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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


molecules. Furthermore, it offers the possibility to recover
Alkaloids are secondary metabolites isolated from sev-
compounds abandoned in previous pharmacologic studies. In
eral source such as plants, bacteria, fungi, marine sponges
this review, we present a set of selected alkaloids and deriva-
and slugs, arthropods, amphibians, birds and mammals, and
they show different biological activities [1, 2]. Alkaloids, tives that have mitochondria as a central component of their
such as other natural products, exhibit a wide variety of anticancer action and, in our opinion, could benefit of selec-
structural arrangements with many stereogenic centers, het- tive targeting studies (Fig. 1).
eroatoms, several H-bond donors and acceptors and a low In recent years we have witnessed a change in the para-
ratio between the aromatic rings and total heavy atoms [3]. digm of mitochondrial functioning inside the cell. It is now
As a consequence, alkaloids exhibit a wide spectrum of mo- clear that mitochondria are central to cell death, cell differen-
lecular targets. However, when a molecule interacts with tiation, innate immune system, hypoxia sensing, metabolism
several targets, only a fraction of the total concentration is of calcium and amino acids, iron sulfur center and heme bio-
available for action on each one [2]. Despite that, alkaloids synthesis [8-10]. Disruption to these processes contributes to
have shown to be an important component of the current several pathologies, such as cancer, making mitochondria an
cancer chemotherapy [4]; these compounds affect the pro- important therapeutic target [11-15]. In cancer cells, mito-
gression of cell cycle by alteration of microtubule polymeri- chondria have an essential role in the neoplasic phenotype,
zation or inhibition of topoisomerases [2]. However, recent especially resistance to apoptosis, limitless proliferative po-
evidences show that an increasing number of alkaloids, in- tential and metabolic reprogramming [16, 17]. It has been
cluding the classical anticancer alkaloids, can present several suggested that the most efficient mitochondrially-targeted
cellular targets that affect selectively to cancer cells and in- therapies would affect mitochondrial processes that partici-
volve mitochondria [5, 6]. On the other hand, the severe tox- pate in the establishment of several of this features [16].
icity and development of chemoresistance have impulsed to Consistently, alteration in mitochondrial dynamics (i.e. fis-
search strategies or new targets to enhance tumor selectively sion and fusion) and damage to mitochondrial macromole-
[4, 7]. In this sense, selective targeting is currently a very cules, can induce cell death by apoptosis or autophagy [18].
active field of research, whose findings allows fully Besides, mitochondria control the programmed cell death via
several mechanisms that can be activated by disruption of
*Address correspondence to these authors at the Department of Organic and mitochondrial bioenergetics, alteration of cellular redox bal-
Physical Chemistry, Faculty of Chemical and Pharmaceutical Sciences,
University of Chile, Santiago de Chile; Tel: 56-2-29782874; Fax: 56-2- ance and release or activation of pro-apoptotic factors [11-
29782868; Emails: raraya@ciq.uchile.cl and felix.urra@qf.uchile.cl 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 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 17 2173

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

3. INCREASE OF ROS LEVELS AND MITOCHON- tant tumors, such as pancreatic cancer and glioblastoma cells
DRIAL DEPOLARIZATION BY CROSS-TALK BE- [64].
TWEEN ENDOPLASMIC RETICULUM (ER) AND
In human glioblastoma T98G cells, berberine (3) in-
MITOCHONDRIA duces ER stress mediated by mitochondrial dysfunction, in-
A particular mechanism of increase of the intracellular volving mitochondrial membrane potential dissipation and
ROS levels involves alterations in endoplasmic reticulum elevation of ROS levels. These events produce activation of
(ER)-mitochondria interactions. These two organelles play PERK with subsequent phosphorylation of eIF2,
an important role in the control of ROS and calcium levels GRP78/Bip and CHOP/GADD153, which is a transcriptional
and are in tight contact, sharing sensor proteins involved in factor implicated in activation of caspase-3 and apoptosis
induction of cell death [56]. Alterations in this inter- progression [65].
organelles cross-talk participate in the progression of several For capsaicin (2), a mechanism that involves ER and mi-
pathologies [57-60]. In cancer cells, ER participates in the tochondria is also reported. In no-malignant human breast
regulation of environmental challenges, especially hypoxia, MCF10A cells, it induces ER stress with activation of sensor
angiogenesis and chemoresistance, that affect to cellular sur- protein IRE1 signaling, increase of intracellular Ca2+, calpain
vival and growth [61]. Different repertories of response are activation; producing mitochondrial membrane potential
utilized when ER stress is present, which is sensed by three dissipation, release of cyt-c and activation of caspases [66].
ER proteins: PERK, IRE1 and ATF6. In acute ER stress, Capsaicin (2) can also induce a similar mechanism in hu-
sensor proteins promote protective effect conferring resis- man tongue cancer SCC-4 cells, inducing primary increase
tance to radiation and chemotherapy [62]. In contrast under a ROS and Ca2+ levels, mitochondrial membrane potential
prolonged ER stress, cell death is induced [63]. dissipation and nuclear translocation of AIF, ATF-4 and
Therefore, compounds that can produce stress in ER, CHOP/GADD153, [67].
such as certain alkaloids, can trigger pro-oxidative events Alkaloid derivatives that incorporate the 2-phenyl 6-
eventually ending in the cell death (Fig. 2D). The induction pyrrolidinyl-4-quinazolinone moiety exhibit anticancer ac-
of an organelle-related stress response has been described as tivities [68, 69]. MJ-29 (5) is a novel derivative that induces
a novel therapeutic strategy for the treatment of highly resis- 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 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 17 2175

presents antileukemic activity by induction of ER-stress and Autophagy primarily functions as a cell survival adaptive
intrinsic apoptosis [69]. It stimulates the protein levels of mechanism during induced cellular stress conditions. How-
calpain-1, CHOP, phosphorylated eIF2 pathways, and ever, when this condition is persistent it can promote exten-
ROS-mediated mitochondrial dysfunction, involving MPTP sive autophagy, triggering cell death [88]. Moreover, mito-
opening, mitochondrial potential dissipation, cardiolipin oxi- chondria have been recognized to play an important role in
dation and up-regulation of intrinsic pro-apoptotic signaling the establishment of oxidative stress, favoring autophagic
in WEHI-3 leukemic cells [69]. process [9]. A cancer therapy strategy is to induce oxidative
stress and autophagic cell death [89]. This view can be use-
4. APOPTOSIS MEDIATED BY MITOCHONDRIA ful if it is considered that frequently cancers cells are resis-
(INTRINSIC PATHWAY) tant to apoptosis or develop drug resistance, offering
autophagic cell death an effective alternative therapy [87,
Control of apoptosis by mitochondria is essential in can- 88].
cer cells [23]. Molecular adaptations to mitochondrial level,
involving mutations, allow them the development of resis- Some alkaloids with anticancer activities have been re-
tance to induction of cell death [16, 71]. Alterations in the ported as modulators of autophagy. Interestingly, they can be
mitochondrial functions via increase of ROS levels, affecting classified as autophagic inhibitors or inductors (Fig. 3B).
mitochondrial membrane potential, is a crucial event that can Tetrandrine (10) is a bisbenzylisoquinoline alkaloid that at
precede to intrinsic pathway apoptosis. Several alkaloids 5 M concentration induces autophagy in human hepatocel-
have been reported as highly selective anticancer agents and lular carcinoma cells [90]. The mechanism involves mito-
their mechanism of action involve disruption of this control chondrial dysfunction. Initially, tetrandrine (10) produces
on the cancer cell life [6]. Table 1 summarizes the alkaloids mitochondrial depolarization that precedes the increase of
that induce intrinsic pathway apoptosis. intracellular ROS levels, which is blocked by cyclosporine
A, an inhibitor of the MPTP opening. Moreover, it induces
Alkaloids isolated from different natural sources have the expression of Atg7, LC3-II, the formation of acidic auto-
been described as inductors of mitochondria-dependent phagolysosome vacuoles, and ROS-induced activation of
apoptosis, where mitochondrial potential dissipation, accom- ERK MAP kinase signaling, which all are involved in
panied sometimes with increase ROS levels, produce release tetrandrine-induced autophagy. Similar results are produced
of pro-apoptotic factors as cytochrome-c and AIF with the in vivo [90]. Interestingly, at high concentrations (>20 M),
consequent caspases activation and degradation of PARP this alkaloid induces apoptosis in the same carcinoma cells
(Fig. 3A). Moreover, up-regulation of pro-apoptotic proteins [91]. A pancratistatin alkaloid-derivative compound JCTH-4
(e.g. Bax, Bak) and down-regulation of anti-apoptotic pro- (11) also can induce apoptosis and autophagy in cancer cells
teins (e.g. Bcl-2, Bcl-xl) are events induced by alkaloids. [92, 93]. Decrease of mitochondrial membrane potential,
Interestingly, harmine (6) only produces down-regulation of ROS production, and appearance of autophagic marker LC3-
anti-apoptotic proteins Bcl-2, Mcl-1 and Bcl-xl, without II have been described in the JCTH-4-induced autophagy in
changes in Bax[72]. Pancratistatin (7) induces ROS- p53 positive and p53 negative human colorectal cancer cells
mediated apoptosis and in combination with the anti- [92]. In addition, the parent alkaloid pancratistatin (7) has
estrogen tamoxifen can have a synergistic effect, inducing also been described as inductor of apoptosis and autophagy
apoptosis in both estrogen receptor positive (MCF-7) and in other cancer cells [94].
estrogen receptor negative (HS578T) cell lines [73-75].
Recently, the anticancer mechanism of noscapine deriva-
On the other hand, increase in ROS levels can activate tive Red-Br-nos (12), (R)-9-bromo-5-((S)-4,5-dimethoxy-
the stress-sensor JNK as is the mechanism reported for vi- 1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,
norelbine (8) and ellipticine (9) [76, 77]. This latter is a 8-tetrahydro-[1,3]-dioxolo[4,5-g]isoquinoline, has been de-
pyridocarbazole alkaloid with known anticancer activity me- scribed in human prostate cancer PC-3 cells [95]. Red-Br-
diated by induction of DNA damage, involving topoi- nos-induced autophagy is protective to the induction of
somerase II inhibition and DNA adduct formation [78-82]. apoptosis and is an early detectable event that involves dou-
Several strategies of delivery based in self-assembling pep- ble membrane vacuoles, acidic vesicular organelles, increase
tide have been designed for ellipticine (9). These peptides of expression of LC3-II and beclin-1. Interestingly, mito-
are organized in nanofibers and stabilize this hydrophobic chondria control apoptosis and autophagy and these two
anticancer agent [83-85]. This approach for a selective deliv- pathways can cross-talk [95]. Red-Br-nos (12) induces al-
ery can favor an increase in activity and reduce toxic events. terations in mitochondrial architecture, particularly in the
intracristal compartment, accompanied of mitochondrial po-
5. AUTOPHAGY MEDIATED BY MITOCHONDRIA tential dissipation and ROS production, which is essential for
Cancer cells exhibit increased ROS levels compared to autophagy and caspase-independent ROS-dependent apopto-
normal cells because of increased metabolism and mito- sis [95]. At contrary, chloroquine (13) is an agent that inhib-
chondrial dysfunction [34]. Additionally, events such as de- its the autophagic process through prevention of lysosome-
creased OXPHOS, low levels of oxygen and acid microenvi- autophagosome fusion and the degradation of autophagoso-
ronment, contribute to establish cell signaling for survival mal content [96]. In solid tumor, hypoxia conditions allow
and proliferation [86]. On the other hand, certain evidence the development of resistance to treatment, especially
suggests that ROS regulates autophagy by control of auto- acute/cycling hypoxia accompanied of ROS production. In
phagy genes beclin-1 and Atg4, p62 mediated by NF-E2- this condition, cancer cells can acquire adaptations to mini-
related factor 2 (NRF2) and inhibition of mTOR signaling mize ROS production, involving reduction of mitochondrial
[87]. 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 PATHWAYS
adaptative process [97, 98]. In human cancer cells MCF-7, Mitochondria have an essential participation in cell life,
HT29 and U373, inhibition of autophagy by chloroquine especially its function as power plant based in the ATP
(13), prevents the tolerance to acute hypoxia that allows spe- synthesis. Other classic metabolic pathways that are con-
cific degradation of mitochondria to decrease ROS levels in trolled by this organelle include Krebs cycle or also known
reoxygenation [99]. It has been suggested that this action of as tricarboxylic acid cycle (TCA), heme synthesis, steroi-
chloroquine (13) decreases the hypoxic portion within tu- dogenesis, -oxidation of fatty acids and amino acid metabo-
mors, being an opportunity to enhance antitumor therapy lism [10]. A recent study, using an approach by proton
[99]. NMR spectroscopy-based metabolomics, identified new
2178 Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 17 Urra et al.

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 cells, producing glutamate and aspartate accumulation [100].
with known anticancer activities (Fig. 2B) [100]. In addition, lamellarin-D (4) do not affect the mitochondrial
ROS levels, indicating that do not have effect on ROS-
Ascididemin (14) is a pyridoacridine alkaloid that inhib-
dependent aconitase inhibition [100].
its topoisomerase II and induces cancer cell death involving
mitochondrial ROS production and JNK-dependent activa- 7. ALTERATION OF MITOCHONDRIAL MOR-
tion of caspases [101]. Interestingly, recent evidence indi- PHOLOGY AND BIOGENESIS.
cates that this alkaloid produces accumulation of citrate, an
initial product of TCA cycle and decrease of metabolites Mitochondrial biogenesis is a coordinated process that
related with bioenergetic pathways as adenosine phosphates, requires expression of nuclear and mitochondrial genomes.
acetate, lactate and N-acetylaspartate in MCF7 breast cancer Several nucleus-encoded proteins that control mitochondrial
cells [100]. Alterations induced by ascididemin (14) in the transcription, translation and replication participate of this
citrate metabolism are due to inhibition of ATP-citrate lyase, process [102-104], and it increases mtDNA copy number
a common enzyme for cholesterol and de novo fatty acid and function [102]. In cancer cells, mitochondrial biogenesis
synthesis, and inhibition of cytosolic and mitochondrial aco- is altered and favors cell proliferation and invasiveness
nitase, enzymes known as Aco1 and Aco2 respectively, that [104]. On the other hand, recent evidences indicate that the
catalyze dehydrogenation of citrate into isocitrate [100]. modification in microtubule network can induce intrinsic
Consistently, aconitase inhibition can occur by ROS, an oxi- pathway apoptosis and altered mitochondrial dynamics [105,
106]. Moreover, evidences indicate that classic microtubule-
dative product that can be increased by ascididemin (14)
targeted agents require of mitochondria for their anticancer
(Fig. 2B).
effectiveness [5]. In this view, alkaloids that are known to
Lamellarin-D (4) exhibits anticancer actions through alter the microtubule networks could represent a group of
topoisomerase I inhibition and direct action on mitochondria, anticancer agents with new mechanisms by alterations of
as discussed previously. However, it can also inhibit the cy- mitochondrial morphology and biogenesis, being a potential
cle malate-aspartate shuttle (MAS) in MCF7 breast cancer 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 Urra et al.

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Received: October 10, 2012 Revised: June 18, 2013 Accepted: July 09, 2013