Molecular Biology Reports

https://doi.org/10.1007/s11033-019-04743-5

REVIEW

Marine macroalga Caulerpa: role of its metabolites in modulating

cancer signaling
Richa Mehra1,2 · Satej Bhushan1,5 · Felix Bast3 · Sandeep Singh4

Received: 14 November 2018 / Accepted: 5 March 2019

© Springer Nature B.V. 2019

Abstract
Cancer, the leading causes of death worldwide, causes multiple metabolic and physiological alterations, leading to an unregu-
lated proliferation of cells. The existing anticancer therapies are usually nonspecific with side effects and or are extremely
expensive, thus hunt for better therapeutics is still on, specially efforts are made to look for naturally occurring molecules.
Sea harbors several organisms which are unexplored for their biological potentials. Green macroalga genus, Caulerpa, is
one such invaluable repository of bioactive metabolites like alkaloids, terpenoids, flavonoids, steroids and tannins with
reported bioactivities against many diseases including cancer. Anti-cancerous metabolites of Caulerpa like caulerpenyne
(Cyn), caulerpin, caulersin, and racemosin C, possess unique structural moieties and are known to exhibit distinct effects
on cancer cells. Theses metabolites are reported to affect microtubule dynamics, unfolded protein response, mitochondrial
health, cell cycle progression, metabolic and stress pathways by their cross-talk with signalling proteins like AMPK, GRP78,
GADD153, Bid, Bax, AIF, Bcl2, P21, cyclin D, cyclin E, caspase 9, and PTP1B. Targeting of multiple cancer hallmarks by
Caulerpa metabolites, with concomitant modulations of multiple signalling cascades, displays its multifactorial approach
against cancer. Evaluation of anti-cancer properties of this genus is particularly important as Caulerpa species are widely
edible and utilized in several delicacies in the coastal countries. This is the first review article providing a consolidated
information about the role of Caulerpa in cancer with major contributing metabolites and plausible modulations in cancer
signaling and prospects.

Keywords Cancer · Caulerpa · Caulerpenyne · Secondary metabolites · Marine algae · Anti-cancer

Abbreviations
Cyn Caulerpenyne
MXR Multixenobiotic resistance
Richa Mehra and Satej Bhushan have contributed equally to this
ER Enodplasmic reticulum
work.
UPR Unfolded protein response
* Sandeep Singh MAPs Microtubule associated proteins
[email protected]
1
Centre for Biosciences, Central University of Punjab, Mansa
Road, Bathinda, Punjab 151001, India Introduction
2
Present Address: Advanced Technology Platform Centre,
Regional Centre for Biotechnology, NCR Biotech Science Natural products represent a significant share in global phar-
Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, maceutical industry and include anti-cancer drugs like vel-
Faridabad, Haryana (NCR Delhi) 121001, India ban (Vinblastine), oncovin (Vincristine), etoposide and teni-
3
Department of Plant Sciences, Central University of Punjab, poside, while many more remain unexplored [1–3]. Where
Mansa Road, Bathinda, Punjab 151001, India conventional terrestrial resources are being exploited for
4
Laboratory of Molecular Medicine, Department of Human many decades, marine resources largely remain untapped.
Genetics and Molecular Medicine, Central University The earliest report of marine-derived anti-cancerous agents
of Punjab, Mansa Road, Bathinda, Punjab 151001, India dates back to 1950s, wherein spongouridine was isolated
5
Present Address: Computational Biology Laboratory, from a Caribbean sponge, Tectitethya crypta (formerly
National Institute of Plant Genome Research, Cryptotethya crypta) [4]. However, due to technical hurdles,
New Delhi 110067, India

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fewer reports emerged thereafter. In the past two decades, a metabolites include various bioactive compounds for
renewed interest in marine-derived products is seen, espe- defense, communication, reproduction, competition and
cially from algae. Caulerpa, a green macroalgal genus of infection [14]. Initial probing of this genus was initiated
family Caulerpaceae, is one such store-house of bioactive because of the avoidance of Caulerpa species by herbivores
ingredients. This siphonous green alga derived its name and a peppery taste of edible species, which fascinated
from two Greek words: caulos denoting “stem” and erpos researchers for chemical profiling of several species [15].
signifying “I creep”. The genus Caulerpa (J V Lamourox Caulerpa spp. produce several unprecedented secondary
1809) consists of 97 species, and over 100 varieties [5]. metabolites and most of them are linear or monocyclic ter-
These coenocytic algae have creeping rhizome with color- penoids possessing aldehydic and enol-acetate functional
less rhizoids and erect fronds. The fronds occur in variable groups. A terminal bis-enol acetate group is uniquely found
shapes ranging from oval grapes and flat blades to feather- in this genus of marine algae. This functional group is
like structures [6]. These are salty and peppery in taste and represented by an acetylated bis-enol category of 1,4-dial-
are consumed by many around the world, where C. lentillif- dehyde group imparting biological activity to several spe-
era and C. racemosa are most widely edible with common cies [16]. Several solvent-based extraction techniques and
names viz. sea grapes, lelato, green caviar, limu-fuafua, and chromatographic-purification methods are available that can
lai–lai [7]. These species have fetched enormous attention be utilized for the isolation of these metabolites subject to
in the international food market due to their high nutritional minor seasonal variations [17–19]. Our group is working
value [8]. Many Caulerpa species were extensively utilized on the isolation of bioactive metabolites from methanolic
in aquaria, owing to their aesthetically pleasing phenotype extracts of C. racemosa and C. taxifolia. Major metabolites
and highly adaptable nature [9]. On the contrary, Caulerpa documented from genus Caulerpa and their bioactivities are
species are also listed in the ‘world’s worst invasive algal listed in Table 1 and major metabolites (Fig. 1) with anti-
species’ as a noxious weed and consequently termed as killer cancer activity are discussed in brief below.
algae [9]. In fact, the genus gained much attention since
last three decades mainly because of the invasive potential Caulerpin
of species like C. taxifolia and C. cylindracea (previously
recognised as C. racemosa var. cylindracea) [10]. Caulerpin (C24H18N2O4), ‘dimethyl-6,13-dihydrodibenzo
Caulerpa spp. are distributed in the intertidal and [b,i] phenazine-5,12-dicarboxylate methyl ester’, is a red
intratidal tropical and semitropical marine waters. Due to bis-indole alkaloid containing two indole moieties fused to
inter-tidal zone habitation, these species are periodically a central cyclooctatetraene diester, with a molar mass of
exposed to various kinds of stresses like UV, salt, nutrient 398.418 g/mol. Its chemical structure was first elucidated
limitation, light, temperature, shear and desiccation stress by Santos in 1970 and later revised by Maiti and Thompson
etc. which leads to the production of many stress molecules in 1977 [22, 23]. A major setback for exploring biological
[11]. In response to stress, these species produce many sec- effects of caulerpin was its lower yield, however, a recent
ondary metabolites like bisindole alkaloids and diterpenoids, report suggests an increased total yield from 11 to 25%
of which particular interest lies in diterpenoids and sesquit- achieved by Li’s group following modified Chay’s synthesis
erpenoids with an aldehyde or/and enol acetate. Many of scheme [24]. Two caulerpin analogues i.e. CLP I and CLP
these compounds exhibit a diverse range of bioactivities like II, have also been reported from C. racemosa. It was initially
insecticidal, anti-microbial, anti-fouling, feeding deterrent, reported as a major constituent of C. racemosa, but was later
ichthyotoxic, anti-inflammatory, plant growth regulatory, obtained from several species viz. C. sertularioides, C. ser-
cytotoxic, anti-proliferative, and anti-metastatic activities rulata, C. lamourouxii [25], C. racemosa var. macrophysa,
[12, 13]. Since Caulerpa species are edible and have phar- C. racemosa var. laetevirens, C. ashmeadii, C. cupressoides,
macologically active metabolites, these may provide preven- C. paspaloides, C. prolifera, C. sertularioides, C. peltata, C.
tive as well as curative benefits. In this paper anti-cancer racemosa var. clavifera, C. taxifolia, C. serrulata [26, 27],
activity of Caulerpa metabolites and their intervention in and other green and red algae like Halimeda incrassate and
cancer signaling cascades is discussed for the first time in Laurencia majuscula, respectively [28]. Caulerpin exhib-
this context. its in-vitro anti-tumor activity [29], anti-microbial activity
[30, 31], antinociceptive, anti-inflammatory [32], multix-
enobiotic resistance (MXR) pump inhibitor in algae [33],
Bioactive metabolites of Caulerpa plant growth regulatory [34] and PTP1B inhibitory activities
[35]. In comparison to taxol the activity is relatively lower,
The uniqueness of secondary metabolites of Caulerpa can however, it is still considered a potential drug lead due to its
be attributed to distinct marine environment and physi- efficacy on a range of cancer cells and low toxicity in mice
ological adaptations through evolutionary processes. These model [24].

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Table 1 Bioactivity of semi-purified extracts and pure compounds obtained from various species of Caulerpa
S. no. Compound Activity References

1 Caulerpenyne Anti-bacterial; anti-neoplastic; neurotoxic; allelotoxic; anti-mitotic; [44, 45, 56, 58]
phytotoxic; and anti-proliferative activity
2 Caulerpin Anti-tumor; anti-inflammatory; anti-mitotic, anti-microbial; AMPKα [32, 74, 91]
modulatory; and antinociceptive activity
3 Racemosin C PTP1B inhibitory activity [21]
4 Caulersin PTP1B inhibitory activity [21]
5 10,11-epoxycaulerpenyne Cytotoxic [93]
6 Flexilin anti-bacterial, anti-fungal [94]
7 (23E)-3β-hydroxy-stigmasta-5,23-dien-28-one PTP1B inhibitory; and neuroprotective activity [47]
8 40,50 -dehydrodiodictyonema A PTP1B inhibitory activity [47]
9 Trans-phytol PTP1B inhibitory activity, MAPK inhibitory activity [47, 96]
10 Trans-phytyl acetate PTP1B inhibitory activity [47]
11 α-tocopherol quinone PTP1B inhibitory activity [47]
12 α-tocospirone PTP1B inhibitory; and neuroprotective activity [47]
13 (3β,24R)-stigmasta-5,28-diene-3,24- diol PTP1B inhibitory activity [47]
14 (3β,24S)-stigmasta-5,28-diene-3,24-diol PTP1B inhibitory activity [47]
15 (22E)- 3β-hydroxy-cholesta-5,22-dien-24-one PTP1B inhibitory; and neuroprotective activity [47]
16 Taraxerol Anti-viral; phosphatase inhibitory; anti-nephretic; phospholipase-C [95, 97]
(PLC) inhibitory activity, anti-cancer
17 β-sitosterol PLC inhibitory; nephrotoxic, Transcription factor inhibitory; acylg- [95]
lycerol lipase inhibitory; hepatoprotectant; phosphatase inhibitory
activity
18 Palmitic acid Superoxide dismutase (SOD) inhibitory; Catalase inhibitory; NADPH [95]
inhibitory; NADH inhibitor; Succinate-CoA ligase inhibitory; apopto-
sis agonistic activity
19 Sulfoquinovosyldiacylglycerol (SQDG) anti-viral activity, DNA pol inhibitory activity [98, 99]
20 Two unnamed compounds isolated from C. Phospholipase-A2 inhibitory activity [100]
prolifera and C. bikinensis, respectively
21 Sulphated polysaccharide fractions Antinociceptive; anti-inflammatory; anti-coagulant activity; anti- [101–103]
herpetic activity

Caulersin climate and habitat. Cyn production is reported maximum

during fall (September–October) and minimum during
Caulersin is another bis-indole alkaloid, first isolated from spring (March–May). In addition, C. taxifolia facing com-
C. serrulata in 1997 and is the only natural product known petition from Posidonia oceanica has been observed to yield
so far to have a central troponoid bridging bis-indole frame- lower Cyn as compared to non-competitive habitat, which
work [36]. It has three isomers named caulersin-A, B, and C. can possibly be an adaptive strategy to win the competition
Caulersin was, synthetically synthesised and characterized [41]. A queueing theory is also proposed to estimate the
by many researchers [37, 38] and is reported to inhibit activ- increase or decrease in Cyn yield, before reaching a critical
ity of Protein Tyrosine Phosphatase 1B (PTP1B), a known level [42]. Cyn has well documented biological activities
negative regulator of insulin signaling [21]. Considering the viz. anti-bacterial, anti-neoplastic, neurotoxic, allelotoxic,
essential role of PTP1B inhibitors in cancer, it is assumed anti-mitotic, phytotoxic, and anti-proliferative activity
that caulersin is a potential candidate in cancer therapy [39]. [43–45]. It modulates organelles’ Ca2+ storage, DNA syn-
thesis, protein phosphorylation and is cytotoxic to eight dif-
Caulerpenyne ferent tumor cells of human origin. It also blocks the cell
cycle of sea urchin embryos at a metaphase-like stage and
Caulerpenyne (Cyn) (C21H26O6) is a sesquiterpene with inhibits the activation of MAPK (mitogen activated protein
molar mass 374.433 g/mol and was first isolated from C. kinases) proteins [46]. On the contrary, there are reports of
prolifera in 1978 [40]. It is the most studied metabolite of neurological disorders in the patients who consumed C. taxi-
this genus and its maximum yield is reported from C. tax- folia, accidently, and Cyn mediated modulation of the activ-
ifolia. Variations in Cyn yield may appear with different ity of Na+ induced Na+/K+ ATPase in leech neurons [45].

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(a) (b)

(c) (a)

Fig. 1 Chemical Structures of secondary metabolites from genus Caulerpa : a Caulerpin; b Caulersin; c Caulerpenyne; and d Racemosin C [20,
21]

Racemosin C Major signaling pathways affected by Caulerpa are dis-

cussed below.
Three novel bisindole alkaloids, named racemosin A-C,
were isolated from C. racemosa by and its two isomers by Microtubule dynamics perturbation
Liu et al., in 2013 and Yang et al., in 2014 [47, 48]. These
metabolites displayed significant neuroprotective activity Microtubules, a mainstay of the cytoskeleton, are crucial in
against cell damage induced by Aβ25−35 in SH-SY5Y cells various cellular processes like development, maintenance
and PTP1B inhibitory activity. Racemosin C is the first natu- of cell shape, cargo transport, cell signaling, and cell divi-
ral product possessing an 8-hydroxy-2,4,6-cyclooctatrienone sion [52]. These are chiefly synthesised by polymerisation
ring. Its structure is similar to photoactive π-homotropolons of α-tubulin and β-tubulin heterodimers following non-
like 5,7-π-homotropolone. A 4-step biosynthetic pathway equilibrium dynamics i.e. ‘treadmilling’ and ‘dynamic insta-
from caulerpin was proposed [48]. bility’ [53]. Polymerization dynamics of microtubules are
tightly monitored both spatially and temporally by an array
of microtubule-associated proteins (MAPs), comprising
Interplay of Caulerpa with cancer signaling dynein and kinesin motor proteins as well as other regula-
tory proteins like survivin, dynactin, stathmin, TOG, MAP4,
Despite several promising claims of scientists about assured MCAK, FHIT and RAC1 [54]. Differential expression of
cures of cancer, it still persists as enigmatic trouble. One some of these proteins is predominant in certain cancer
major reason for this is the notorious survival strategies cells, while others are involved in the development of drug
of cancer cells by modifying multiple signaling pathways resistance. The conventional microtubule drugs like vinca
[49]. Researchers are now attempting to target cancer cells drugs and taxanes stabilize microtubule assembly, thereby
the same way, so that cancer cells don’t survive multiple inhibiting depolymerisation and disassembling microtu-
damages [50]. Secondary metabolites and crude extracts of bules, leading to paracrystal formation [55]. Although these
Caulerpa have shown promising results in vitro and in vivo drugs act in a non-specific manner but are useful in highly
and are considered potential candidates against cancer [51]. aggressive and metastatic cancers. Unfortunately, tumors

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have developed resistance against these drugs, and prob- microenvironment i.e. hypoxia, acidity, nutrient depriva-
ing for novel tubulin binding agents is in progress. The first tion, reactive oxygen species (ROS), and low vascularization
report of Cyn interfering with microtubule dynamics came [64]. In general, GRP78 has an anti-apoptotic function, but
in 1998, wherein abnormal DNA replication and metaphase- when overexpressed it gets translocated to the cell surface, it
like cell cycle arrest were highlighted [56]. Another report behaves as a receptor for pro-apoptotic ligands like kringle-5
claims neurite inhibition by dry and wet methanolic extracts (K5) and Par-4, thereby triggers apoptosis [65]. Similarly,
of C. racemosa on mouse neuroblastoma cells, NA2B [57]. GADD153 or CHOP (C/EBP homologous protein) is acti-
A similar study revealed that Cyn induces compaction of vated by the PERK pathway and plays multifaceted role in
microtubules in SK-N-SH cells (human neuroblastoma), suppression of bcl-2, stimulation of Bim, and/or activation
thereby inhibiting their proliferation [44]. Unlike conven- of Ero1, which lead to apoptosis [66]. The exact mechanism
tional anti-mitotic drugs like paclitaxel or vincristine, which of action of Cyn is not clear and needs further exploration.
usually disrupt or stabilize the microtubule synthesis, Cyn
results in neurite disappearance and peripheral condensation Inhibition of PTP1B
of microtubules, which has never been reported previously
[58, 59]. It also inhibits in vitro polymerisation of pig brain Protein tyrosine phosphatases (PTPs) constitute an enzyme
tubulin, and MAPs, in time and concentration-dependent family that works in a coordinated manner with protein
manner, revealing a giant cold-irreversible aggregation of tyrosine kinases (PTKs) and monitors diverse signaling
tubulin and clustering of microtubules. Interestingly, half pathways [67]. PTKs mediate the phosphorylation events,
inhibitory concentration of Cyn is higher as compared to mostly initiating the signaling cascade while PTPs are
colchicine, vinblastine, dolastatin or podophyllotoxin, but a responsible for dephosphorylation and thus, causing cessa-
pre-incubation with the tubulin is necessary for the desired tion of the signal. Normal cells maintain a balance between
results [44]. Usually, drugs requiring a pre-incubation period phosphorylation/dephosphorylation events whereas can-
for hindering tubulin assembly as they act by binding on cer cells have a dysregulated balance either due to hyper-
sulfhydryl group of tubulin, but this was not the case with activated protein kinases or loss of PTPs [68]. PTP1B is
Cyn where two potential binding sites have been proposed one such oncogenic phosphatase protein involved in growth
i.e. C-terminal domain of α-tubulin, and N-terminal domain factor signaling and is over-expressed in breast, gastric,
of β-tubulin [60]. prostate and ovarian cancer and hence, receiving renewed
interest as a validated target of multiple signaling interac-
Endoplasmic reticulum stress and unfolded protein tions involved in cancer [69, 70]. Secondary metabolites
response isolated from C. racemosa viz. 4 ,5 -dehydrodiodictyonema
A (1), (23E)-3β-hydroxystigmasta-5,23-dien-28-one (2),
Endoplasmic reticulum (ER) stress is another important α-tocopherolquinone (3), α-tocospirone (4), and (3β,24R)-
determinant of cell fate and can either lead to its progres- stigmasta-5,28-diene-3,24-diol (5) exhibit PTP1B inhibi-
sion towards survival or death. ER stress may be induced by tory activity with IC50 values of 2.30, 3.85, 11.01, 3.80
an imbalance between folded and unfolded proteins, hyper- and 10.34 µM, respectively. Of these the three most potent
accumulation of proteins, or altered redox potential [61]. compounds i.e. 1, 2 and 3 also displayed high selectivity
In response, unfolded protein response (UPR) is generated over other homologous PTPs like TCPTP, LAR, CDC25B,
which can be accomplished by an independent or combined SHPs. More structural discernments revealed that the addi-
action of three trans-membrane signaling molecules viz. tion of hematinic acid ester group at C(1) hydroxyl group
IRE1 (inositol-requiring protein-1), PERK (protein kinase in linear diterpenoids drastically increases their PTP1B
RNA (PNR)-like ER kinase), and ATF6 (activating tran- inhibitory activity [66]. Another study reported PTP1B
scription factor-6). UPR may signal cells to shut down the inhibitory activity of racemosin-C and caulersin with IC50
translation process, up-regulate ER chaperones, induce of 5.86 ± 0.57 and 7.14 ± 1.00 µM, respectively [21, 43].
ER-associated degradation, induce rescue response or to Interestingly, PTP1B exerts both tumor-promoting and
trigger apoptosis [62]. In murine leukaemia WEHI-3 cells, tumor-suppressing effect depending on the surrounding cel-
Cyn treatment has been reported to upregulate expression lular signals [71], for example, in breast cancer, increased
of GRP78 (glucose-regulated protein-78) and GADD153 PTP1B and ErbB2 expression is associated with tumori-
(growth arrest and DNA damage), in a calcium-dependent genesis. ErbB2 activation activates the PI3K-Akt signaling
manner which can further lead to apoptosis (Fig. 2) [63]. pathway leading to cancer progression and down-regulation
GRP78, also known as BiP (binding immunoglobulin pro- of anti-apoptotic signals [39]. Various bioactive constituents
tein), is a heat shock protein produced in response to ER from Caulerpa act up on PTP1B and are believed to shut
stress. Cancer cells consistently produce GRP78 as they down these events, thereby, inhibiting cell tumor progres-
are in a constant state of stress resulting from their normal sion (Fig. 2).

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Fig. 2 Proposed mechanism of action of Caulerpa in cancer sign- ways are depicted, that subsequently result in metabolic reprogram-
aling. Complex network of modulations induced by Caulerpa on ming, apoptosis and cell-cycle arrest in cancer cells. Translocation is
AMPK (light brown), ER Stress (blue), mitochondrial stress (dark depicted by dashed arrows, and inhibition by red arrows. (Color fig-
brown), PTP1B inhibition (green) and cell cycle arrest (purple) path- ure online)

AMPK pathway modulations and metabolic response to AMPK activation to counterbalance the loss
reprogramming of ATP, however, after 60 min the level keeps decreasing
until death. Different isoforms of AMPK exhibit differential
Dysregulated cellular metabolism or Warburg effect, is one responses where AMPKα1 mediates the action of cauler-
of the cancer hallmarks, which states that cancer cells rely on pin during cell death while AMPKα2 failed to display any
both mitochondrial oxidative phosphorylation (OXPHOS) effect [76]. AMPK inactivates mTOR signaling pathway for
and glycolysis as a survival method [72]. Caulerpin is known cellular stress, thereby, resulting in cell death (Fig. 2). Sev-
to induce mitochondrial dysfunctions, thereby, disrupting eral reports suggest that AMPK attenuates mTOR activity
the crucial energy balance of cells [73]. It incurs inhibitory by directly phosphorylating either tumor suppressor TSC2
effects on complex I of electron transport chain (ETC) and (tuberin) complex in mTORC1-raptor subunit which blocks
decreases oxygen consumption rate in SW480 and LOVO the phosphorylation of substrates of mTORC1 kinase viz.
cells (colorectal cancer) with a concomitant elevation of eIF4E-binding protein (4E-BPs) and p70S6K (cell growth
ROS and decrease in ATP production [74]. LKB1, possibly, processes) [77].
senses the elevated AMP:ATP ratio and activates the meta-
bolic regulator AMPK, in a CAMKK2 dependent manner Cell cycle arrest
[75]. The expression levels of GLUT1, HKII and PFKB3
were reduced after 48 h of caulerpin treatment. The level Cell cycle progression is a well-ordered and tightly-mon-
of glucose, during initial 30 min of treatment increases, in itored process involving several checkpoints ensuring cell

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size, DNA quality, and integrity. These checkpoints are c interacts with the cytosolic monomer of apoptosis protease
mediated by cyclin-dependent kinases (CDKs) and cyclin- activating factor-1 (APAF-1) which undergoes an ATP medi-
dependent kinase inhibitors (CKIs), which act as positive ated conformational change leading to its oligomerization
and negative regulators, respectively, in cell cycle progres- to an ‘apoptosome’. The apoptosome binds to caspase-9,
sion [78]. Cancer is frequently associated with abnormal cell that further activates executioner caspases i.e. caspase-3 and
cycle regulation and may originate from genomic instability caspase-7, leading to apoptosis. Alternatively, AIF is one
(GIN), chromosomal instability (CIN), or other changes, that of the lethal factor released from mitochondria, and causes
lead to an abnormal expression of positive and/or negative cell apoptosis in a caspase-independent manner [85]; the
cell cycle regulators [79]. Cyn interferes with DNA replica- mechanism, however, is poorly understood. CME downregu-
tion and causes cell cycle arrest at metaphase-like-stage in lates bcl-2, and upregulates Bid, Bax and AIF, suggesting
sea urchin embryos, as discussed previously [53]. Likewise, its possible role in both caspase-independent and caspase-
CME downregulates the expression of cyclin D, cyclin E, dependent apoptotic mitochondrial pathway (Fig.  2). In
CDK6, CDK2 and upregulates p21, p27, p53 in WEHI cells, addition, C. sertularoides methanolic extract exhibits strong
inducing cell cycle arrest. It suggests CME-induced cell anti-telomeric activity in acute lymphoblastic leukaemia
damage activates p53 protein and subsequently p21 and p27, MOLT-4 cells, and thus, causes apoptosis [86]. It is evident
thus, inhibiting cell cycle check-point-proteins i.e. CDK6/ that in cancer cells telomerase activity is responsible for the
cyclin D and CDK2/cyclin E, respectively, blocking the cell stability and protection of chromosomes from degradation,
cycle at G0/G1 phase (Fig. 2) [63]. Another study reports causing uninterrupted proliferation and its inhibition may
that methanolic extract of C. racemosa collected from Sri contribute to the timely death of cancer cells [87].
Lankan coast, induces G0/G1 phase arrest in promyelocytic
leukaemia HL60 cells, in concentration-dependent manner Inhibition of hypoxia inducible factor 1 (HIF-1)
[80]. CDKs are necessary for driving the cells to next phase
and Caulerpa causes cell cycle arrest by inhibiting specific Transcription factor, HIF-1, is an imperative target for
CDKs. anti-tumour drugs as it renders them to survive under
reduced oxygen conditions by regulating oxygen homeo-
Apoptosis stasis and promoting angiogenesis [88]. HIF-1 is ubiq-
uitously present and consists of HIF-1α (O 2-regulated
Dysregulated apoptosis disrupts the subtle balance between expression) and HIF-1β (constitutively expressed). At
cell proliferation and cell death leading to cancer [81]. This normoxic state, HIF-1 remains inactive, because of pro-
deregulation can be in terms of mutations in pro-apoptotic lyl hydroxylases (PHDs) or/and asparaginyl hydroxylases
proteins, up-regulation of expression of anti-apoptotic pro- induced degradation of HIF-1α. Hypoxia inhibits these
teins, down-regulation of apoptotic proteins or inability hydroxylases and thus, activates HIF-1 and its downstream
to respond to cellular stresses [82]. C. microphysa pepsin signaling pathways [89]. In addition, iron chelators, inac-
digested extract (CME) reportedly induces the apoptotic tivation of tumour suppressor genes and/or activation
pathway as indicated in myelomonocytic leukemia (WEHI- of oncogenes can also trigger activation of HIF-1 [90].
3) cells. It disrupts the cellular homeostasis by inducing Caulerpin treatment results in inhibition of hypoxia, by
Ca2+ release and decreasing mitochondrial membrane poten- inhibiting HIF-1α activation and mitochondrial respiration
tial (MMP), thus, initiating apoptotic events. Downregula- at complex I in ETC, in T47D cells [91]. ELISA based
tion of protein levels of bcl-2 and upregulation of Bid, Bax, detection of proteins also revealed that caulerpin sup-
AIF (apoptosis inducing factor), caspase-9 and caspase-3, presses the induction of vascular endothelial growth factor
are reported in WEHI cells [63]. In breast cancer MCF-7 (VEGF) and glucose transporter-1 (GLUT-1) in hypoxic
cells, apoptosis was indicated by chromatin condensation, conditions but not in normoxic conditions. The anti-angi-
chromatin fragmentation and poly ADP-ribose polymerase ogenic activity was confirmed by tube formation assay on
(PARP) degradation by β-1,3 xylooligosaccharides, obtained human-umbilical vein endothelial cells (HUVEC) suggest-
from C. lentillifera [80, 83]. Likewise, PARP-1, caspase-9, ing that caulerpin suppresses angiogenesis in tumour cells
and caspase-3 activation are also reported by caulerpin, by reducing VEGF levels in hypoxia. It is evident that
in LOVO cells [74]. Mitochondrial pathway of apoptosis HIFs help cancer cells to survive under stressed conditions
largely depends on MMP, which is controlled by a balance and activate genes utilised for Warburg effect. Notably,
of anti-apoptotic and pro-apoptotic signal molecules like Warburg described that cancer cells/tissues generally have
Bcl-2, bid, Bax, AIF and others [84]. The membrane per- an increased uptake of glucose (via GLUT-1) and con-
meabilization leads to the release of several inter-membranal vert this glucose to lactate [72]. Thus, hypoxia inhibiting
proteins including cyto-c, Smac/Diablo, AIF, Endo G etc., agents (HIAs) that can reduce ROS and/or reactivate PHDs
of which, our focus will be limited to cyto-c and AIF. Cyto under hypoxic state can be of great therapeutic value [92].

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Anti-oxidants like vitamin C and N-acetylcysteine (NAC) Compliance with ethical standards
are reported to diminish ROS, genomic instability, and
DNA damage, thereby inhibiting tumorigenesis. Cyn Conflict of interest Richa Mehra declares that she has no conflict of
inhibits HIF1, GLUT-1, and VEGF, which suggests its interest. Satej Bhushan declares that he has no conflict of interest. Fe-
lix Bast declares that he has no conflict of interest. Sandeep Singh
intricate role in combating cancer, by disrupting Warburg declares that he has no conflict of interest.
effect, angiogenesis and hypoxia.
Ethical approval This article doesn’t contain any studies with human
participants or animal models performed by any of the authors.

Informed consent This study didn’t require any formal consent.

Conclusion and future prospects

This review presents a detailed insight into potential of

various Caulerpa species on cancer signaling and thus References
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