Biomedicine & Pharmacotherapy 149 (2022) 112827

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Advances in indole-containing alkaloids as potential anticancer agents by

regulating autophagy
Meng-Lan Luo a, Wei Huang a, Hong-Ping Zhu a, b, Cheng Peng a, Qian Zhao a, *, Bo Han a, *
a
State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu
University of Traditional Chinese Medicine, Chengdu, China
b
Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China

A R T I C L E I N F O A B S T R A C T

Keywords: Cancer is a leading cause of death worldwide, and cancer development is often associated with disturbances in
Indole the autophagy process. Autophagy is a catabolic process involved in many physiological processes, crucial for cell
Autophagy-related growth and survival. It is an intracellular lysosomal/vacuolar degradation system. In this system, inner cyto­
Cancer therapy
plasmic cell membrane is degraded by lysosomal hydrolases, and the products are released back into the cyto­
Signaling pathway
plasm. Indole alkaloids are natural products extensively found in nature and have been proven to possess various
Cell survival
Cell death pharmacological activities. In recent years, pharmacological studies have demonstrated another potential of
indole alkaloids, autophagy regulation. The regulation may contribute to the efficacy of indole alkaloids in
preventing and treating cancer. This review summarizes the current understanding of indole alkaloids’ effect on
tumor cells and autophagy. Then, we focus on mechanisms by which indole alkaloids can target the autophagy
process associated with cancer, including the PI3K/Akt/mTOR signaling pathway, MAPK signaling pathway,
ROS signaling pathway, Beclin-1, and so on. Literature has been surveyed primarily from 2009 to Nov. 2021, and
some semisynthetic or fully synthetic indole derivatives are also discussed.

1. Introduction compounds in traditional medicine remains a popular and fruitful

Cancer is a leading cause of death and a significant barrier to
increasing life expectancy in every country in the world. Statistical data
published by the World Health Organization International Agency for
Cancer Research have recorded 19.3 million new cancer cases world­
wide and nearly 10 million cancer deaths [1]. Despite the immense
treatments and techniques available for cancer treatment and preven­
tion, many drugs currently have high side effects and multidrug resis­
tance in clinical practice [2]. In this context, developing safer and more
reliable alternatives is essential. Identifying plant-based lead
approach [3–6]. Numerous natural products have been isolated from
plants and proved to have high cytotoxicity and antitumor activity [7].
Indole alkaloids, one of the most abundant and complex alkaloids,
ubiquitously exist in natural products. Various indole-containing natural
compounds have already been proven to exhibit a broad of pharmaco­
logical activities, such as antibacterial, antifungal, antimalarial, anti-
inflammatory, anti-HIV, anti-plasmodial, and especially antitumor ac­
tivities [8–19]. The prominent role of indole alkaloids’ biological ac­
tivity over the past decades may reflect their increasing utility for
synthesizing pharmaceuticals and bioactive compounds. In addition,

Abbreviations: PI3K, Phosphatidylinositol 3-kinase; Akt, Protein kinase B; mTOR, Mammalian target of rapamycin; MAPK, Mitogen-activated protein kinase 1;
ROS, Reactive oxygen species; NSCLC, Non-small cell lung cancer; CMA, Chaperone-mediated autophagy; ATP, Adenosine triphosphate; ULK1, Unc-51-like kinase 1;
FIP200, Family kinase-interacting protein 200; Atg, Autophagy-related gene; mTORC1, Rapamycin complex 1; PE, Phosphatidyl Ethanolamine, SNAP, Synaptosomal-
associated protein; VAMP, Vesicle-associated membrane protein; AMPK, 5’-AMP-activated protein kinase; Bcl-2, B-cell lymphoma 2; MNZQ, Muniziqi granule; VEGF,
Vascular endothelial growth factor; I3C, Indole-3-carbinol; ERK, Extracellular signal-related kinases; LAMP, Lysosomal-associated membrane protein 1; JNK, c-Jun N-
terminal kinase; 11-MT, 11-methoxytabersonine; CAA, Calothrixin A; OSCC, Oral squamous cell carcinoma; ER, Endoplasmic reticulum; VPS, Vacuolar protein
sorting; BH3, Bcl-2-homology-3 domain; Hsp, Heat shock protein; NADPH, Nicotinamide adenine dinucleotide phosphate; FoxO3, Forkhead box protein O3; R-scy,
Reduced scytonemin; UBA, Ubiquitin-associated; LIR, LC3-interacting region; PB1, N-terminal phox-BEM1; PPARA, Peroxisome proliferator-activated receptor alpha;
CPT, Carnitine palmityl transferase; NAFLD, Non-alcoholic fatty liver disease.
* Corresponding authors.
E-mail addresses: zhaoqian@cdutcm.edu.cn (Q. Zhao), hanbo@cdutcm.edu.cn (B. Han).

https://doi.org/10.1016/j.biopha.2022.112827
Received 27 January 2022; Received in revised form 3 March 2022; Accepted 14 March 2022
Available online 19 March 2022
0753-3322/© 2022 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
M.-L. Luo et al. Biomedicine & Pharmacotherapy 149 (2022) 112827

many indole alkaloids and their derivatives are commonly applied in
clinical practice to treat various types of cancer, such as acute leukemia,
malignant lymphoma, small-cell lung cancer, and breast cancer [20–27]
(Fig. 1). Thus, the indole framework is a fascinating and privileged
scaffold for the development of novel drugs. Moreover, in the contin­
uous research of our group on bioactive indole derivatives, we have also
explored a series of indole compounds with high biological activity
[28–34]. Therefore, these chemical entities can be used as lead com­
pounds in new-drug development. Actually, increasing evidence in­
dicates that bioactive indole alkaloids exert their antitumor activity
through autophagy regulation.
Autophagy, a catabolic process, plays an essential role in regulating
cellular homeostasis in physiological and pathophysiological conditions
[35,36]. To date, three primary types of autophagy have been described:
macroautophagy, microautophagy, and chaperone-mediated autophagy
(CMA) [37–39]. The term “autophagy” is usually referred to macro­
autophagy, which is the most extensively studied one. In eukaryotic
cells, autophagy is caused by a series of factors, such as reduced insulin
levels, amino acid starvation, decreased ATP levels, and hypoxia. The
process of autophagy consists of five steps: initiation, nucleation,
maturation, fusion, and degradation. The initiation of autophagy is
controlled by Unc-51-like kinase 1 (ULK1) complex, which is comprised
of the serine/threonine-protein kinase ULK1, family kinase-interacting
protein 200 (FIP200), autophagy-related gene 13 (Atg 13) [40]. Upon
autophagy stimuli, such as amino acid starvation and decreased insulin
levels, rapamycin complex 1 (mTORC1) is inhibited, which can lead to
activation of the ULK1 complex [41]. In the nucleation step of auto­
phagy, the ULK1 complex phosphorylates and activates the
Beclin-1-class III phosphatidylinositol 3 Kinase (PI3K) complex. This
complex is comprised of Beclin-1, vacuolar protein sorting (VPS34, a

Fig. 1. The chemical structures of anti-cancer indole alkaloids and indole derivatives. (1). Vinblastine is an anti-cancer drug extracted from Catharanthus roseus. This
drug is given to treat Hodgkin lymphoma, non-small cell lung cancer (NSCLC), head and neck cancer. (2). Vincristine is an indole alkaloid isolated from leaves of the
Madagascar periwinkle plant, Catharanthus roseus. Vincristine is used in the treatment of low-grade gliomas and anaplastic oligodendrogliomas. (3). Vinorelbine is a
semi-synthetic derivative of vinblastine and is used in NSCLC, breast, and ovarian cancers. (4). Rucaparib camsylate is a poly ADP-ribose polymerase inhibitor and is
the world’s first third-line treatment for ovarian cancer. (5). Alectinib hydrochloride is an anaplastic lymphoma kinase inhibitor and is used in the treatment of
recurrent non-small cell lung cancer. (6) Osimertinib is the first and only NSCLC drug approved for the EGFR T790M mutation. (7). Anlotinib Dihydrochloride is a
small molecule multi-target tyrosine kinase inhibitor used in the treatment of alveolar soft tissue sarcoma. (8). Panobinostat is the first histone deacetylase inhibitor
for the treatment of multiple myeloma.

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M.-L. Luo et al.
class III phosphatidylinositol 3-kinase), and other proteins [42]. Two
ubiquitin-like binding reaction systems are involved in the formation of
autophagosomes: 1) LC3-Phosphatidyl Ethanolamine (PE) binding re­
action system, 2) Atg12-Atg5 binding reaction system [43]. In the fusion
process, the formation of the conjugates promotes the fusion of auto­
phagosomes and lysosomes. The conjugates include
synaptosomal-associated protein (SNAP)29, lysosomal
vesicle-associated membrane protein (VAMP)7/VAMP8, and SNARE
[44] (Fig. 2). LC3-II protein is often used as an autophagosome marker.
Several signaling pathways have been implicated in autophagy regula­
tion, including pathways mediated by PI3K/Akt/mammalian target of
rapamycin (mTOR), 5’-AMP-activated protein kinase (AMPK)/mTOR,
Mitogen-activated protein kinase (MAPK), Beclin-1, Bcl-2, p53, and p38
(Fig. 3) [45].
The antitumor activity of indole alkaloids has been extensively
studied in the field of drug development. A mechanistic study has
revealed that indole alkaloids regulate autophagy participating in the
PI3K/Akt/mTOR signaling pathway, MAPK signaling pathway, ROS
signaling pathway, and Beclin-1, leading to antitumor activity. Despite
this progress, no comprehensive review has been devoted to this topic.
In this review, we systemically presented recent advances in indole al­
kaloids as anticancer agents by regulating autophagy categorized as
follows: (1) targeting the PI3K/Akt/mTOR signaling pathway, (2) tar­
geting the MAPK signaling pathway, (3) targeting Beclin-1, (4) targeting
the ROS signaling pathway, (5) targeting P62/SQSTM1, and (6) tar­
geting miscellaneous pathways. Literature has been surveyed primarily
from 2009 to Nov. 2021, and some semisynthetic or fully synthetic
indole derivatives are also discussed. A list of chemical structures indole-
containing molecules is presented in Fig. 4.
2. Targeting the PI3K/Akt/mTOR signaling pathway
The PI3K/Akt/mTOR signaling pathway extensively exists in human
cells and plays an important role in maintaining normal cellular activity.
It is also a critical pathway for autophagy regulation [46]. The
PI3K/Akt/mTOR signaling pathway comprises three important
signaling molecules: PI3K, Akt, and mTOR. PI3K is the first
Fig. 2. The process of autophagy. Under the amino acid or nutrient starvation conditions, the ULK1 complex (ULK1, Atg13, FIP200, and Atg101) gets activated by
coordinated inputs from the mTORC1, which allows the initiation of autophagy. The ULK1 complex phosphorylates and activates the Beclin-1/Vps34 complex in the
nucleation step of autophagy. In the process of vesicle expansion and completion, two ubiquitin-like binding reaction systems are involved in forming autopha­
gosomes, namely the LC3-PE binding reaction system and the Atg12-Atg5 binding reaction system. The conjugates included SNAP29, VAMP7/VAMP8, and SNARE
play a vital role in the fusion process.
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Biomedicine & Pharmacotherapy 149 (2022) 112827
signal-transduction enzyme in this signaling pathway and is a lipid ki­
nase that catalyzes the phosphorylation of the phosphatidylinositol at
D3 in the cytoplasm [47,48].
As a crucial downstream target kinase of PI3K, Akt is a serine/thre­
onine kinase, also known as Protein kinase B. Two activated sites,
namely, Thr308 and Ser473, can fully activate Akt together [49]. mTOR
is a central regulator of autophagy and a serine/threonine kinase
belonging to the phosphoinositol 3-kinase-related protein kinase family
[50]. It comprises two distinct signaling complexes named mTORC1 and
mTORC2. However, as the main effector of the PIK downstream
pathway, mTORC1 plays a key role in direct autophagy regulation
[51–53]. mTORC1 can directly inhibit the activity of ULK1 by phos­
phorylating the complex of ULK1, which constitutes ULK1, Atg13,
FIP200, and Atg101. Under nutrient-poor conditions, dephosphoryla­
tion of mTORC1 results in the departure from the ULK1 complex, which
allows the activation of ULK1. Concomitantly, ULK1 undergoes auto­
phosphorylation and dephosphorylates ATG 13 and FIP200, which are
involved in autophagy initiation [54–56]. Many indole alkaloids and
their derivatives can more accurately and specifically regulate the
autophagy activity of tumor cells by targeting
PI3K/Akt/mTOR-mediated autophagy to exhibit antitumor activity.
β-Carboline alkaloids are a remarkable family of natural indole-
containing compounds, and they are widely distributed in many kinds
of medicinal plants. Recently, these alkaloids have been the focus of
interest, due to their diverse biological activities, such as antitumor,
antiviral, antiparasitic, and anxiolytic. Abe and his coworkers [57]
demonstrated that harmol induces autophagy and subsequently induces
apoptotic cell death in U251MG human glioma cells by reducing phos­
phorylation of Akt, mTOR, and its downstream targets. Notably, here
harmol-induced autophagy is a pro-death mechanism by suppressing
survivin protein expression. Compound Muniziqi granule (MNZQ) is a
traditional Chinese multi-component herbal preparation and can treat
endocrine disorders caused by acne, chloasma, dysmenorrhea, meno­
pausal syndrome, and melanoma [58]. Harmine is one of the most
potent anti-melanoma agents extracted from MNZQ. Harmine has been
reported to induce the formation of autophagosomes via the increase of
LC3-II in B16 cells, which shows that it is an autophagy inducer [59]. In
M.-L. Luo et al. Biomedicine & Pharmacotherapy 149 (2022) 112827

Fig. 3. Targeting signaling cascades regulating autophagy. Various pathways regulate autophagy. mTOR kinase is an important regulatory molecule that induces
autophagy. Activated mTOR inhibits autophagy, while negative regulation of mTOR promotes autophagy. AMPK and P53 activate autophagy directly via phos­
phorylating ULK1 or indirectly via phosphorylating TSC1/2, which suppresses mTORC1 activity. Akt and MAPK activate mTORC1 to inhibit autophagy. ROS ac­
tivates autophagy via multiple pathways, including NOX4 activation, which promotes the PERK/eIF2α/ATF4 pathway.

addition, the result indicated that harmine-mediated autophagy was
activated by inhibiting the Akt/mTOR pathway and partly activating the
ERK1/2 pathway. The cell death induced by harmine suggests it could
be a promising therapeutic agent for the treatment of melanoma. Af­
terward, Li et al. [60] proved that harmine significantly upregulates
autophagy and apoptosis activity in human gastric cancer cells, which is
involved in cell death. This induction is mediated by the inhibition of the
Akt/mTOR/p70S6K signaling pathway and the AMPK signaling
pathway, which is related to the expression of Beclin-1, LC3-II, and p62
[60].
Fascaplysin, a marine natural active product, has wide-ranging bio­
activities, such as antibacterial, antifungal, antiviral, antimalarial, and
anticholinesterase [61]. Kumar’s group found that fascaplysin induces
cell death in HL-60 cells attributed to the cooperative interaction be­
tween apoptosis and autophagy. The effect on autophagy is activated by
inhibiting the PI3K/Akt/mTOR signaling pathway, resulting in
increased expression of LC3-II, ATG7, and Beclin-1 [62]. This suggests
that the synergy of autophagy and apoptosis plays a crucial role in the
antitumor effect of fascaplysin. Sharma et al. [63] synthesized a series of
marine sponge alkaloid fascaplysin analogs. One of the compounds,
fascaplysin chloride, inhibits vascular endothelial growth factor
(VEGF)-mediated angiogenesis and induces autophagy and apoptosis
through the interference with the PI3K/Akt/mTOR signaling pathway in
MDAMB-231 cells [63]. This finding suggests that fascaplysin derivative
has antiangiogenesis and antiproliferative potential. The results of both
studies show that fascaplysin and its derivatives could be a good
candidate drug for cancer treatment.
Bisleuconothine A, a novel bisindole alkaloid isolated from Leuco­
notis griffithii, has higher inhibitory activity in MCF7 cells and A549
cells, and the effect is associated with autophagy-mediated by disturbing
the PI3K/Akt/mTOR signaling pathway. Notably, bisleuconothine A
induces autophagosome formation but inhibits autophagic flux [64].
Staurosporine is a natural product with a bisindole structure extracted
from the bacterium Streptomyces staurosporeus. In HepG2 cancer cells,
staurosporine significantly induces autophagy by inhibiting the
PI3K/Akt/mTOR signaling pathway, which allows the cytotoxicity
response [65]. The effect provides a novel mechanism by which staur­
osporine exerts its therapeutic effects. Indole-3-carbinol (I3C) is an
indole alkaloid extracted from cruciferous vegetables. It exerts anti­
cancer, antioxidant, and anti-inflammatory effects. Jiang and his co­
workers found that I3C exerts protective effects on hyperlipidemia
zebrafish larvae by promoting autophagy. Moreover, the induction of
autophagy has been shown by the enhancement in LC3-II and Beclin-1,
as well as the reduction in P62, Bcl-2, Akt, and mTOR, through the
PI3K/Akt/mTOR pathway [66].
3. Targeting the MAPK signaling pathway
MAPKs are signaling components that are essential for converting
extracellular stimuli into a wide array of cellular processes [67]. MAPK
signaling pathway is also one of the most important transduction
pathways that mediate signal transfer from the cell surface to the

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Fig. 4. The chemical structures of indole alkaloids and indole derivatives that regulate autophagy.

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M.-L. Luo et al.
intracellular. It plays a crucial role in the process of autophagy through
different mechanisms [68]. Three MAPK pathways involved in the
regulation of cellular activities have been studied. They are the ERK1/2,
JNK, and p38/MAPK signaling pathways [69].
ERK1/2 are activated by mitogens and transmit extracellular signals
into the nucleus through cell-membrane receptors, thus mediating the
expression of the intracellular gene and participating in the regulation of
cell proliferation, differentiation, apoptosis, autophagy, and other
functions [70,71]. Numerous studies have shown that the activation of
ERK1/2 can directly promote the upregulation of the autophagy marker
proteins LC3 and p62 to initiate autophagy [72]. Meanwhile, it can
cause the downregulation of lysosomal-associated membrane protein 1
(LAMP1) and LAMP2, followed by the prevention of the binding of
autophagosomes to lysosomes, which inhibits the reduction of auto­
phagosomes [73].
Another MAPK pathway protein is c-Jun N-terminal kinase (JNK).
The JNK signaling pathway can induce autophagy through the Beclin-1-
dependent or Beclin-1-independent pathway. On the one hand, the JNK
signaling pathway can phosphorylate Bcl-2 family proteins to promote
the release of Beclin-1 from the Beclin-1/Bcl-2 complex and bind to
Vps34 to promote autophagy. On the other hand, JNK can promote
autophagy by mediating the upregulation of Atg gene expression. The
autophagy induced by the JNK pathway plays a protective role in pro­
moting cancer-cell survival, which counters apoptosis [74–77].
The P38/MAPK signaling pathway is also extensively involved in
autophagy regulation. It comprises five subtypes, namely, p38α, p38β1,
p38β2, p38γ, and p38δ. The p38/MAPK signaling pathway exerts a
critical role in the regulation of cell-cycle arrest, apoptosis, autophagy,
growth inhibition, and differentiation [78]. The p38/MAPK signaling
pathway serves a dual role in autophagy regulation, namely positive
regulator and negative regulator. Sometimes autophagy can be induced
by activating this signaling pathway [79,80]. Meanwhile, the
p38/MAPK signaling pathway has a negative role in autophagy regu­
lation. Several studies have proven that autophagy can be induced by
inhibiting this pathway [81,82]. Thus, targeting ERK1/2, p38, and JNK
MAPK to regulate autophagy is a strategy against cancer cells that is
worth exploring.
An aspidosperma-type alkaloid, 11-methoxytabersonine (11-MT),
has been isolated from the roots of Tabernaemontana Bovina Lour. Ge
et al. [83] demonstrated that 11-MT could induce protective autophagy
in A549 and H157 cells to avoid 11-MT-induced necroptosis. Mechanism
research has suggested that the alkaloid regulates autophagy through
the AMPK/mTOR and JNK signaling pathways [83]. Shimizu and his
coworkers demonstrated that the JNK signaling pathways are crucial to
autophagic cell death. In return, the activation of autophagy can trigger
JNK [84]. Evodiamine is a naturally occurring indole alkaloid and is the
main biologically active component of the traditional Chinese medicine
evodiae fructus. Liu et al. [85] revealed that evodiamine induces auto­
phagy and apoptosis in human glioblastoma cells [85]. The apoptosis
induced by evodiamine is mediated by the calcium pathway, which is
shown by the decrease of cytosolic calcium elevation, apoptosis, and
mitochondrial depolarization under calcium channels blockade. In
addition, blockade of calcium channels and inactivation of JNK inhibits
the autophagy-mediated by evodiamine, which suggests that evodi­
amine mediates autophagy via a calcium-JNK signaling pathway. Yang
et al. [86] synthesized a series of calothrixin A (CAA) analogs, one of
which is CAA45. Their investigation confirmed that CAA45 blocks
cell-cycle arrest, induces cell apoptosis and autophagy, and inhibits the
cells migration. Notably, apoptosis and autophagy-mediated by CAA45
are regulated by the Akt/JNK/p53 signaling pathway [86].
Isomahanine is an alkaloid containing an indole skeleton isolated
from Murraya koenigii and exhibits wide-ranging bioactivities. Utaipan
et al. [87] found that isomahanine induces apoptosis and autophagy,
playing a prodeath role in the multidrug‑resistant oral squamous cell
carcinoma (OSCC) cell line CLS-354/DX. These effects are associated
with the activation of the P38/MAPK signaling pathway mediated by
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Biomedicine & Pharmacotherapy 149 (2022) 112827
endoplasmic reticulum (ER) stress [87]. Hu’s group isolated a series of
indole notoamide-type alkaloids from a coral-associated fungus Asper­
gillus ochraceus LZDX-32–15. Notoamide G exerts potent cytotoxicity in
the HepG2 and Huh-7 cells via autophagy and apoptosis. Notoamide
G-mediated autophagy is shown by the upregulation of Beclin-1 and
LC3B, the key protein of autophagy [88]. Further investigation revealed
that notoamide G promotes P38 and JNK phosphorylation. This suggests
that notoamide G induces autophagy and apoptosis through P38/JNK
pathway, which indicates that notoamide G may serve as a potent lead
for further development as an antitumor agent.
Abe and his coworkers reported that harmol, a β-carboline alkaloid,
exhibits significant antitumor activity in human NSCLC A549 cells. The
alkaloid promotes cell death by inducing autophagy rather than
apoptosis, as shown by the increase in LC3II, a reliable molecular marker
for autophagy detection. The induction is partly provoked by the ERK 1/
2 signaling pathway [89]. Additionally, Ishimwe et al. [90] demon­
strated that brucine, a clinically-used small molecule in traditional
Chinese medicine, exerts the effect of inhibition of autophagy. The
inhibitory effect is achieved by disturbing autolysosomal degradation
and exerting the regulation of ERK1/2-mTOR-p70S6K signaling cascade
[90]. The inhibition of autophagy plays a vital role in inducing immu­
nogenic cell death, which improves its application in cancer treatment.
Chaetoglobosin G is a fungal secondary metabolite and exhibits anti­
cancer activity. Chen and his coworker showed that chaetoglobosin af­
fects the arrest of cell proliferation, and the inhibition is mediated by the
induction of autophagy and apoptosis, which is regulated by the
EGFR/MEK/ERK pathway. The result is the increased expression of P21
and LC3II, G2/M phase arrest, and decreased Bcl-2 protein [91]. Table 1.
4. Targeting Beclin-1
Beclin-1 gene is the first mammalian autophagy gene to be found by
yeast two-hybrid screening in 1998 by Beth Levine’s group. It is located
on chromosome 17q21 and is an ortholog of the autophagy gene Atg6/
Vps30 protein in yeast [92]. Beclin-1, a 60-kDa protein of 450 amino
acids, possesses three identified functional domains: an evolutionarily
conserved domain (amino acids 244–337) [93], a central coiled-coil
domain (amino acids 144–269) [94], and a BH3 domain (amino acids
114–123) at the N-terminus [95]. As a major regulator, Beclin-1 regu­
lates autophagy by forming complexes with some other proteins. As an
essential member of Class III PI3K complexes, Beclin-1 can produce two
types of complexes: PI3KC3-C1 and PI3KC3-C2. PI3KC3-C1 is crucial to
autophagic vesicle enucleation at the start of autophagosome formation,
comprising Beclin-1, Vps34, Vps15, and Atg14. PI3KC3-C2 is associated
with autophagolysosomal maturation and contains Beclin-1, Vps34,
Vps15, and UV Radiation Resistance Associated Gene Protein [96,97].
Beclin-1 was first identified as a Bcl-2 interacting partner, and Bcl-2
and Bcl-XL exert a critical role in autophagy regulation activity by
combining with Beclin-1. They can inhibit autophagy by binding to the
BH3 domain of Beclin-1 so that Beclin-1 cannot interact with other
proteins to form the PI3KC3 complex [98]. Under normal conditions,
Bcl-2 inhibits Beclin-1. However, under stress conditions, various signals
can regulate the interaction between Bcl-2/Bcl-XL and Beclin-1. The
phosphorylation of Bcl-2/Bcl-XL and Beclin-1 is the major regulator to
regulate the combination. First, the phosphorylation of Bcl-2 may
regulate the Bcl-2-Beclin 1 complex. Under starvation conditions, JNK1
can phosphorylate Bcl-2 at T69, S70, and S97, thereby contributing to
the dissociation of Bcl-2-Beclin 1 and leading to the induction of auto­
phagy [99]. Second, the phosphorylation of Beclin-1 plays a dual role in
autophagy regulation. The overexpression of death-inducing kinase and
serine/threonine Rho kinase 1 promotes the phosphorylation of Beclin-1
at the threonine 119 site of the BH3 domain, thereby leading to the
dissociation from Bcl-2 and initiation of autophagy through Beclin-1
binding to the Vps34 complex [100,101]. Conversely, Beclin-1 can be
phosphorylated at the T108 site of the BH3 domain by proapoptotic
kinase mammalian Ste20-like kinase 1, but the interaction between
M.-L. Luo et al. Biomedicine & Pharmacotherapy 149 (2022) 112827

Table 1
Regulation of indole alkaloids and indole derivatives on autophagy.
Targets Compounds Cell lines Effect Dual Role References
onAutophagy ofAutophagy

PI3K/Akt/mTOR pathway Harmol U251MG cells Induces Pro-death [57]

Harmine B16 cells Induces Pro-death [59]
Harmine MGC-803 cells;SGC-7901 Induces Pro-death [60]
cells
Fascaplysin HL-60 cells Induces Pro-death [62]
Fascaplysin chloride MDAMB-231 cells Induces Pro-death [63]
Bisleuconothine A MCF7 cells;A549 cells Induces Pro-death [64]
Staurosporine Hepg2 cells Induces Pro-survival [65]
Indole-3-carbinol Zebrafish larvae Induces Pro-survival [66]
MAPK pathway JNK/MAPK pathways 11-methoxytabersonine A549 cells;H157 cells Induces Pro-survival [83]
JNK/MAPK pathways Evodiamine Glioblastoma cells Induces Pro-death [85]
JNK/MAPK pathways Calothrixin A 45 A549 cells Induces Unknown [86]
P38/MAPK pathways Isomahanine CLS-354/DX cells Induces Pro-death [87]
P38/MAPK pathways Notoamide G Hepg2 cells;Huh-7 cells Inhibits Unknown [88]
Erk1/2/MAPK pathways Harmol A549 Cells Induces Pro-death [89]
Erk1/2/MAPK pathways Brucine MDA-MB-231 cells;CT26 Inhibits Pro-death [90]
cells
Erk1/2/MAPK pathways Chaetoglobosin G A549cells Induces Pro-death [91]
Beclin-1 Evodiamine SGC-7901 Cells Induces Pro-death [104]
Vincristine Zebrafish larvae neuronal Inhibits Pro-death [105]
cells
Vincristine MDA-MB-231 Cells Induces Unknown [106]
Violacein Neck carcinoma cells Induces Pro-death [107]
IF203 HepG2 cells Inhibits Unknown [108]
ROS pathways Evodiamine Hela cells Inhibits Pro-survival [113]
Reduced scytonemin T-lymphoid Jurkat cell Induces Pro-death [114]
Indole alkaloid derivative B HT-29 cells Induces Pro-death [115]
(IADB)
Fascaplysin Vascular endothelia cells Induces Pro-survival [116]
P62 Reserpine HEK293 cell Inhibits Pro-death [121]
Racemocin B derivative C25 MDA-MB-231 cells Inhibits Pro-death [122]
Conophylline Fatty liver cells(in vivo) Induces Pro-survival [123]
Taberine D Hela cells Inhibits Pro-survival [124]
Indole-3-carbinol Ehrlich ascites carcinoma Inhibits Pro-death [125]
cells
Miscellaneous P53/AKT pathway Ellipticine A549 cells Induces Pro-death [126]
pathways NF-κB p65 pathway BMA155Cl HepG2 cells Induces Pro-death [128]
JAK2/STAT3 pathway Bufothionine HCC cells Induces Pro-death [129]
ER stress Aplysinopsin Derivative EE-84 K562 cells Induces Pro-death [130]
ER stress CTet MDA-MB-231 cells Induces Dual role [131]
Depending on the mTOR Corynoxine Neuronal cell lines Induces Pro-survival [132]
pathway

Beclin-1 and Bcl-2/Bcl-xl is promoted and autophagy is inhibited [102].
Other regulators can also regulate the Bcl-2-Beclin-1 interaction, such as
a BH3-only protein/mimetic, which induces autophagy by disrupting
the Bcl-2-Beclin-1 complex [103].
The natural product evodiamine is an alkaloid isolated from the
traditional Chinese medicine evodiae fructus, which is the dried fruit of
Evodia rutaecarpa Bentham. It exerts a deleterious effect on SGC-7901
human gastric adenocarcinoma cells. Evodiamine reportedly induces
apoptosis, autophagy, and cell-cycle arrest at the G2/M phase. These
effects lead to the downregulation of Bcl-2 and upregulation of Bax.
Moreover, Beclin-1 is associated with evodiamine-induced autophagy
[104]. Hu and his coworkers investigated the relationship between
autophagy and vincristine neurotoxicity. They found that vincristine
inhibits autophagy but induces apoptosis in the dopaminergic neurons
of zebrafish, leading to neurotoxicity. Here, Beclin-1 plays a dominant
role in regulating autophagy, suggesting that Beclin-1 may be a potential
molecular target to reduce vincristine neurotoxicity [105]. Furthermore,
Sun et al. [106] demonstrated that vincristine blocks the combination of
sirt 2 and heat shock protein (Hsp)70, which leads to Hsp70 acetylation
at K126. The acetylation of Hsp 70 enhances the combination of Hsp 70
and Bcl-2, thereby promoting the upregulation of Beclin-1 and playing a
pivotal role in autophagy [106]. Masuelli et al. [107] demonstrated that
the indole-derived violacein, a purple-colored natural pigment, exerts
remarkable activities to inhibit a panel of head and neck carcinoma cell
lines. This study revealed that violacein could inhibit the growth of head
and neck cancer cells in vitro and in vivo by inducing autophagy and
apoptosis. Violacein increased PARP-1 cleavage, Bax/Bcl-2 ratio, inhi­
bition of ERK1/2 phosphorylation, and light chain 3-II (LC3-II) expres­
sion. Furthermore, violacein disturbs Bcl-2-Beclin-1 interaction by
decreasing the expression of Bcl-2, thereby leading to upregulation of
Beclin-1 expression, which serves as a key regulator in autophagy to
regulation [107]. This is the first report demonstrating
violacein-mediated autophagy in cancer cells, which provides a new
mechanism for violacein as an anticancer molecule. Shang et al. [108]
demonstrated that IF203, a novel indole derivative, has an efficient
inhibitory effect on HepG2 cell growth, and this effect is caused by
cell-cycle arrest, apoptosis, and autophagy induced by IF203. In addi­
tion, autophagy activation is triggered by the positive expression of the
autophagy-related proteins Atg5, Atg12, ULK1, Beclin-1, and LC3II
[108].
5. Targeting the ROS signaling pathway
Reactive oxygen species (ROS) is a general term for oxygen-
containing free radicals and peroxides that easily form free radicals
related to oxygen metabolism in the organism. As a product of normal
redox reactions in the body, ROS is involved in the regulation of steril­
ization, detoxification, and various metabolic pathways [109]. ROS
include oxygen anions, free radicals, and hydrogen peroxide [110] and
originates from two major pathways: mitochondria and nicotinamide

7
M.-L. Luo et al.
adenine dinucleotide phosphate (NADPH) oxidase [111].
ROS, especially mitochondria-derived ROS, can reportedly regulate
autophagy [112]. The molecular mechanism of ROS regulation of
autophagy primarily depends on various molecular signal pathways,
such as ROS-FOXO3-LC3/BNIP3-autophagy, ROS-NRF2-P62-autophagy,
ROS-HIF1-BNIP3/NIX-autophagy, and ROS-TIGAR-autophagy. The
accumulation of ROS leads to the oxidative-stress response and activates
HIF-1, p53, FOXO3, and NRF2, respectively. These proteins induce the
transcription of BNIP3 and NIX, TIGAR, LC3, and BNIP3 and p62,
respectively. The corresponding protein regulates autophagy through
various autophagy pathways, such as MAPKs, mTOR, and AMPK/Akt.
Evodiamine is an alkaloid isolated from the dried, unripe fruit of
Evodia rutaecarpa (Juss.) Benth. It shows remarkable activities inhib­
iting human cervix carcinoma HeLa cells. It induces apoptosis, which
plays a critical role in cell death and is dependent on the ROS pathway.
Notably, moderate ROS/NO leads to autophagy, protecting against cell
death. However, massive ROS/NO plays a negative role in autophagy,
which promotes cell death [113]. Reduced scytonemin (R-scy), isolated
from N. commune Vaucher, reportedly possesses a higher inhibitory
activity in human T-lymphoid Jurkat cells. The cytotoxicity of R-scy
depends on the autophagic death induced by the natural compound.
ROS pathway plays pivotal roles in cell death mediated by R-scy, which
is involved in the induction of mitochondrial dysfunction [114].
Bi and his coworkers synthesized a new indole derivative B (IADB)
which shows potent cytotoxicity to tumor cells and is nontoxic to cardiac
cells [115]. It selectively induces autophagic cell death mediated by ROS
overproduction in cancer cells in colon cancer HT29 cells due to dif­
ferences in redox status between normal and tumor cells. In normal cells,
IADB treatment in combination with chemotherapy can mitigate
5–Fluorouracil-Induced Cardiotoxicity. The study about IADB may
support novel therapeutic targets to improve chemotherapeutic efficacy
with decreased off-target effects. Meng and his partner demonstrated
that fascaplysin, a red pigment isolated from a Fijian marine sponge
(Fascaplysinopsis sp.), provokes autophagy in vascular endothelial cells
by activating the ROS pathway. ROS pathway-mediated autophagy
plays a protective role in vascular endothelia cells to inhibit apoptosis
and its anti-angiogenesis activity, providing a novel anticancer appli­
cation of fascaplysin [116].
6. Targeting P62/SQSTM1
P62/SQSTM1 is a multifunctional protein and exerts multiple effects
on cell-signaling transduction, cell proliferation, apoptosis, and tumor­
igenesis [117]. As the main component of many protein complexes in
cells, P62 contains multiple distinct domains, regulating different
signaling pathways by interacting with other proteins [118], such as the
Keap1-Nrf2, mTOR, and NF-κB pathways.
P62 is known to play an important role in autophagy through its
series of distinct domains, including ubiquitin-associated (UBA), LC3-
interacting region (LIR), and N-terminal phox-BEM1 (PB1) domains,
which contribute to the binding of p62 to ubiquitin, LC3, and many
other proteins [119]. Ser407 in the UBA domain of p62 is phosphory­
lated by autophagy-associated protein 1. Subsequently, Ser403 in the
UBA domain is phosphorylated by Casein kinase 2 or Tank-binding ki­
nase 1, leading to p62 ubiquitination and thus promoting autophagy
degradation [118]. The PB1 domain of P62 can promote the packaging
of ubiquitinated substrates through self-oligomerization and subse­
quently transport the packaged substrates to the autophagy pathway to
participate in autophagosome formation. P62 interacts with LC3
through its LIR domain to form a complex, which is degraded together in
autophagy lysozyme as an autophagy-specific substrate [120]. P62 is
degraded by autophagy and in turn regulates the autophagy process.
During normal autophagy, p62 protein is continuously degraded in the
cytoplasm. When autophagy activity is weakened, and autophagy
function is defective, P62 protein continuously accumulates in the
cytoplasm, so P62 is a marker protein that reflects autophagy activity.
8
Biomedicine & Pharmacotherapy 149 (2022) 112827
Reserpine, an indole alkaloid isolated initially from the snakeroot of
the rauchia plant, is used to treat hypertension and schizophrenia. Lee
et al. [121] demonstrated that reserpine blocks autophagic flux, leading
to cell death in GFP-LC3 cells and neuronal cells through the upregu­
lation of LC3II and p62/SQSTM1 expression. In neuronal cells, reserpine
induces the accumulation of α-synuclein protein, which is crucial to PD
pathogenesis by inhibiting autophagy flux. Interestingly, treating
neuronal cells with the combination of reserpine and rapamycin can
enhance the effect of reserpine, leading to reduced cell viability [121].
Xiao and his coworkers synthesized a series of novel derivatives of
racemocin B, an indole natural product isolated from the green alga
Caulerpa racemose. C25 possesses potent anticancer activity, effectively
inducing cell-cycle arrest, apoptosis, and cell death in the triple-negative
breast cancer cell line MDA-MB-231. Inhibition of autophagy plays a
role in these effects by inducing the expression of LC3II and
p62/SQSTM1, the marker of blocking autophagic flux [122]. Con­
ophylline is a naturally occurring indole alkaloid present in the leaves of
the tropical plant Tabernaemontana divaricate. Conophylline can
reportedly alleviate hepatic steatosis by promoting the expression of
peroxisome proliferator-activated receptor alpha (PPARA), carnitine
palmityl transferase (CPT)1, and CPT2-related β-oxidation. It can also
induce autophagy by regulating Atg7 and p62, which play crucial roles
in hepatic lipotoxicity, thereby providing a novel molecular mechanism
to prevent hepatic steatosis in non-alcoholic fatty liver disease (NAFLD)
[123].
Zhang et al. [124] obtained several bisindole alkaloids from Taber­
naemontana corymbose. They also found that taberine D causes
dysfunction in lysosomes by attenuating lysosomal acidification, which
is involved in the block of autophagic flux in HeLa cells. The blocking
process is shown by the increase in LC3II and p62/SQSTM1 [124]. I3C is
an active natural product of cruciferous vegetables, which is known as
an antitumor substance. Donia and his partner reported that the coad­
ministration of I3C with hydroxychloroquine exerts a deleterious effect
on ehrlich ascites carcinoma cells by regulating apoptosis and auto­
phagy. The process is mediated by significant upregulation in LC3B and
downregulation in p62 gene expression [125].
7. Targeting miscellaneous pathways
Apart from the pathways described above, to exert antitumor ac­
tivity, indole alkaloids and their derivatives can also regulate autophagy
through other pathways, such as the P53/Akt and JAK2/STAT3 path­
ways, as well as ER stress. Fang and his partners demonstrated that
ellipticine, a famous topoisomerase II inhibitor, has higher inhibitory
activity in human NSCLC cells. It can induce autophagy and apoptosis
and arrest the cell cycle at the G2/M phase, associated with ellipticine-
induced cytotoxicity. The autophagy caused by ellipticine is also
mediated by the corporation of p53 and Akt [126]. Afterward, the same
group further proved that the presence of P53 facilitates the nucleus
translocation of phosphorylated Akt and the activation of the autophagy
pathway, thereby leading to apoptotic cell death [127]. These studies
provide a new molecular mechanism for ellipticine as an effective
antitumor therapy agent. BMA155 is a derivative of bisindolylmalei­
mide alkaloid synthesized from the indole skeleton, which exhibits su­
perior inhibitory activity in HepG-2 cells. Sun et al. [128] proved that
BMA-155Cl, which is easily obtained from BMA-155, has a remarkable
antitumor effect by inducing apoptosis and autophagy in human hep­
atocarcinoma HepG-2 cells. In the process, BMA-155Cl induces auto­
phagy by activating the NF-κB p65 pathway, promoting the subsequent
apoptosis and serving as a protective method [128].
Bufothionine is known as the main active ingredient of cinobufacini,
which is isolated from the skins and parotid venom glands of the toad
Bufo gargarizans Cantor and Bufo melanostictus Schneider. Kong et al.
[129] reported that bufothionine could inhibit cell proliferation and
promote apoptosis and autophagy in SMMC7721 cells. The activation of
autophagy is suggested by the positive expression of autophagy-related
M.-L. Luo et al.
proteins, such as Atg5, Atg7, Beclin-1, and LC3II. The inhibition of the
JAK2/STAT3 pathway plays an important role in bufothionine-induced
autophagy [129]. Song et al. [130] demonstrated that the aplysinopsin
derivative EE-84 could induce cellular morphologic change and
cell-stress responses, which trigger autophagy and ER stress in chronic
myeloid leukemia cells. Moreover, EE84-induced autophagy is related to
the PERK-eIF2a-ATF4-CHOP UPR pathway, which is provoked by
EE84-induced ER stress. These results show that EE84 is expected to be a
potential drug agent for leukemia treatment due to its excellent prop­
erties of antileukemia [130]. I3C and its metabolic products are
considered as the main anticancer active ingredient from cruciferous
vegetables. Galluzzi’s group showed that the autophagy induced by CTet
is activated by ER stress in MDA-MB-231 cells. Meanwhile,
CTet-mediated autophagy plays a protective role at early time points,
resulting in autophagic cell death with time [131]. Another group re­
ported that conophylline, a vinca alkaloid, can also induce autophagy,
suppress protein aggregation, and protect cells from cell death. Notably,
conophylline-induced autophagy does not depend on the mTOR
pathway; instead, it is induced independently of the mTOR pathway
[132].
8. Conclusion and perspective
As an evolutionarily conserved mechanism, Autophagy is rather
complex but essential under basal conditions and settings of diseases.
Over the past few years, increasing indole-containing alkaloids are
emerging with autophagy-regulating capacity in experimental anti­
tumor therapies. Actually, a large body of evidence has indicated that
indole alkaloid-mediated autophagy plays dual roles in cancer. In this
review, we summarize the pharmacological action of indole alkaloids
and derivatives and their regulation mechanism of autophagy based on
previous findings. As summarized in our article, indole alkaloids regu­
late autophagy by modulating the activity of various signaling path­
ways, including those involving PI3K/Akt/mTOR, MAPK, Beclin-1, and
ROS. As discussed above, some indole alkaloids activate autophagic cell
death, whereas some others inhibit it. Furthermore, as discussed above,
the same indole alkaloid can activate different signaling pathways to
regulate autophagy.
All studies described above fails to explore further the causative role
of autophagy in the anticancer effect of indole alkaloids. This role re­
quires determining whether autophagy is a major independent cell
killer, an early phase of cell death occurring prior to apoptotic cell death,
or a passive bystander with an effect that occurs concomitantly with
apoptotic cell death. Thus, an increased understanding of autophagy
associated with indole alkaloids with cancer therapy is urgently
required. At present, most mechanistic studies have focused on in vitro
cellular models. Conversely, the establishment of appropriate experi­
mental models to evaluate the role of autophagy in vivo also has
fundamental significance in evaluating the therapeutic effects and safety
as new anticancer agents for cancer therapy. In summary, we hope that
more indole-contain compounds or naturally indole alkaloids can be
found and synthesized. The autophagy-regulation mechanism and
structure-activity relationship of these compounds can be deeply
explored to shed light on the development of strategies for cancer
treatment.
CRediT authorship contribution statement
Bo Han and Qian Zhao contributed to the conception and design of
the study. Meng-Lan Luo and Wei Huang organized the database, per­
formed the statistical analysis, and wrote the first draft of the manu­
script. Hong-Ping Zhu and Cheng Peng contributed to the manuscript
revision. All authors read and approved the submitted version.
9
Biomedicine & Pharmacotherapy 149 (2022) 112827
Acknowledgment
We are grateful for financial support from National Natural Science
Foundation of China (82073998, 22107015), Sichuan Science and
Technology Program (2022JDRC0045, 2022JDRC0125, 2019YJ0321),
the China Postdoctoral Science Foundation and Xinglin Scholar
Research Promotion Project of Chengdu University of TCM.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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