several H-bond donors and acceptors and a low
ratio between the aromatic rings and total heavy atoms [3].
As a consequence, alkaloids exhibit a wide spectrum of mo-
lecular targets. However, when a molecule interacts with
several targets, only a fraction of the total concentration is
available for action on each one [2]. Despite that, alkaloids
have shown to be an important component of the current
cancer chemotherapy [4]; these compounds affect the pro-
gression of cell cycle by alteration of microtubule polymeri-
zation or inhibition of topoisomerases [2]. However, recent
evidences show that an increasing number of alkaloids, in-
cluding the classical anticancer alkaloids, can present several
cellular targets that affect selectively to cancer cells and in-
volve mitochondria [5, 6]. On the other hand, the severe tox-
icity and development of chemoresistance have impulsed to
search strategies or new targets to enhance tumor selectively
[4, 7]. In this sense, selective targeting is currently a very
active field of research, whose findings allows fully
*Address correspondence to these authors at the Department of Organic and
Physical Chemistry, Faculty of Chemical and Pharmaceutical Sciences,
University of Chile, Santiago de Chile; Tel: 56-2-29782874; Fax: 56-2-
29782868; Emails: raraya@ciq.uchile.cl and felix.urra@qf.uchile.cl
molecules. Furthermore, it offers the possibility to recover
compounds abandoned in previous pharmacologic studies. In
this review, we present a set of selected alkaloids and deriva-
tives that have mitochondria as a central component of their
anticancer action and, in our opinion, could benefit of selec-
tive targeting studies (Fig. 1).
In recent years we have witnessed a change in the para-
digm of mitochondrial functioning inside the cell. It is now
clear that mitochondria are central to cell death, cell differen-
tiation, innate immune system, hypoxia sensing, metabolism
of calcium and amino acids, iron sulfur center and heme bio-
synthesis [8-10]. Disruption to these processes contributes to
several pathologies, such as cancer, making mitochondria an
important therapeutic target [11-15]. In cancer cells, mito-
chondria have an essential role in the neoplasic phenotype,
especially resistance to apoptosis, limitless proliferative po-
tential and metabolic reprogramming [16, 17]. It has been
suggested that the most efficient mitochondrially-targeted
therapies would affect mitochondrial processes that partici-
pate in the establishment of several of this features [16].
Consistently, alteration in mitochondrial dynamics (i.e. fis-
sion and fusion) and damage to mitochondrial macromole-
cules, can induce cell death by apoptosis or autophagy [18].
Besides, mitochondria control the programmed cell death via
several mechanisms that can be activated by disruption of
mitochondrial bioenergetics, alteration of cellular redox bal-
ance and release or activation of pro-apoptotic factors [11-
15, 19].

1873-5294/13 $58.00+.00 2013 Bentham Science Publishers

2172 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 17 Urra et al.

Fig. (1). Structures of the reviewed anticancer alkaloids.

Treating the origins of disorders located within the mito- velop particular strategies to target them selectively [20].
chondria is a challenge. Although several compounds are These strategies must take into account that mitochondria are
known to act on these organelles and it is necessary to de- located inside the cell and, in turn, the targets of drugs are
Mitochondria: A Promising Target for Anticancer Alkaloids
located inside mitochondria. This imposes crossing several
membranes and therefore many physicochemical require-
ments to the molecules for a selective accumulation in these
organelles [21-28]. It is very likely that many potential drug
molecules do not exhibit adequate tumor and mitochondria-
specific accumulation. Therefore a concerted effort to de-
velop tumor-targeted mitochondria-specific approaches
might be a significant aid towards exploiting mitochondrial
targets for cancer therapy, enhancing mitochondria-specific
accumulation of the drug. Specific approaches have been
described, for instance the linkage of a triphenylphospho-
nium cation to structurally different molecules has been used
to deliver them into the mitochondria [29]. Also, the leader
sequences of some matrix proteins have been used to medi-
ate the mitochondria-specific accumulation of bioactive
compounds [19]. Besides, pharmaceutical nanocarriers like
liposomes micelles and solid nanoparticles have been used
for this purpose [19, 21-29]. With this in mind, we are con-
vinced that the biological activity of many alkaloids could be
increased via their selective delivery to mitochondria.
Fig. 2 and 3 show the actions of alkaloids on some func-
tions of the tumor mitochondria by 1) modulation of oxida-
tive phosphorylation (OXPHOS) and the ADP/ATP trans-
port, 2) increase of ROS levels and mitochondrial potential
dissipation by cross-talk between endoplasmic reticulum
(ER) and mitochondria, 3) induction of mitochondria-
dependent apoptosis and autophagy, 4) inhibition of mito-
chondrial metabolic pathways and 5) alteration of morphol-
ogy and biogenesis of this organelle. These activities are
discussed below.
2. ALTERATION OF MITOCHONDRIAL BIOENER-
GETICS: MODULATION OF OXPHOS AND TRANS-
PORT OF ADP/ATP
Oxidative phosphorylation involves electron transport
chain (ETC), composed by four complexes: NADH-
ubiquinone oxidoreductase (Complex I), succinate-
ubiquinone oxidoreductase (Complex II), ubiquinol-
cytochrome-c oxidoreductase (Complex III) and cyto-
chrome-c oxidase (Complex IV) and ATP synthase. Com-
plex I and Complex II oxidize NADH and FADH2 to reduce
molecular oxygen to water. This process involves electron
transfer, which is coupled to the pumping of protons to the
intermembrane space by complexes I, III and IV forming the
mitochondrial membrane potential (MMP). ATP synthase
utilizes this proton-motive force to generate ATP at the mi-
tochondrial matrix [30]. In cancer cells, deficiencies in ETC
produced by mutations in mitochondrial genome (mtDNA)
and in some nuclear-coded components [31, 32] and meta-
bolic reprogramming involving elevated glycolysis in the
presence of oxygen (Warburg effect) [33], are characteristics
that have allowed the development of a broad group of mito-
chondriotoxic agents known as mitocans [34, 35]. Interest-
ingly, alterations in different levels of OXPHOS, especially
inhibition or uncoupling of respiration or inhibition in the
transport of ADP/ATP, are events that produce ATP deple-
tion with induction of selective cancer cell death (Fig. 2A).
In this view, at least four alkaloids have been identified
that affect ETC with consequent decreasing of ATP levels.
Sanguinarine (1), a benzophenanthridine alkaloid, exhibits
Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 17 2173
antiproliferative activity on several human tumor cells [36,
37]. This alkaloid presents a dual action in invasive mouse
melanoma cells: it primarily accumulates in cell nuclei, caus-
ing inhibition of cell proliferation and cell death, but at low
concentrations, induces alteration in mitochondrial function
[38]. Sanguinarine (1) affects preferentially to Complex I,
stimulates respiratory state 4 and state 4+Oligomycin and
produces inhibition of the uncoupled respiration and state 3,
indicating that induce uncoupling of respiration. Addition-
ally, it induces opening of MPTP and display a mixed effect
on calcium loading capacity. At low concentrations, sangui-
narine decreases calcium loading capacity however, at high
concentrations increases this capacity [38]. In contrast, in
others cancer cell lines others mechanisms of apoptosis have
been reported, including mitochondrial alterations such as a
ROS-mediated mitochondrial pathway [39, 40].
Capsaicin (2), induces apoptosis through cellular stress,
involving mitochondria and endoplasmic reticulum (See be-
low) [41]. In several human cancer cells, it produces mito-
chondrial membrane potential dissipation, increase of ROS
production, increase of Bax expression, down-regulation of
Bcl-2, release of cytochrome c and AIF in the cytosol, and
activation of caspase 3 [41-43]. Similar results have also
been obtained with in vivo studies [43, 44]. Recently, it has
been reported that capsaicin (2) can induce oxidative stress
by alteration in the mitochondrial electron transport chain
[45]. It inhibits selectively complexes I and III with conse-
quent ATP depletion in pancreatic cancer cells. This effect is
dependent of the ROS generation, favoring progression to
apoptosis. It has been recognized that mutations in subunits
of the ETC play a central role in tumorigenesis and that res-
piratory complexes act as inhibitors for apoptosis induction
[32]. Therefore, alterations in it functions result in a strategy
for selective cytotoxicity.
Berberine (3), an isoquinoline alkaloid, has several
pharmacological properties [46, 47] and can affect in differ-
ent levels the mitochondrial functions [48, 49]. In mouse
melanoma cells, it selectively accumulates in mitochondria,
depending of mitochondrial potential. Moreover, it induces
oxidative stress and inhibition of complex I that result in
ATP depletion, alterations in mitochondrial structure and
reduction in mtDNA copy number [48]. It has also been sug-
gested that induction of MPTP opening and respiration inhi-
bition are events due to interaction with ANT [50]. This pro-
tein facilitates the exchange of ADP/ATP across the mito-
chondrial inner membrane and several isoforms can be in-
volved in the progression of cancer, being a regulator of ac-
quisition of resistance to apoptosis [51, 52].
Lamellarin-D (4), a hexacyclic pyrrole alkaloid, has
anticancer activity on several tumor cells. It induces apopto-
sis by two mechanism of action: topoisomerase I inhibition
and induction of apoptosis intrinsic pathway of a p53 nuclear
signaling-independent manner [53, 54]. However, a recent
report indicates that lamellarin-D (4) primarily produces
changes in mitochondrial bioenergetics, reducing Complex
III activity with decrease of mitochondrial respiration, ATP
synthesis, and mitochondrial potential dissipation. These
alterations result in MPTP opening and apoptosis in human
melanoma cells [55].
2174 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 17 Urra et al.

3. INCREASE OF ROS LEVELS AND MITOCHON-
DRIAL DEPOLARIZATION BY CROSS-TALK BE-
TWEEN ENDOPLASMIC RETICULUM (ER) AND
MITOCHONDRIA
A particular mechanism of increase of the intracellular
ROS levels involves alterations in endoplasmic reticulum
(ER)-mitochondria interactions. These two organelles play
an important role in the control of ROS and calcium levels
and are in tight contact, sharing sensor proteins involved in
induction of cell death [56]. Alterations in this inter-
organelles cross-talk participate in the progression of several
pathologies [57-60]. In cancer cells, ER participates in the
regulation of environmental challenges, especially hypoxia,
angiogenesis and chemoresistance, that affect to cellular sur-
vival and growth [61]. Different repertories of response are
utilized when ER stress is present, which is sensed by three
ER proteins: PERK, IRE1 and ATF6. In acute ER stress,
sensor proteins promote protective effect conferring resis-
tance to radiation and chemotherapy [62]. In contrast under a
prolonged ER stress, cell death is induced [63].
Therefore, compounds that can produce stress in ER,
such as certain alkaloids, can trigger pro-oxidative events
eventually ending in the cell death (Fig. 2D). The induction
of an organelle-related stress response has been described as
a novel therapeutic strategy for the treatment of highly resis-
tant tumors, such as pancreatic cancer and glioblastoma cells
[64].
In human glioblastoma T98G cells, berberine (3) in-
duces ER stress mediated by mitochondrial dysfunction, in-
volving mitochondrial membrane potential dissipation and
elevation of ROS levels. These events produce activation of
PERK with subsequent phosphorylation of eIF2,
GRP78/Bip and CHOP/GADD153, which is a transcriptional
factor implicated in activation of caspase-3 and apoptosis
progression [65].
For capsaicin (2), a mechanism that involves ER and mi-
tochondria is also reported. In no-malignant human breast
MCF10A cells, it induces ER stress with activation of sensor
protein IRE1 signaling, increase of intracellular Ca2+, calpain
activation; producing mitochondrial membrane potential
dissipation, release of cyt-c and activation of caspases [66].
Capsaicin (2) can also induce a similar mechanism in hu-
man tongue cancer SCC-4 cells, inducing primary increase
ROS and Ca2+ levels, mitochondrial membrane potential
dissipation and nuclear translocation of AIF, ATF-4 and
CHOP/GADD153, [67].
Alkaloid derivatives that incorporate the 2-phenyl 6-
pyrrolidinyl-4-quinazolinone moiety exhibit anticancer ac-
tivities [68, 69]. MJ-29 (5) is a novel derivative that induces
inhibition of tubulin polymerization, mitotic arrest [70] and

Fig. (2). Mitochondrial functions affected by anticancer alkaloids, A) Alteration in mitochondrial bioenergetics, B) Alteration in mitochon-
drial metabolic pathways, C) Alteration in mitochondrial morphology and biogenesis, and D) Alteration in cross-talk between ER-
mitochondria. VDAC: voltage-dependent anion channel, ANT: adenine nucleotide traslocator, OAA: oxaloacetic acid, Cit.: citrate, -KG: -
ketoglutarate, Mal.: malate, Asp: aspartic acid, Glut: glutamic acid, Lam-D: lamellarin-D, Asc: ascididemin, MAS: malate-aspartate shuttle,
Aco2: mitochondrial aconitase-2, mtDNA: mitochondrial DNA, MMP: mitochondrial membrane potential.
Mitochondria: A Promising Target for Anticancer Alkaloids
presents antileukemic activity by induction of ER-stress and
intrinsic apoptosis [69]. It stimulates the protein levels of
calpain-1, CHOP, phosphorylated eIF2 pathways, and
ROS-mediated mitochondrial dysfunction, involving MPTP
opening, mitochondrial potential dissipation, cardiolipin oxi-
dation and up-regulation of intrinsic pro-apoptotic signaling
in WEHI-3 leukemic cells [69].
4. APOPTOSIS MEDIATED BY MITOCHONDRIA
(INTRINSIC PATHWAY)
Control of apoptosis by mitochondria is essential in can-
cer cells [23]. Molecular adaptations to mitochondrial level,
involving mutations, allow them the development of resis-
tance to induction of cell death [16, 71]. Alterations in the
mitochondrial functions via increase of ROS levels, affecting
mitochondrial membrane potential, is a crucial event that can
precede to intrinsic pathway apoptosis. Several alkaloids
have been reported as highly selective anticancer agents and
their mechanism of action involve disruption of this control
on the cancer cell life [6]. Table 1 summarizes the alkaloids
that induce intrinsic pathway apoptosis.
Alkaloids isolated from different natural sources have
been described as inductors of mitochondria-dependent
apoptosis, where mitochondrial potential dissipation, accom-
panied sometimes with increase ROS levels, produce release
of pro-apoptotic factors as cytochrome-c and AIF with the
consequent caspases activation and degradation of PARP
(Fig. 3A). Moreover, up-regulation of pro-apoptotic proteins
(e.g. Bax, Bak) and down-regulation of anti-apoptotic pro-
teins (e.g. Bcl-2, Bcl-xl) are events induced by alkaloids.
Interestingly, harmine (6) only produces down-regulation of
anti-apoptotic proteins Bcl-2, Mcl-1 and Bcl-xl, without
changes in Bax[72]. Pancratistatin (7) induces ROS-
mediated apoptosis and in combination with the anti-
estrogen tamoxifen can have a synergistic effect, inducing
apoptosis in both estrogen receptor positive (MCF-7) and
estrogen receptor negative (HS578
T) cell lines [73-75].
On the other hand, increase in ROS levels can activate
the stress-sensor JNK as is the mechanism reported for vi-
norelbine (8) and ellipticine (9) [76, 77]. This latter is a
pyridocarbazole alkaloid with known anticancer activity me-
diated by induction of DNA damage, involving topoi-
somerase II inhibition and DNA adduct formation [78-82].
Several strategies of delivery based in self-assembling pep-
tide have been designed for ellipticine (9). These peptides
are organized in nanofibers and stabilize this hydrophobic
anticancer agent [83-85]. This approach for a selective deliv-
ery can favor an increase in activity and reduce toxic events.
5. AUTOPHAGY MEDIATED BY MITOCHONDRIA
Cancer cells exhibit increased ROS levels compared to
normal cells because of increased metabolism and mito-
chondrial dysfunction [34]. Additionally, events such as de-
creased OXPHOS, low levels of oxygen and acid microenvi-
ronment, contribute to establish cell signaling for survival
and proliferation [86]. On the other hand, certain evidence
suggests that ROS regulates autophagy by control of auto-
phagy genes beclin-1 and Atg4, p62 mediated by NF-E2-
related factor 2 (NRF2) and inhibition of mTOR signaling
[87].
Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 17 2175
Autophagy primarily functions as a cell survival adaptive
mechanism during induced cellular stress conditions. How-
ever, when this condition is persistent it can promote exten-
sive autophagy, triggering cell death [88]. Moreover, mito-
chondria have been recognized to play an important role in
the establishment of oxidative stress, favoring autophagic
process [9]. A cancer therapy strategy is to induce oxidative
stress and autophagic cell death [89]. This view can be use-
ful if it is considered that frequently cancers cells are resis-
tant to apoptosis or develop drug resistance, offering
autophagic cell death an effective alternative therapy [87,
88].
Some alkaloids with anticancer activities have been re-
ported as modulators of autophagy. Interestingly, they can be
classified as autophagic inhibitors or inductors (Fig. 3B).
Tetrandrine (10) is a bisbenzylisoquinoline alkaloid that at
5
M concentration induces autophagy in human hepatocel-
lular carcinoma cells [90]. The mechanism involves mito-
chondrial dysfunction. Initially, tetrandrine (10) produces
mitochondrial depolarization that precedes the increase of
intracellular ROS levels, which is blocked by cyclosporine
A, an inhibitor of the MPTP opening. Moreover, it induces
the expression of Atg7, LC3-II, the formation of acidic auto-
phagolysosome vacuoles, and ROS-induced activation of
ERK MAP kinase signaling, which all are involved in
tetrandrine-induced autophagy. Similar results are produced
in vivo [90]. Interestingly, at high concentrations (>20
M),
this alkaloid induces apoptosis in the same carcinoma cells
[91]. A pancratistatin alkaloid-derivative compound JCTH-4
(11) also can induce apoptosis and autophagy in cancer cells
[92, 93]. Decrease of mitochondrial membrane potential,
ROS production, and appearance of autophagic marker LC3-
II have been described in the JCTH-4-induced autophagy in
p53 positive and p53 negative human colorectal cancer cells
[92]. In addition, the parent alkaloid pancratistatin (7) has
also been described as inductor of apoptosis and autophagy
in other cancer cells [94].
Recently, the anticancer mechanism of noscapine deriva-
tive Red-Br-nos (12), (R)-9-bromo-5-((S)-4,5-dimethoxy-
1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,
8-tetrahydro-[1,3]-dioxolo[4,5-g]isoquinoline, has been de-
scribed in human prostate cancer PC-3 cells [95]. Red-Br-
nos-induced autophagy is protective to the induction of
apoptosis and is an early detectable event that involves dou-
ble membrane vacuoles, acidic vesicular organelles, increase
of expression of LC3-II and beclin-1. Interestingly, mito-
chondria control apoptosis and autophagy and these two
pathways can cross-talk [95]. Red-Br-nos (12) induces al-
terations in mitochondrial architecture, particularly in the
intracristal compartment, accompanied of mitochondrial po-
tential dissipation and ROS production, which is essential for
autophagy and caspase-independent ROS-dependent apopto-
sis [95]. At contrary, chloroquine (13) is an agent that inhib-
its the autophagic process through prevention of lysosome-
autophagosome fusion and the degradation of autophagoso-
mal content [96]. In solid tumor, hypoxia conditions allow
the development of resistance to treatment, especially
acute/cycling hypoxia accompanied of ROS production. In
this condition, cancer cells can acquire adaptations to mini-
mize ROS production, involving reduction of mitochondrial
content by specific autophagy (known as mitophagy) or
2176 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 17 Urra et al.

Table 1. Anticancer Alkaloids that Induce Apoptosis Mediated by Mitochondria (Intrinsic Pathway).

Alkaloid Mechanism of apoptosis Cell type Comments Ref.

O O
H H
N N MMP dissipation, release of intracel-
Br O B6 is a synthetic molecule based on
lular Ca2+, activation of caspase-3 Several human
pyrrole alkaloid aldisin isolated from [125]
Br and -9, arrest in G1 phase of cell cancer cells.
marine organism.
cycle.
Aldisin-derivative B6 (18)
O
Arrest in S phase, MMP dissipation,
O
- release of Cyt-c, activation of Benzo[c]phenanthridine alkaloid
N Cl Human Hepatoma
O caspase-3, cleavage of PARP, up- present in several plant species (e.g. [126]
O SMMC-7721 cells.
regulation Bid and Bax, down- Chelidoniummajus).
Chelerythrine (19) regulation Bcl-xl.

Arrest G2/M phase of the cell cycle, Alkaloid isolated from Apocyanaceae
N
release of cyt-c and AIF, activation of RL95-2 human plants with several anticancer mecha-
N
H caspases, MMP dissipation, increase endometrial cancer nism reported: topoisomerase II inhi- [77]
intracellular ROS levels, activation of cells. bition and formation of DNA adducts
Ellipticine (9) ERK and JNK. [78].

N O Up-regulation of Bax and p53, down- Alkaloid isolated from Chinese herbal
N Human Colorectal
H H
N regulation of Bcl-2, MMP dissipa- medicine Evodiarutaecarpa with
Carcinoma cells [127]
tion, activation of caspase-3, arrest in antioxidant, anti-inflammatory activi-
COLO-205.
G2/M phase of cell cycle. ties reported.
Evodiamine (20)

Nuclear fragmentation and chromo- Harmine is a major component iso-

N
somal condensation, MMP dissipa- Human hepatocellu- lated from Peganumharmala L. (Zy-
O N tion, caspase-3 and caspase-9 activa- lar carcinoma cell gophyllaceae) seed extract. [72]
H
tion, down-regulation of Bcl-2, Mcl-1 line HepG2. Other effect reported: antinociceptive
Harmine (6) and Bcl-xl, without change in Bax. and DNA topoisomerase inhibitor.
H 3C
Increase of ROS levels, MMP dissi-
H pation, release of cyt-c, caspase-3 [129]
Alkaloid isolated from plant Lycopo-
N O activation, chromatin condensation, HeLa cells.
H diumclavatum [128].
inter-nucleosomal DNA fragmenta-
tion
Lycopodine (21)
OH
HO
Release of cyt-c, activation of Amaryllidaceae alkaloid [130]. Its [133]
O Human leukemia
caspase-3 and -9, degradation of anticancer derivatives also act induc-
O
N cells.
PARP, down-regulation of Mcl-1. ing apoptosis [131, 132].
Lycorine (22)
O
H
N
H MMP dissipation, release of cyt-c,
Human multiple- Alkaloid isolated from the traditional
ratio Bcl-2/Bax protein decreased [134]
H H myelomacells. Chinese herb Sophoraflavescens.
N caspase-3 activation.

Matrine (23)

N H
N
N N
HO
O N O Imidazole alkaloid identified in ma-
MMP dissipation, activation of A431 epidermoid
rine sponge Leucettachagosensis [136]
caspase-3, -8 and -9. carcinoma cells.
O [135].

Naamidine-A (24)
Mitochondria: A Promising Target for Anticancer Alkaloids Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 17 2177

(Table 1) contd.

Alkaloid Mechanism of apoptosis Cell type Comments Ref.

O N
Up-regulation of Bax and release
O Several human
O
Cyt-c, down-regulation of Bcl-2 Alkaloid with antitussive activity
gastric cancer cell [137]
O protein, activation of caspase-3 known.
O
O
lines.
and -9.
Noscapine (25)
Br
O

O
N
MMP dissipation, increase of PUMA, Human prostate
O BAX, caspase-3 activation, cleavage cancer cell lines PC- Brominated analog of the plant-
O
[138]
PARP, arrest G2/M phase, activation 3, LNCaP, C4-2 and derived alkaloid noscapine.
O
O
O
of the mitotic checkpoint. C4-2B.

Noscapine-derivative EM011 (26)

OH O
O NH

O
OH Increase ROS production, ATP de- Human breast can- Alkaloid isolated from Hawaiian
pletion, MMP dissipation, caspase cer cell lines MCF-7 spider lily [139]. [73]
HO OH
OH activation. and Hs-578-T.

Pancratistatin (7)
N
Cl
O
Up-regulation of pro-apoptotic Bax Alkaloid isolated from marine Strep-
Human leukemic
and FasL, MMP dissipation, degrada- tomyces sp. with antiangiogenic activ- [140]
N U937 cells.
H
tion PARP, caspase-3 activation. ity reported.
Streptochlorin(27)
N
OH Up-regulated of Bax, down-regulated Alkaloid isolated from plant as the
H of Bcl-2 expression, release of cyt-c, Human Lung Can- Australian legume Swainsonacanes-
OH
OH [141]
caspase -3 and -9 activation, cleavage cer A549 cells. cens and in many Astragalus and
Swainsonine (28) of PARP. Oxytropis species (Leguminosae).

OH HO

HN NH
MMP dissipation, increase of mito-
Lung cancer cells, SK228 exhibits cancer cell-specific
chondrial ROS levels, DNA damage,
cytotoxicity and inhibits also cancer
HN NH release of cyt-c, activation of Esophageal carci- [142]
cell invasion, affecting FAK/Paxillin
OH HO caspase-3 and -9, down-regulation of noma cells.
signaling.
Bcl-xl, up-regulation of Bad.
Vinca alkaloid-derivative SK228
(29)
N

H N
MMP dissipation, down-regulation
N
H O AS2 human lung
O O Mcl-1, increase of ROS levels, acti-
O N
OH adenocarcinoma Vinca alkaloid [76]
O H
vation of JNK. JNK-regulated DNA
O O
cells.
damage in prometaphase.
Vinorelbine (8)

removal of intracellular aggregates. Consequently, moderate 6. INHIBITION OF MITOCHONDRIAL METABOLIC

hypoxia can trigger mitophagy with reduced respiration as an
adaptative process [97, 98]. In human cancer cells MCF-7,
HT29 and U373, inhibition of autophagy by chloroquine
(13), prevents the tolerance to acute hypoxia that allows spe-
cific degradation of mitochondria to decrease ROS levels in
reoxygenation [99]. It has been suggested that this action of
chloroquine (13) decreases the hypoxic portion within tu-
mors, being an opportunity to enhance antitumor therapy
[99].
PATHWAYS
Mitochondria have an essential participation in cell life,
especially its function as power plant based in the ATP
synthesis. Other classic metabolic pathways that are con-
trolled by this organelle include Krebs cycle or also known
as tricarboxylic acid cycle (TCA), heme synthesis, steroi-
dogenesis,
-oxidation of fatty acids and amino acid metabo-
lism [10]. A recent study, using an approach by proton
NMR spectroscopy-based metabolomics, identified new
2178 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 17
Fig. (3). Types of mitochondria-mediated cell death that are induced or inhibited by anticancer alkaloids, A) Intrinsic pathway apoptosis, B)
Autophagy. VDAC: voltage-dependent anion channel, ANT: adenine nucleotide translocator, MMP: mitochondrial membrane potential.
mitochondrial metabolic targets for two marine alkaloids
with known anticancer activities (Fig. 2B) [100].
Ascididemin (14) is a pyridoacridine alkaloid that inhib-
its topoisomerase II and induces cancer cell death involving
mitochondrial ROS production and JNK-dependent activa-
tion of caspases [101]. Interestingly, recent evidence indi-
cates that this alkaloid produces accumulation of citrate, an
initial product of TCA cycle and decrease of metabolites
related with bioenergetic pathways as adenosine phosphates,
acetate, lactate and N-acetylaspartate in MCF7 breast cancer
cells [100]. Alterations induced by ascididemin (14) in the
citrate metabolism are due to inhibition of ATP-citrate lyase,
a common enzyme for cholesterol and de novo fatty acid
synthesis, and inhibition of cytosolic and mitochondrial aco-
nitase, enzymes known as Aco1 and Aco2 respectively, that
catalyze dehydrogenation of citrate into isocitrate [100].
Consistently, aconitase inhibition can occur by ROS, an oxi-
dative product that can be increased by ascididemin (14)
(Fig. 2B).
Lamellarin-D (4) exhibits anticancer actions through
topoisomerase I inhibition and direct action on mitochondria,
as discussed previously. However, it can also inhibit the cy-
cle malate-aspartate shuttle (MAS) in MCF7 breast cancer
Urra et al.
cells, producing glutamate and aspartate accumulation [100].
In addition, lamellarin-D (4) do not affect the mitochondrial
ROS levels, indicating that do not have effect on ROS-
dependent aconitase inhibition [100].
7. ALTERATION OF MITOCHONDRIAL MOR-
PHOLOGY AND BIOGENESIS.
Mitochondrial biogenesis is a coordinated process that
requires expression of nuclear and mitochondrial genomes.
Several nucleus-encoded proteins that control mitochondrial
transcription, translation and replication participate of this
process [102-104], and it increases mtDNA copy number
and function [102]. In cancer cells, mitochondrial biogenesis
is altered and favors cell proliferation and invasiveness
[104]. On the other hand, recent evidences indicate that the
modification in microtubule network can induce intrinsic
pathway apoptosis and altered mitochondrial dynamics [105,
106]. Moreover, evidences indicate that classic microtubule-
targeted agents require of mitochondria for their anticancer
effectiveness [5]. In this view, alkaloids that are known to
alter the microtubule networks could represent a group of
anticancer agents with new mechanisms by alterations of
mitochondrial morphology and biogenesis, being a potential
target to explore (Fig. 2C).
Mitochondria: A Promising Target for Anticancer Alkaloids Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 17 2179

Capsaicin (2) has showed inhibitory effects against dif- bule-stabilizing/destabilizing drugs on mitochondria could
ferent tumor cell lines, including colon carcinoma, human explain its anti-proliferative action against various tumor cell
small cell lung, breast, tongue and prostate cancer cells [41, lines.
107-110]. Mitochondria turns out be the target of this com-
In conclusion, we have focused on selected examples of
pound, and there a series of mechanisms have been reported anticancer alkaloids, to highlight the potential of this type of
in relation to the induction of apoptosis, such as ER stress,
compounds in the emerging field of mitochondrial pharma-
mitochondria depolarization, ROS generation, caspasa-3
cology. It is particularly relevant the use of the developed
activation and cytochrome-c release [41-43, 45, 66, 111]. An
strategies to direct the molecules to the mitochondrial targets
interesting mechanism is the one that affects the mitochon-
with the purpose to obtain improved anticancer activities.
drial morphology and that would be related to the interaction
between capsaicin and prohibitin-2 (PBH2) [112, 113], pro- CONFLICT OF INTEREST
tein that together with prohibitin-1 might exert a scaffolding
function for the maintenance of mitochondrial morphology, The authors confirm that this article content has no con-
controlling the mitochondrial cristae morphogenesis and flicts of interest.
processing the components of the mitochondrial fusion ma-
ACKNOWLEDGEMENTS
chinery [114]. Capsaicin (2) binds to PHB2, which is nor-
mally localized at the inner mitochondrial membrane, and This work was supported by FONDECYT grants N
induces its translocation to the nucleus. This union also in- 1110176, 1130772 (JF) and anillo ACT-1107 (RAM), FAU
duces the dissociation of PHB2 from adenine nucleotide thanks to CONICYT for a PhD fellowship. ORR thanks to
translocator 2 (ANT2), inhibiting ANT activity and directly FONDECYT postdoctoral grant No. 3120235.
promotes the release of cytochrome-c and PHB2 from mito-
chondria, with the consistent cellular death by apoptosis in ABBREVIATIONS
human myeloid leukemia cells [114]. AIF = Apoptosis-inducing factor
Colchicine (15) is an alkaloid used for a long time for ANT = Adenine nucleotide translocator
gout treatment; nowadays it is administrated to persons with
familial mediterranean fever [115], liver fibrosis, cirrhosis, Bak = Bcl-2 antagonist/killer
Behet's disease, and recurrent pericarditis [116]. In the last Bax = Bcl-2 associated X protein
years the researches have focused in the potential use of col-
chicine (15) for the treatment of diverse types of cancers, Cyt-c = Cytochrome-c
such as, breast carcinoma, cervical, esophageal, lung and ER = Endoplasmic reticulum
gastric cancer and chronic granulocytic leukemia [117]. Be-
ERK = Extracellular signal-regulated kinase
sides, colchicine analogues have showed anti-proliferative
1/2
action against multidrug-resistance (MDR) negative MDA-
MB-231 breast cancer cell line and MDR-positive MCF7 ETC = Electron transport chain
ADRr cell lines [118, 119]. The principal mechanism in-
FAK = Focal adhesion kinase
volved in the anticancer action of this compound is related to
its ability to binds tubulin molecules, producing inhibition of JNK = c-JunN-terminal kinase
microtubules polymerization and the consistent cytoskeleton MAPK = Mitogen activated protein kinase
disruption [120]. By disrupting the cytoskeleton, colchicines
(15) can inhibit many signaling pathways including intracel- Mcl-1 = Myeloid cell leukemia-1 protein
lular vesicle motility and secretion of endogenous mediators MMP = Mitochondrial membrane potential
such as cytokines and chemokines [121], which accounts for
the majority of anti-inflammatory effects of this alkaloid. MPTP = Mitochondrial permeability transi-
Interestingly, it has been reported that this microtubule- tion pore
destabilizing drug is capable of inhibiting mitochondrial bio- mtDNA = Mitochondrial DNA
genesis through inhibition of mitochondrial mass increase
and mtDNA replication in human osteosarcoma cell line OXPHOS = Oxidative phosphorylation
143B cells and rat liver-derived RL-34 cells. This suggests PARP = Poly-ADP-ribose polymerase
the important role of the interphase microtubules in the regu-
ROS = Reactive oxygen species
lation of this mitochondrial process in mammalian cells.
Similar effects on mitochondrial mass and mtDNA content PERK = PKR-like ER kinase
have been reported to nocodazole (16) and opposite effects CHOP/GADD153 = CCAAT/enhancer-binding protein
showed the microtubule-stabilizing drug paclitaxel (17) in
(C/EBP)-homologous protein/growth
cancer cells, suggesting that changes in the physicochemical
arrest and DNA damage-inducible
state of microtubules can modify cellular environment sur-
gene 153
rounding mitochondria, leading to changes in the rate of mi-
tochondrial biogenesis [122]. Evidence shows that mito- GRP78/Bip = Glucose-regulated protein
chondrial biogenesis could control the tumor growth, for 78/immunoglobulin heavy chain-
example, increased mitochondrial biogenesis has been linked binding protein
to breast, gastric, lung, and esophageal cancers and to in- eIF2 = Eukaryotic translation initiation fac-
creased tumorigenesis [123, 124]. This effect of microtu- tor-2
2180 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 17
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Received: October 10, 2012 Revised: June 18, 2013 Accepted: July 09, 2013
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