Targeting Notch signaling pathways with natural bioactive compounds: a promising approach against cancer

Abstract

Notch signaling pathway is activated abnormally in solid and hematological tumors, which perform essential functions in cell differentiation, survival, proliferation, and angiogenesis. The activation of Notch signaling and communication among Notch and other oncogenic pathways heighten malignancy aggressiveness. Thus, targeting Notch signaling offers opportunities for improved survival and reduced disease incidence. Already, most attention has been given to its role in the cancer cells. Recent research shows that natural bioactive compounds can change signaling molecules that are linked to or interact with the Notch pathways. This suggests that there may be a link between Notch activation and the growth of tumors. Here, we sum up the natural bioactive compounds that possess inhibitory effects on human cancers by impeding the Notch pathway and preventing Notch crosstalk with other oncogenic pathways, which provoke further study of these natural products to derive rational therapeutic regimens for the treatment of cancer and develop novel anticancer drugs. This review revealed Notch as a highly challenging but promising target in oncology.

Full text

Targeting Notch signaling
pathways with natural bioactive
compounds: a promising
approach against cancer
Jia Yang
1
,
2
,
3
, Qihui Sun
1
,
4
, Xiaoyun Liu
5
, Yong Yang
5
,
Rong Rong
1
,
2
*, Peiyu Yan
2
* and Ying Xie
3
*
1
College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China,
2
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and
Technology, Taipa, Macao SAR, China,
3
State Key Laboratory of Traditional Chinese Medicine Syndrome,
The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong,
China,
4
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China,
5
Key
Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University
of Traditional Chinese Medicine, Jinan, Shandong, China
Notch signaling pathway is activated abnormally in solid and hematological
tumors, which perform essential functions in cell differentiation, survival,
proliferation, and angiogenesis. The activation of Notch signaling and
communication among Notch and other oncogenic pathways heighten
malignancy aggressiveness. Thus, targeting Notch signaling offers
opportunities for improved survival and reduced disease incidence. Already,
most attention has been given to its role in the cancer cells. Recent research
shows that natural bioactive compounds can change signaling molecules that are
linked to or interact with the Notch pathways. This suggests that there may be a
link between Notch activation and the growth of tumors. Here, we sum up the
natural bioactive compounds that possess inhibitory effects on human cancers by
impeding the Notch pathway and preventing Notch crosstalk with other
oncogenic pathways, which provoke further study of these natural products
to derive rational therapeutic regimens for the treatment of cancer and develop
novel anticancer drugs. This review revealed Notch as a highly challenging but
promising target in oncology.
KEYWORDS
notch signaling, crosstalk, oncogenic pathways, phytochemicals, cancer
OPEN ACCESS
EDITED BY
Antonella D’Anneo,
University of Palermo, Italy
REVIEWED BY
Magesh Muthu,
Wayne State University, United States
Armel Hervé Nwabo Kamdje,
University of Garoua, Cameroon
Maria Pia Felli,
Sapienza University of Rome, Italy
*CORRESPONDENCE
Ying Xie,
leoxieying16@outlook.com
Peiyu Yan,
pyyan@must.edu.mo
Rong Rong,
rosierong@163.com
RECEIVED 05 April 2024
ACCEPTED 27 June 2024
PUBLISHED 18 July 2024
CITATION
Yang J, Sun Q, Liu X, Yang Y, Rong R, Yan P and
Xie Y (2024), Targeting Notch signaling
pathways with natural bioactive compounds: a
promising approach against cancer.
Front. Pharmacol. 15:1412669.
doi: 10.3389/fphar.2024.1412669
COPYRIGHT
© 2024 Yang, Sun, Liu, Yang, Rong, Yan and Xie.
This is an open-access article distributed under
the terms of the Creative Commons Attribution
License (CC BY). The use, distribution or
reproduction in other forums is permitted,
provided the original author(s) and the
copyright owner(s) are credited and that the
original publication in this journal is cited, in
accordance with accepted academic practice.
No use, distribution or reproduction is
permitted which does not comply with these
terms.
Abbreviations: Notch1/2/3/4, Notch receptor 1/2/3/4; DLL1/3/4, Delta-like protein 1/3/4; ADAM, A
disintegrin and metalloprotease; NECD, extracellular domain; NICD, intracellular domain of Notch; CSL,
CBF1, Suppressor of Hairless, Lag-1; EGCG, Epigallocatechin-3-gallate; GSIs, gamma-secretase
inhibitors; RBPJ, recombination signal-binding protein of immunoglobulin kappa J region; PTCH,
patched receptor; SMO, smoothened; SUFU, suppressor of fused; COS2, costal 2; PKA, protein
kinase A; SLIMB, supernumerary limbs; Ci/Gli, Cubitus interruptus/zinc finger protein-Glioma-
associated oncogene homolog1; ErbB2, HER2/Neu; PDGF, platelet-derived growth factor; EGFR,
epidermal growth factor receptor; TGF-β, transforming growth factor type beta; PTEN, phosphatase
and tensin homolog; PP2A, protein phosphatase 2; TCF/LEF, T-cell factor/lymphoid enhancer factor;
PI3K, Phosphatidylinositol 3-Kinase; AKT, protein kinase B; ERK, extracellular signal-regulated kinase;
mTOR, mammalian target of rapamycin.
Frontiers in Pharmacology frontiersin.org01
TYPE Review
PUBLISHED 18 July 2024
DOI 10.3389/fphar.2024.1412669

GRAPHICAL ABSTRACT
1 Introduction
Cancer is a highly destructive illness that poses a significant threat to
human wellbeing (Bray et al., 2021). Treatment choices include
radiotherapy, chemotherapy, surgery, immunotherapy, and targeted
therapy (Ullah et al., 2023). However, there has been limited
improvement in the poor prognosis, adverse reactions, drug resistance,
and high recurrence rates. Therefore, discovering new therapeutic drugs
or targets for cancer is required. Notch, an ideal molecular target, is
predominantly expressed in cancerous cells (Espinoza and Miele, 2013).
Notch signaling is a highly conserved pathway that is present in
various types of human malignancies, such as breast, colorectal,
lung, pancreatic, prostate tumors, and glioblastoma (Majumder
et al., 2021). It plays a crucial role in various cellular processes,
including cell proliferation, differentiation, and the maintenance of
cancer stem cells (Zhou et al., 2022).
Clinical research demonstrates an adverse correlation between the
level of Notch expression and patient survival in different kinds of
cancer, indicating that increased Notch activation is associated with
strengthened cancer aggressiveness (Takebe et al., 2014). Thus,
modulating the expression levels of the Notch pathway is a potential
therapeutic approach to treating cancer. Several inhibitors targeting the
Notch pathway have been developed, but their safety and efficacy are
still being evaluated and are not in clinical use (Takebe et al., 2014).
Searching for natural inhibitors of Notch with low toxicity and high
safety,aswellaselucidatingtheir mechanism, could to some extent
address the gap of inhibitors that have not yet been utilized in clinical
practice. On the other hand, recent work indicates that oncogenic
pathways affected by natural bioactive compounds may be linked to or
interact with the Notch pathways, suggesting a potential connection
between Notch signaling and tumor progression.
In this review, we summarize the role of bioactive natural
products in regulating the Notch signaling pathway, particularly
focusing on its activation and interaction with other oncogenic
signaling pathways in various types of cancer. The aim of this study
is to investigate the potential therapeutic applications of natural
products targeting Notch in cancer treatment.
2 Notch signaling pathway
The Notch signaling pathway includes two primary categories:
the canonical pathway and the non-canonical pathway. The
canonical Notch signaling pathway plays a crucial role in
determining cell fate, including cellular communication,
differentiation of embryos and tissues, gene expression, as well as
the development of both benign and malignant diseases (Yamamoto
et al., 2014).
The architecture of the pathway comprises Notch receptors
(Notch 1–4), Notch receptor ligands, namely, Delta-like (DLL1,
-3, and -4) or Serrate-like (commonly known as Jagged 1 and Jagged
2), transcription elements, co-activators, co-repressors, and
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downstream effectors (Zhou et al., 2022). The activation of the
Notch signaling pathway occurs when the Notch ligand combines
with the Notch receptor in signal-receiving cells. The Notch
receptors undergo three cleavages before translocating into the
nucleus in order to regulate the transcription of target genes
(Majumder et al., 2021). It is noteworthy that a diverse range of
cellular activities can be triggered by identical signaling pathways in
distinct circumstances. Considering this, cancer progression
activities initiated by Notch and its cross talks are dependent on
the context (Guo et al., 2011). The Notch signaling pathway is
summarized as depicted in Figure 1.
3 Phytochemicals treated cancers via
modulating Notch pathway
Various studies have shown that natural bioactive compounds
offer substantial protection against cancer by influencing Notch
signaling pathways. This includes suppressing Notch pathway
activation, inhibiting gamma-secretase expression, Notch
transcription complex, and Notch downstream target genes, as
well as preventing communication between Notch and other
cancer-causing pathways.
3.1 Phytochemicals suppressed the Notch
signaling pathway’s activation
Notch is initiated by the binding of the extracellular domain of
the Notch receptors (Notch1-4) to its ligands (DLL 1, -3, -4, and
Jagged1, -2), which are typically present on the surface of
neighboring signal-sending cells (Reichrath and Reichrath, 2020).
Activation of the Notch signaling pathway controls cell fate and
proliferation in both non-cancerous and cancerous diseases (Zhou
et al., 2022). The following topics are addressed in our discussion on
the regulation of Notch activation using natural products: 1) the
FIGURE 1
Notch receptors are initially produced as a solitary polypeptide in signal-receiving cells. These receptors are subsequently divided by Furin-like
convertase(s) in the trans-Golgi network (S1) and combine to create a heterodimer. During trafficking, this heterodimeric receptor is conveyed to the
cellular membrane. In the meantime, Notch ligands in sender cells can attach to Notch receptors in receiver cells. The contact between the receptor and
ligand triggers a second cleavage (S2) in the extracellular domain, which is facilitated by the ADAM (A disintegrin and metalloprotease). The Notch
extracellular domain (NECD) has a role in the binding of the ligand. Subsequently, a third cleavage (S3) takes place within the transmembrane domain,
facilitated by the gamma-secretase function of the presenilin, Nicastrin, Anterior pharynx-defective 1 (APH-1), and Presenilin enhancer 2 (PEN-2) multi-
protein complex. Lastly, the intracellular domain of Notch (NICD) is liberated and migrates to the nucleus, where it interacts with the transcription factor
CSL (CBF1, Suppressor of Hairless, Lag-1). This connection results in the stimulation of transcription by blocking co-repressors and simultaneously
attracting co-activators like mastermind, so facilitating the transcription of Notch target genes. Note: Mastermind-like (MAML); Histone acetyl
transferases (HATs); Ski-interacting protein (SKIP); MYC proto-oncogene (Myc); Cold-inducible RNA-binding protein (CIR); Histone deacetylases (HDAC);
Nuclear receptor corepressor 2 (SMRT); C-terminal binding protein (CtBP).
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FIGURE 2
Phytochemicals suppress the activation of the Notch signaling pathway.
TABLE 1 Phytochemicals on Notch downstream target genes in different types of cancer.
Phytochemical Cancer type Hes-1 Hes-5 Hey-1 Hey-2 References
Curcumin Colorectal Carcinoma ↓Chen et al. (2017a)
Pancreatic Cancer ↓Wang et al. (2006a)
Melanoma Cancer ↓Tang and Cao (2022)
Cholangiocarcinoma ↓Koprowski et al. (2015)
Esophageal Cancer ↓Subramaniam et al. (2012)
Honokiol Colon Cancer ↓Ponnurangam et al. (2012)
Curcumin Colon Cancer ↓Bounaama et al. (2012)
EGCG T-ALL ↓Wang et al. (2020)
Tongue Cancer ↓Wei et al. (2022)
3,6-Dihydroxyflavone Breast Cancer ↓Chen et al. (2016a)
Resveratrol Osteosarcoma ↓↓↓ ↓ Liu et al. (2016)
Triptolide Triple-Negative Breast Cancer ↓↓Ramamoorthy et al. (2021)
Silybin Hepatocellular Carcinoma ↓Zhang et al. (2013)
Withaferin A Breast Cancer ↓↓ Lee et al. (2012)
Carvacrol Prostate Cancer Khan et al. (2019)
Retinoic Acid Glioblastoma ↓Ying et al. (2011)
Oleandrin T-ALL ↓↓ Arai et al. (2018a)
Cowanin T-ALL ↓↓ Arai et al. (2018b)
↓showed decreased expression.
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modulation of Notch ligands and receptors expression, and 2) the
interference with ligand-receptor binding.
Epigallocatechin-3-gallate (EGCG), the main polyphenol in
green tea, decreased the expression of Notch receptors including
Notch1 (Hossain et al., 2012;Lee et al., 2013;Toden et al., 2016;
Wang et al., 2020;Ashry et al., 2022) and Notch2 (Jin et al., 2013)in
several cancer models. Notch was activated in the tongue cancer
mice and EGCG significantly blocked the activation by decreasing
the expression of Notch1, which induced cell apoptosis and
inhibited the proliferation (Wei et al., 2022). In addition, EGCG
also promotes suppression of Notch1 and cleaved Notch1 in 5-
Fluorouracil -resistant cell lines (Toden et al., 2016), suggesting that
EGCG may overcome the 5-Fluorouracil resistance by modulating
the activation of Notch. However, no studies have indicated that
EGCG could regulate Notch ligands.
Resveratrol, isolated from grapes, peanuts, and blueberries,
possesses antitumor and antioxidant properties. It has the
potential to inhibit cell cycle and growth (Pinchot et al., 2011;Yu
X. M. et al., 2013;Zhang et al., 2014), stimulate apoptosis and re-
differentiation (Yu XM. et al., 2013), prevent tumor recurrence
(Giordano et al., 2023), and impede autophagy (Giordano et al.,
2021) in cancer through downregulation of Notch receptors and
ligands, including Notch1, Notch2, Notch4, DLL1, DLL4, and
Jagged1. These studies indicated that resveratrol could hinder the
activation of the Notch pathway through repression of Notch
receptors and ligands in several tumors. However, Notch
signaling might not play a universally critical role in human
medulloblastoma cells given its limited relevance to resveratrol-
induced differentiation and apoptosis (Lacerda-Abreu et al., 2021).
The combined use of a Notch inhibitor and resveratrol
demonstrated greater effectiveness in blocking autophagy,
suggesting its potential as a therapeutic intervention for cancer
(Giordano et al., 2021).
Curcumin, also termed diferuloylmethane, a bright yellow
bioactive compound derived from the plants of the Curcuma
longa species. Curcumin decreased the levels of Notch1 (Liu
et al., 2014;Chen G. P. et al., 2017;Gupta et al., 2017;Siddappa
et al., 2017;Li et al., 2018;Zhdanovskaya et al., 2022), Notch3
(Zhdanovskaya et al., 2022) and Jagged1 (Kiesel and Stan, 2022),
leading to cell death mediated by DNA damage and hindering
cellular self-renewal, apoptosis (Howells et al., 2011;Liu et al.,
2014), motility, migration, and invasion. Importantly, curcumin
could upregulate the levels of miR222-3p (Tang and Cao, 2022)
and miR-34a (Toden et al., 2018) while downregulating miR-27a
(Han et al., 2020), paralogous proteins, and gamma-secretase
protein complex (Subramaniam et al., 2012), ultimately leading
FIGURE 3
An illustrative depiction of the phytochemicals could influence the interaction between the Notch and Wnt/Hedgehog signaling pathways. In the
figures provided, the term “promote”signifies that the chemical(s) could enhance the expression or activity of the specific protein. Conversely, the term
“inhibit”suggests that the compound(s) can decrease the expression of the protein or hinder its activity.
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to the inactivation of Notch1. Curcumin treatment suppressed
invasion in human osteosarcoma U2OS cells, and overexpressing
Notch1 reversed this effect (Sha et al., 2016), indicating that the
antitumor effect of curcumin is mediated through Notch1.
However, curcumin had no impact on the expression of
Notch1, but it did hinder the DNA-binding capacity of
cleaved Notch1 in human prostate DU145 cells (Yang
et al., 2017).
Silybin, derived from milk thistle seed, is mainly used in
chronic liver disease and is well known for its anti-
inflammatory, hepatoprotective, antiviral, neuroprotective, and
cardioprotective. Results regarding the efficacy of silybin as a
Notch modulator are clear. Notably, the antitumor activity of
silybin was weakened by recombinant human Jagged1,
suggesting that Jagged1 may be utilizedasananti-tumortarget
(Zhang et al., 2013;Kim et al., 2014). However, the synergistic
effect of Notch1 siRNA in vitro or DAPT (C
23
H
26
F
2
N
2
O
4
), a well-
known Notch inhibitor) in vivo, augmented the anticancer potency
of silybin, suggesting that silybin may improve the efficacy of
Notch inhibitors.
Activation of Notch signaling has been implicated in
pathogenesis of various hematologic tumors including
leukemias (Hubmann et al., 2020;Zhang et al., 2022;Skelin
et al., 2024) and lymphomas (Alderuccio and Lossos, 2022).
For example, in lymphopoiesis, the Notch1 activation may be
involved in the correct differentiation of T and B cells (Okatani
et al., 2024). In chronic lymphocytic leukaemia, Notch1 may
represent a potential druggable target (Pozzo et al., 2022),
suggesting that phytochemicals, such as EGCG and curcumin,
may be beneficial in the treatment of chronic lymphocytic
leukemia (CLL). Suppressing the activity of Notch1 or
Notch2 resulted in an enhanced response of CLL cells to
fludarabine (Del Papa et al., 2019) or venetoclax (Fiorcari
et al., 2022), respectively, indicating that natural compounds
with the ability to decrease Notch activation may be able to
overcome resistance in CLL. It is crucial to highlight that in T cell
acute lymphoblastic leukemia (T-ALL), the Notch1 activating
mutations typically occurs laterinasequenceofgenomic
damages, suggesting that Notch1-based therapies may impede
the efficacy targeted Notch1 therapy (De Bie et al., 2018).
Other agents could also inhibit Notch pathway activation by
controlling the expression of both Notch receptor and ligand, such
as emodin (Deng et al., 2015), carvacrol (Khan et al., 2019),
withaferin A (Lee et al., 2012) and quercetin (Okuhashi et al.,
2011;Peiffer et al., 2020). In summary, several natural bioactive
compounds suppress Notch activation to downregulate cancer
aggressiveness as shown in Figure 2.
3.2 Phytochemicals modulate the Notch
signaling pathway
Phytochemicals may play an anti-tumor role by modulating
other components of the Notch pathway, such as the gamma
secretase complex, the Notch transcription complex and Notch
downstream target genes.
FIGURE 4
An illustrative depiction of the phytochemicals could influence the interaction between the Notch and EGFR/PDGF/TGF-β/VEGF
signaling pathways.
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3.2.1 Gamma-secretase inhibitors
The gamma-secretase complex, which consists of presenilin,
Nicastrin, APH-1, and PEN-2 proteins, plays a crucial role in
producing the NICD. Inhibition of secretase activity has shown
significant antitumor efficacy in cancers, including lung cancer,
colorectal cancer, melanoma, and ovarian cancer (Takebe et al.,
2014). Several gamma-secretase inhibitors (GSIs) have advanced
from preclinical testing to early clinical stages and observed
antitumor activity (Mccaw et al., 2021). Unfortunately, clinical
trials had to be stopped due to serious adverse events, such as
gastrointestinal toxicities, skin disorders, and diarrhea, making the
use of inhibitors less attractive for Notch blockade to arrival
antitumor effects. Therefore, it is necessary to explore new
strategies via inhibiting gamma-secretases.
Cucurbitacin B and I, decrease the expression of Notch receptors
and ligands, repressing the activity of gamma-secretases,
suppressing NICD production, binding to Notch1, subsequently
repressing downstream genes of Notch, inhibiting tumor growth in
colon cancer (Dandawate et al., 2020;Mccaw et al., 2021). Celastrol
and triptolide both reduced the expression of Notch1 and its
downstream target proteins, hence regulating the renewal of stem
cells in triple negative breast cancer (Ramamoorthy et al., 2021).
Additionally, quercetin also decreases the expression of all five
proteins (presenilin1, presenilin2, Nicastrin, APH1, PEN2) of the
gamma-secretase complex in colorectal cancer (Li et al., 2020).
Combining quercetin with a gamma-secretase inhibitor
(Okuhashi et al., 2011) or ionizing radiation (Liao et al., 2023)
could enhance the overall anti-tumor efficacy, implying that
quercetin may be used to reduce the toxicity of GSIs.
3.2.2 Notch transcription complex inhibitors
The interaction between NICD and CSL plays a crucial role in
determining the activation or deactivation of downstream genes in
the nucleus within the Notch signaling pathway. Phytochemicals
inhibit the binding of CSL and NICD, as well as the expression of co-
activators, while boosting the expression of co-repressors, resulting
in antitumor effects. For example, silybin suppresses the Notch
signaling system by activating the apoptotic pathway, leading to the
inhibition of NICD activity in human cancer cells. Silybin reduces
the expression of intracellular domain of Notch1 (N1ICD) and RBPJ
(recombination signal-binding protein of immunoglobulin kappa J
region) activity in hepatocellular carcinoma with a CSL-dependent
manner (Zhang et al., 2013), suggesting that blocking CSL and
N1ICD interactions is a good idea in tumor therapy. Resveratrol
FIGURE 5
An illustrative depiction of the phytochemicals could influence the interaction between the Notch and PI3K/AKT/mTOR signaling pathways.
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TABLE 2 Phytochemicals on Notch and other pathways crosstalk.
Phytochemical Cancer type Cross talk Reference
EGCG Neuroblastoma Notch, AKT, VEGF Hossain et al. (2012)
Liver cancer Notch, Hedgehog, NF-κBAshry et al. (2022)
Resveratrol Cervical cancer Notch, STAT3, Wnt Zhang et al. (2014)
Ovarian cancer Notch, STAT3, Wnt Zhong et al. (2015)
T-ALL Notch, PI3K/AKT Cecchinato et al. (2007)
Ovarian cancer Notch, PTEN, AKT Kim et al. (2019)
Emodin Glioma stem cells Notch, Wnt, STAT3 Kim et al. (2015)
Glioma stem cells EGFR, Notch, Wnt, STAT3 Kim et al. (2018)
Quercetin Breast cancer Notch, PI3K/AKT Cao et al. (2018)
Breast cancer Notch, Death-associated factor 6 Takebe et al. (2014)
Histiocytic lymphoma Notch, AKT, mTOR, VEGF Chen et al. (2016b)
Curcumin Oral cancer Notch, NF-κBLiao et al. (2011)
Lung cancer Notch, HIF1α, VEGF, NF-κBLi et al. (2018)
Pancreatic cancer Notch, Hippo Zhou et al. (2016)
Triptolide Brain cancer Notch, PI3K/AKT Zhang et al. (2018)
Triptonide Gastric cancer Notch, NF-κBXiang et al. (2020)
Trichostatin A Gastric cancer Notch, NF-κBYao et al. (2012)
Genistein Breast cancer Notch, Death-associated factor 6 Peiffer et al. (2020)
Pancreatic cancer Notch, NF-κBWang et al. (2006c)
Colon cancer Notch, NF-κB, Ecadherin Zhou et al. (2017)
Pancreatic cancer Notch, NF-κBWang et al. (2006b)
Prostate cancer Notch, AKT, foxm1 Wang et al. (2011a)
Breast cancer Notch, NF-κBPan et al. (2012)
Pancreatic cancer Notch, EMT Wang et al. (2009)
Pancreatic cancer Notch, Cancer Stem Cells Wang et al. (2011b)
Silybin Breast cancer Notch, AKT, ERK Kim et al. (2014)
Berberine Gastric cancer Notch, MAPK, NF-κBWang et al. (2021)
Withaferin A T-ALL Notch, eIF2A Sanchez-Martin et al. (2017)
Colon cancer Notch, JNK Koduru et al. (2010)
Colon cancer Notch, AKT, Bcl-2 Koduru et al. (2009)
Ovarian cancer Notch, AKT, Bcl-2 Zhang et al. (2012)
Physciosporin Colorectal cancer Notch, Hedgehog Yang et al. (2019)
(-)-Gossypol Glioma stem cells Notch, Hedgehog Linder et al. (2019)
Cordycepin Breast cancer Notch, Hedgehog Liu et al. (2020)
Esc-3 Ovarian cancer Notch, Wnt Fu et al. (2017)
8,12-Dimethoxysanguinarine Breast cancer Notch, NF-κB, PI3K/AKT, Wnt Yang et al. (2023)
Okadaic Acid Breast cancer Notch, PI3K/AKT, NF-κBLi et al. (2016)
Adriamycin Or Paclitaxel Breast cancer Notch, VEGF Zhang et al. (2016)
(Continued on following page)
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alters the DNA methylation patterns in human breast cancer cells
and inhibits the cancer-causing Notch signaling by controlling the
co-activator (MAML2) transcriptional activity through epigenetic
processes (Lubecka et al., 2016). Similarly, resveratrol also inhibits
the co-activator protein ASCL1 in carcinoid tumors (Pinchot et al.,
2011). Resveratrol could enhance the recruitment of the co-
repressor (HDAC1) in human glioma cells (Yang et al., 2016).
Therefore, it is crucial to limit the activation of co-activators or
promote the activation of co-repressors in tumor cells to avoid the
development of cancer.
3.2.3 Notch downstream target genes inhibitors
The ultimate stage in Notch signaling is the transcription of
downstream target genes. The Hes and Hey protein families are the
most extensively studied targets of Notch (Guo et al., 2011).
Hes1 has been demonstrated to promote the activation of the
Notch signaling pathway, thereby promoting the proliferation
and inhibiting the apoptosis. Natural products, such as oleandrin
and cowanin, have been shown to depress the expression of Hes1/5,
thus controlling the progression of T-ALL (Arai et al., 2018a;Arai
et al., 2018b). Several phytochemicals have shown potential in
treating cancer by influencing the activity of specific genes
downstream of the Notch signaling pathway, as indicated in Table 1.
3.3 Crosstalk between Notch and other
oncogenic pathways
In human cancers, Notch signaling plays multiple roles in
different tissues, acting as both a tumor suppressor and a tumor
promoter. Activation of the Notch signaling pathway upregulates
multiple factors, which subsequently transmit bidirectional signals
among cancerous, stromal, and endothelial cells (Rizzo et al., 2008;
Yamamoto et al., 2014). Thus, it is expected that Notch signaling
intersects with multiple oncogenic signaling pathways, including
Wnt and Hedgehog signaling, growth factors like epidermal growth
factor receptor (EGFR), transforming growth factor type beta (TGF-
β), and vascular endothelial growth factor (VEGF) oncogenic
kinases, and transcription factors like Nuclear factor kappa-B
(NF-κB), PI3K (phosphatidylinositol 3-kinase)/AKT (protein
kinase B)/mTOR (mammalian target of rapamycin) (Guo et al.,
2011). The crosstalk between Notch and other oncogenic signaling
pathways is crucial for various cellular processes such as cell
proliferation, migration, invasion, metastasis, angiogenesis, and
the self-renewal of cancer stem cells, suggesting that Notch
signaling could be a promising approach for cancer therapy.
Here, we have attempted to summarize how natural products
regulate the complexity of cellular responses due to the crosstalk
between signaling pathways.
3.3.1 Interacting with developmental
signaling pathways
During embryogenesis, the Notch pathway interacts with other
developmental pathways, including Wnt and Hedgehog signaling
pathways, which operate in coordination across various types of
cancer (Guo et al., 2011). Interaction among Notch, Hedgehog, and
Wnt signaling pathways involved in regulating self-renewal,
proliferation, and differentiation, ensuring correct organogenesis
(Cerdan and Bhatia, 2010). Therefore, comprehensive knowledge of
the interactive functions of these pathways in cancer may provide
novel options for cancer treatment as shown in Figure 3.
The Wnt signaling pathway is a major developmental pathway
that determines cell proliferation, differentiation, tissue
homeostasis, and epithelial-mesenchymal interactions during
embryogenesis (Arai et al., 2018b;Manoranjan et al., 2020). The
pathway comprises two major categories: the canonical Wnt
pathway, which involves key elements such as Wnt, β-catenin,
and TCF/LEF (T-cell factor/lymphoid enhancer factor)
transcription factors, and the non-canonical Wnt-calcium
pathway, which regulates intracellular calcium levels and
cytoskeleton of cells (Vlashi et al., 2023). Therefore, the
suppression of Wnt activity has received extensive attention in
the study of cancer cells, presenting an opportunity for cancer
treatment (Olson et al., 2006;Seifert and Mlodzik, 2007).
A recent study revealed the expression of Notch ligands
inhibited the transformation of human mammary epithelial cells
induced by Wnt1, suggesting that the involvement of Notch-Wnt
communication in breast tumorigenesis (Ayyanan et al., 2006). ESC-
3, a novel cytotoxic compound, induces apoptosis via inhibiting both
Notch and Wnt/β-catenin pathways, resulting in a reduction in
tumor growth in an ovarian cancer xenograft model (Fu et al., 2017).
Emodin also hinders the Wnt pathway by reducing the level of active
β-catenin in human glioma stem cells (Kim et al., 2018).
β-catenin has been shown to activate Notch signaling by
upregulating the expression of the Notch ligand Jagged1 (Rodilla
et al., 2009;Kode et al., 2014). The efficacy of Bruceine D, which is
derived from the Chinese herb Brucea javanica (L.) Merr, to inhibit
Jagged1 was found to be synergistic following β-catenin knockdown
and reversed following overexpression (Cheng et al., 2017).
However, the levels of β-catenin remained unchanged in
Jagged1 knockdown cells (Cheng et al., 2017). It is reasonable to
assume that the tumorigenesis mediated by β-catenin could be
blocked by Notch inhibitors, such as resveratrol, 8,12-
dimethoxysanguinarine, and emodin. Conversely, the activated
Wnt signal boosts the accumulation of β-catenin in the nucleus.
Subsequently, specific target genes undergo transcriptional
activation, leading to the development of cancer (MacDonald
et al., 2009). Resveratrol inhibited the proliferation of ovarian
cancer cells by reducing the expression of β-catenin and Hes1,
TABLE 2 (Continued) Phytochemicals on Notch and other pathways crosstalk.
Phytochemical Cancer type Cross talk Reference
Nimbolide Oral cancer Notch, VEGF, MMP Kowshik et al. (2017)
Artemisinin Breast cancer Notch, VEGF, HIF1αDong et al. (2020)
Z-Ajoene Glioblastoma multiforme Notch, AKT, TGFβJung et al. (2014)
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suggesting the simultaneous suppression of the biological functions
of Notch and Wnt signaling (Zhong et al., 2015). In summary, the
regulation of β-catenin is vital in the crosstalk between Wnt and
Notch signaling.
The Hedgehog is a developmental signaling pathway that plays
an essential role in embryogenesis, tissue polarity, tissue
regeneration, and carcinogenesis (Lum and Beachy, 2004;Li
et al., 2012). The Hedgehog pathway consists of several key
components, namely, Hedgehog, Patched receptor (PTCH),
Smoothened (SMO), cytosolic intermediates like Suppressor of
Fused (SUFU) and Costal 2 (COS2), as well as inhibitors such as
Protein Kinase A (PKA) and Supernumerary Limbs (SLIMB).
Additionally, the pathway involves the transcription factors
Cubitus interruptus/Zinc Finger protein -Glioma-associated
oncogene homolog1 (Ci/Gli) (Cortes et al., 2019). Hedgehog has
three ligands, Sonic hedgehog, which is critical for neuronal
development, Indian hedgehog, which is critical for skeletal
development, and Desert hedgehog, which is critical for gonadal
development (Lee et al., 2016).
According to the literature, Hedgehog is controlled by the Notch
signaling pathway, mainly through the downstream effector of
Notch that controls the transport of Hedgehog component and
Gli levels (Xia et al., 2022). Consequently, Notch target genes play a
central role in controlling Gli gene transcription (Jacobs and Huang,
2019). Physciosporin, derived from P. granulata, decreased the
transcriptional activity of the Gli, Hes1 and CSL (Yang et al.,
2019). Additionally, it markedly reduced the formation of
spheroids in human CSC221 cells that overexpressed Gli1/2 or
Delta EN1 (a membrane-bound and S2-cleaved type of human
Notch1). Nevertheless, it did not decrease the formation of
spheroids in cells that overexpressed both Gli1/2 and Delta EN1,
proposing that physciosporin can downregulate the cancer stemness
of human colon cells by controlling the Sonic Hedgehog and Notch
signaling pathways (Yang et al., 2019). Additionally, NUMB
endocytic adaptor protein (NUMB) negatively regulates Notch
signaling by binding directly to NICD, preventing NICD from
initiating gene transcription (Flores et al., 2014). NUMB is also a
suppressor of Hedgehog signaling and specifically targets Gli1 for
ubiquitination through the action of Itch (Di Marcotullio et al.,
2006). Quercetin decreases tumor growth by inhibiting the
activation of NUMB and Hedgehog signaling pathway (Salama
et al., 2019), suggesting that NUMB has potential as a biomarker
for cancer.
Additionally, modulation of the Notch pathway by the
Hedgehog signaling pathway, mainly through inhibition of
Hedgehog downstream effectors, such as Gli proteins and Hes1
(Wall et al., 2009;Dave et al., 2011). Hedgehog signaling may induce
Hes1 expression in Hep2 cells (human), however, this effect can be
reversed by EGCG, which acts as an inhibitor for NICD (Ashry et al.,
2022). Therefore, the Hedgehog signaling pathway may have an
impact on the activity of NICD, leading to the promotion of
Hes1 production. Cordycepin, also known as 3-deoxyadenosine,
encompasses anti-inflammatory, antioxidant, and anti-cancer
activities (Tuli et al., 2014). Cordycepin suppressed the
transcriptional activity of Gli, which in turn reduced the
expression of Notch1, Notch3, Jagged1 and Hes1 in human
triple-negative breast cancer cells (MDA-MB-231 cell line) (Liu
et al., 2020). Notably, knocking out of Gli obstructed cordycepin-
induced influences on the apoptotic, EMT, and Notch pathways,
demonstrating that the regulation of Notch by cordycepin is
dependent on Gli in breast cancer (Liu et al., 2020). Evidence
indicates that the Notch ligand, Jagged 2 is induced by Hedgehog
signaling during carcinogenesis (Katoh, 2007). For example,
cyclopamine inhibits the expression of Notch1, Notch2, Notch3,
Jagged2, and DLL1 correlated with the downregulation of the sonic
hedgehog odontogenic keratocytes (Ren et al., 2012). In summary,
the regulation of processing and nuclear translocating of Gli or
NUMB is vital in the crosstalk between Hedgehog and
Notch signaling.
3.3.2 Interacting with growth factors
Numerous growth factors exert a variety of actions in cancers.
For example, the oncogene gene mutations, amplification or
overexpression of HER2/Neu (ErbB2), platelet-derived growth
factor (PDGF), EGFR and TGF-β(Wang et al., 2010). Growth
factors pathways are associated with the progression of cancers,
including proliferation, invasion, and tumor growth. Not
surprisingly, the interaction between growth factors and the
Notch signaling pathway is frequently observed in several
cancers. A diagram illustrating the interplay among different
genes of Notch, EGFR, PDGF, TGF-β, and VEGF is presented
in Figure 4.
The role of the Notch-EGFR crosstalk has been discovered in
various types of cancer, including breast (Baker et al., 2014), lung
(Konishi et al., 2007), brain (Purow et al., 2008) cancer. Recently,
researchers have continued to explain crosstalk between Notch and
EGFR to dissect the mechanisms for a better understanding of how
cancer cells apply the Notch pathway to counteract the inhibitory
effects of EGFR targeting. Notch signaling could regulate EGFR
activity via regulating the nuclear translocation of the
Notch1 intracellular domain. For example, dioscin markedly
enhanced the expression of Notch1 and Jagged1, and enhanced
the activity of gamma-secretase, leading to EGFR, VEGF, and
Notch-dependent target genes (Xu et al., 2018). Conversely, the
decrease in activity of Notch3 greatly inhibited the growth and
stimulated the programmed cell death of the human ErbB2-negative
tumor cell lines (Yamaguchi et al., 2008). On the other hand, EGFR
signaling may also regulate the Notch pathway. Emodin inhibited
the growth of human glioma stem cells through the induction of
proteasomal degradation of EGFR/EGFRvIII, which subsequently
hindered the activation of stemness signaling pathways, specifically
the Notch pathway (Kim et al., 2018).
PDGF, which is produced in carcinomas, primarily affects the
non-epithelial tumor stroma, and stimulates angiogenesis
(Papadopoulos and Lennartsson, 2018;Li et al., 2022). The
available literature indicates that the PDGF receptor is a novel
Notch target gene (Wu et al., 2021;Vimalraj, 2022). PDGF-D is
a vital factor in the aggressiveness of breast tumors, which is causally
associated with the activation of Notch1 (Ahmad et al., 2011).
Furthermore, the downregulation of PDGF-D results in the
inactivation of the Notch1/Twist1 axis, potentially reversing
epithelial-mesenchymal transition and inhibiting the progression
of colorectal cancer (Chen J. H. et al., 2017). Unfortunately, there are
currently no documented findings on the identification of natural
compounds that modulate the communication between PDGF-D
and Notch signaling in cancer. Nevertheless, studies have
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demonstrated that lycopene, a naturally occurring carotenoid found
in tomatoes, can effectively suppress the growth of certain cancer
cells (Wu et al., 2007). Additionally, it has been observed that
lycopene directly binds to PDGF-BB, indicating that its ability to
inhibit PDGF may play a role in its anti-tumor properties (Wu
et al., 2007).
TGF-β, a multifunctional cytokine, plays a key role in the cancer
pathogenesis involved in cell growth, differentiation, adhesion, and
apoptosis (Gu and Feng, 2018). The diverse roles of TGF-βin cancer
are influenced by its interactions with several signaling pathways,
such as Hedgehog, Wnt, PI3K/AKT, Notch, and RAS-ERK
(extracellular signal-regulated kinase). Heyl, a downstream
effector of the Notch signaling pathway, inhibits the action of
TGF-βby interacting with activated Smads (Han et al., 2014),
providing novel strategies and perspectives for treating breast
cancer. Moreover, Z-ajoene, which is derived from garlic, has
demonstrated a variety of biological activities, such as anti-
proliferative, antioxidant, and antitumor (Naznin et al., 2010;
Jung et al., 2014). Z-ajoene reduced levels of Notch target genes,
and TGF-βis the key mediator of the Z-ajoene effect on glioblastoma
multiforme cancer stem cells (Jung et al., 2014). Furthermore, the
TGF-βpathway is critical in maintaining stem cell properties in
cancer cells (Gurska et al., 2019).
VEGF, a significant angiogenic factor in both normal and
abnormal blood vessel formation, is frequently overexpressed in
human tumors, leading to the malignancy progression across
several tumors and low survival rates of patients (Yang and
Cao, 2022;Ghalehbandi et al., 2023). Both the VEGF and
Notch signaling pathways have been indicated to be key
regulators in developmental and pathological angiogenesis,
including in cancers (Li and Harris, 2009;Blanco and Gerhardt,
2013). VEGF modulates the expression of Notch signaling
components, specifically by upregulating the expression of
DLL4 and Notch receptors, which then promotes the activation
of Notch signaling (Patel et al., 2005;Hainaud et al., 2006;Ridgway
et al., 2006). The combination of survivin shRNA and EGCG
markedly decreased angiogenic (VEGF and b-FGF) factors and
then inhibited Notch1 expression in neuroblastoma, reasonably
inferring that blocking VEGF may enhance the sensitivity of
tumors to anti-Notch therapy (Hossain et al., 2012). Nimbolide,
obtained from neem leaves and flowers, inhibited the activity of
MMP and blocked Notch and VEGF signaling pathways by
targeting miR-21 (Kowshik et al., 2017). Curcumin also could
decrease the tumor weight and size via downregulating the
expression of Notch, HIF-1, VEGF, and NF-κB(Li et al., 2018).
Although VEGF induces Notch signaling, expression of VEGF
ligands and receptors appear to be also regulated by Notch signaling.
For example, quercetin decreased Notch1 expression and then
suppressed the expression of angiogenesis-associated proteins
hypoxia-inducible factor alpha (HIF1α) and VEGF in histiocytic
lymphoma (Chen X. et al., 2016). In breast cancer, artemisinin, an
anti-malarial active compound derived from the sweet wormwood
plant, downregulates the expression of Notch1, DLL4, and Jagged1,
reducing VEGF and HIF-1αlevels (Dong et al., 2020). Providing a
feedback mechanism, another study has found that the inhibition of
Notch signaling or the suppression of Notch4/DLL3 leads to a
decrease in endothelial markers and the function of tumor-
derived endothelial cells following treatment with adriamycin or
paclitaxel via VEGF receptor (Zhang et al., 2016). These data provide
new prospects for the antiangiogenic therapy of human cancer.
3.3.3 Interacting with oncogenic kinases and
transcription factors
The NF-κB pathway comprises two major categories: the
canonical IKK pathway which is dependent on IκB proteins
through an individual kinase signalosome multiprotein complex,
while the non-canonical pathway is triggered by ligands like CD40L
and lymphotoxin (Dolcet et al., 2005). NF-κB activation is evident in
several cancer types and is also associated with the initiation of
tumor angiogenesis (Sarkar and Li, 2008;Prasad et al., 2010). Many
publications have described how natural products can regulate the
NF-κB pathway through Notch, and vice versa, by various context-
dependent mechanisms (Rajasinghe and Gupta, 2017;Ferrandino
et al., 2018;Hossain et al., 2018;Grazioli et al., 2020). Firstly,
evidence shows that Notch serves as a crucial regulator of NF-κB
at an upstream level and regulates NF-κB pathway members (Mishra
et al., 2021). RBPJ functions as a potent transcriptional inhibitor of
p100/p52, but its inhibitory effects can be reversed by activated
Notch1, implying that p100/p52 is regulated by Notch signaling and
can be considered a target gene of Notch (Oswald et al., 1998).
Triptonide, a natural small molecule extracted from Tripterygium
wilfordii Hook F,efficiently inhibits tumor growth and metastasis
via decreasing the levels of Notch1 downstream proteins RBPJ, IKK
alpha, IKK beta, reducing p52 phosphorylation (Xiang et al., 2020).
Notch1 co-localizes with IKK at NF-κB-responsive promoter sites,
enhancing IκB kinase activity and thereby maintaining NF-κB
activity (Song et al., 2008). And inactivation of NF-κB DNA-
binding activity by genistein was partly impeded by the
overexpression of Notch1 in cDNA-transfected BxPC-3 cells
(Wang et al., 2006b). Genistein also inhibits tumor growth in
pancreatic (Wang et al., 2006b), colon (Zhou et al., 2017), and
triple-negative breast cancers (Pan et al., 2012) by inhibiting NF-κB
activity via the Notch1 pathway. Curcumin downregulates
Notch1 expression, blocks Notch1 activation, and inactivates NF-
κB DNA-binding activity (Gupta et al., 2017).
Secondly, NF-κB subunits regulate the transcription of Notch
family members. This finding is supported by Wang et al. (2001)
which revealed that the N-terminal region of Notch1 NICD
specifically associated with the p50 subunit and prevented it
from binding to DNA in NTera-2 cells. Lastly, not all cancer
cells exhibit a close association between the activation of the NF-
κB pathway and the Notch pathway. For example, trichostatin A,
derived from streptomyces, caused gastric cancer cells growth
arrest and apoptosis by controlling NF-κBandp21
WAF1/CIP1
,
without the involvement of the Notch pathway (Yao et al.,
2012). Another is berberine, which inhibits the Notch, MAPK,
and NF-κB signaling pathways by regulating circRNA (Wang
et al., 2021). Sentrin-specific protease-2 (SENP2) could act as a
tumor suppressor in CLL cells via suppressing the Notch and NF-
κBsignalingpathways(Chen et al., 2019). Nevertheless, there is
currently no natural products that regulates the activity of
SENP2 in the therapy of hematologic tumors. Betanidin,
obtained from red beets, could directly bind to SENP2 and
may be used as a treatment for CLL cells (Taghvaei et al.,
2022). These results suggest novel understandings of the
crosstalk between Notch and NF-κB.
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Thirdly, in cancer biology, as mentioned above, the Notch and
NF-κB pathways promote cancer progression by regulating each
other’s activities. The Notch-NF-κB network are typically involved
in regulation of inflammatory disease (Liubomirski and Ben-Baruch,
2020). Nevertheless, the growth of tumor and its reaction to
treatment are controlled by inflammation, which can either
stimulate or inhibit the advancement of tumors, potentially
leading to contrasting impacts on the effectiveness of therapy
(Zhao et al., 2021). Thus, an optimal approach is evidently
necessary to address the interaction between the Notch and NF-
κB pathways to devise innovative treatments for the treatment of
inflammatory illnesses. Utilizing small molecule inhibitors that
specifically target NF-κB, which is the downstream of Notch, and
not necessarily the Notch blockers, may serve as an effective
therapeutic method to disturb the interplay and reduce
inflammation. Many of the transformational events in cancers are
the consequence of amplified signaling within the PI3K/AKT
pathway (Hynes and Stoelzle, 2009;Dillon and Muller, 2010).
The PI3K/AKT/mTOR pathway is crucial in regulating multiple
cellular activities, such as growth, proliferation, metabolism,
motility, migration, invasion, angiogenesis, survival, and
autophagy (McAuliffe et al., 2010). And mTOR is a crucial
protein kinase that frequently acts as a downstream effector of
the PI3K/AKT signaling pathway in various cancer cell types
(Carino et al., 2008). mTOR can also phosphorylate AKT
(Saxton and Sabatini, 2017). The PI3K/AKT pathway plays a
crucial role in promoting EMT during the development of cancer
(Sabbah et al., 2008). Crosstalk between PI3K/AKT and Notch
pathways has been described in prostate cancer (Wang et al.,
2011a), T-ALL (Cecchinato et al., 2007), colon cancer (Koduru
et al., 2009), brain cancer (Xiang et al., 2020) as well as breast cancer
(Cao et al., 2018). Kim et al. (2014) reported that overexpression of
Notch1 reversed the suppression of ERK and AKT phosphorylation
caused by silybin. Additional reports also demonstrated that inhibit
Notch1 activation by Withaferin A, which resulted in the
downregulation of pAKT and Bcl-2 expression (Koduru et al.,
2009). Kim et al. (2019) found that induces cell death through
ROS-dependent downregulation of Notch1, which negatively
controlled the expression of PTEN (Phosphatase and tensin
homolog) and AKT signaling. Curcumin, an inhibitor of Notch,
increases PTEN expression and decreases AKT phosphorylation in
chronic myelogenous leukemia (Chen et al., 2015). Notch inhibits
the dephosphorylation of PI3K/AKT by blocking the activation of
PP2A (Protein phosphatase 2) and PTEN, leading to the promotion
of cancer’s malignant progression (Li et al., 2016). The
downregulation of Notch1 activity by okadaic acid, a PP2A
inhibitor, decreases low cell invasion in breast cancer via
inactivating the AKT, mTOR, and NF-κB signaling pathways (Li
et al., 2016). Moreover, through the downregulation of Notch1/
PTEN/AKT signaling, resveratrol causes the demise of ovarian
cancer cells (Kim et al., 2019).
AKT serves as a regulator of Notch signaling. On the one hand,
Notch1 downregulation is linked to AKT in the induction of cell
growth inhibition and death by genistein in prostate cancer (Wang
et al., 2011a). On the other hand, resveratrol suppresses Notch
signaling in T-ALL cells, resulting in a reduction in AKT activity and
modulating the operation of interacting signaling systems
(Cecchinato et al., 2007). Therefore, strategies aimed at
modulation of Notch-PI3K/AKT/mTOR signaling have the
potential to enable therapeutic intervention. A schematic diagram
depicting the interactions among the Notch, PI3K/AKT/mTOR, and
NF-κB as shown in Figure 5.
3.3.4 Others
In addition, many connections between the Notch pathway and
other signaling pathways such as DXX6, ERK, and Hippo signaling
may also contribute to the complexity of tumor angiogenesis and the
challenge of Notch as a promising target.
The regulation of Notch-related pathways is also irregular with
bioactive natural compounds. Regarding breast cancer, the
repression of Notch4 protein and its downstream targets by
quercetin appears to be independent of death-associated factor 6,
whereas genistein is known to repress Notch signaling solely
through the presence of death-associated factor 6 (Peiffer et al.,
2020). Hippo signaling compounds could regulate Notch pathways.
In pancreatic cancer, curcumin reduces the expression of Yes-
associated protein and transcriptional coactivator with PDZ-
binding motif, two paralogous proteins belonging to the Hippo
signaling pathway, which results in the subsequent suppression of
Notch1 expression (Zhou et al., 2016). Kim et al. (2014) reported
that overexpression of Notch1 prevented silybin-induced inhibition
of ERK and AKT phosphorylation. We summarized the cross talk
between Notch and other signaling pathways in different cancers
with phytochemicals in Table 2.
4 Conclusion and perspective
Recently, there has been an increasing attraction in developing
clinically potent antagonists of the Notch signaling pathway.
Antitumor activity has been observed from gamma-secretase
inhibitors and monoclonal antibodies administered as single
agents in early clinical trials (Takebe et al., 2014). However,
achieving Notch-directed therapeutics remains an unattained
goal. Currently, no compounds, including chemicals and
phytochemicals, that interfere with Notch signaling have been
approved for using in cancer patients. Additionally, it is
imperative to develop competent tools and precise research
techniques to understand the heterogeneity and complexity of the
Notch signaling pathway in cancer.
The research summarized above has shown that Notch
activation and interactions with other oncogenic pathways
strongly promote the malignant phenotype, in vitro and in vivo.
To some extent, natural bioactive compounds can inhibit Notch
activation and cross talk with other oncogenic pathways without any
significant side effects. Further research is needed to elucidate the
significance and mechanisms of Notch pathway activation in cancer,
and to determine whether Notch-based therapies in combination
with chemotherapy or other biologically targeted drugs could
enhance clinical anti-tumor efficacy. And whether there is a need
to discover more sophisticated and potent Notch inhibitors.
Targeting Notch is critical because the pathway communicates
extensively with other signaling pathways, such as Wnt,
Hedgehog signaling, growth factors such as EGFR, TGF-βand
VEGF, oncogenic kinases, and transcription factors such as NF-
κB, PI3K/AKT/mTOR. Therefore, the multi-target properties of
Frontiers in Pharmacology frontiersin.org12
Yang et al. 10.3389/fphar.2024.1412669

natural products and drugs designed to inhibit Notch oncogenic
signaling crosstalk may have potential for therapeutic intervention.
In addition, an important future direction for Notch targeting is
to ascertain the functions of the Notch pathway in various cancer
cells and to develop a biomarker for cancer and stromal sensitivity.
Author contributions
JY: Conceptualization, Writing–original draft, Writing–review
and editing. QS: Writing–review and editing. XL: Writing–review
and editing. YY: Methodology, Writing–review and editing. RR:
Funding acquisition, Investigation, Writing–review and editing. PY:
Writing–review and editing. YX: Conceptualization, Supervision,
Writing–review and editing.
Funding
The authors declare that financial support was received for the
research, authorship, and/or publication of this article. This work
was supported by National Natural Science Foundation of China
(No. 82274397); Natural Science Foundation of Shandong Province
(No. ZR2021LZY012); Opening project of shanghai key laboratory
of compound Chinese medicines (No. 21DZ2270500).
Acknowledgments
Figures in this review were created by BioRender.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations,
or those of the publisher, the editors and the reviewers. Any product
that may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.
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