Cytotoxicity of Salvigenin from Asterohyptis stellulata in Combination with Clinical Drugs Against Colorectal Cancer

Abstract

Flavonoids, abundant polyphenols in various plant-based sources, exhibit diverse health benefits, particularly in cancer prevention and treatment, attributed to their ability to mitigate oxidative stress. Salvigenin, a naturally occurring trimethoxylated flavone from the aerial parts of Asterohyptis stellulata Epling, Lamiaceae, has gained attention for its potential synergistic effects with conventional anticancer drugs. The present study describes the evaluation of salvigenin, a non-cytotoxic flavone (IC 50 > 50 µM), in combination assays with clinical drugs in human colon carcinoma cells (HCT-116), which revealed significant differences as compared to single salvigenin treatments. Remarkably, IC 50 values of 1.8 and 1.5 µM for the combination of salvigenin with sublethal concentrations of podophyllotoxin and colchicine (0.008 µM), respectively, were observed, indicating an enhancement in its cytotoxicity effectiveness. These findings emphasize the potential of salvigenin-based combination therapies as a promising strategy for colorectal cancer treatment, offering improved therapeutic results with reduced clinical drug doses and associated side effects.
Graphical Abstract

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Revista Brasileira de Farmacognosia
https://doi.org/10.1007/s43450-024-00549-0
SHORT COMMUNICATION
Cytotoxicity ofSalvigenin fromAsterohyptis stellulata inCombination
withClinical Drugs Against Colorectal Cancer
BriandAndréRojas‑Castaño1 · AdrianaC.Hernández‑Rojas1 · RogelioPereda‑Miranda1 ·
MabelFragoso‑Serrano1
Received: 4 March 2024 / Accepted: 4 April 2024
© The Author(s) 2024
Abstract
Flavonoids, abundant polyphenols in various plant-based sources, exhibit diverse health benefits, particularly in cancer pre-
vention and treatment, attributed to their ability to mitigate oxidative stress. Salvigenin, a naturally occurring trimethoxylated
flavone from the aerial parts of Asterohyptis stellulata Epling, Lamiaceae, has gained attention for its potential synergistic
effects with conventional anticancer drugs. The present study describes the evaluation of salvigenin, a non-cytotoxic fla-
vone (IC50 > 50 µM), in combination assays with clinical drugs in human colon carcinoma cells (HCT-116), which revealed
significant differences as compared to single salvigenin treatments. Remarkably, IC50 values of 1.8 and 1.5 µM for the
combination of salvigenin with sublethal concentrations of podophyllotoxin and colchicine (0.008µM), respectively, were
observed, indicating an enhancement in its cytotoxicity effectiveness. These findings emphasize the potential of salvigenin-
based combination therapies as a promising strategy for colorectal cancer treatment, offering improved therapeutic results
with reduced clinical drug doses and associated side effects.
Keywords Antioxidants· Antiproliferative potential· Chemotherapeutic drugs· Cytotoxicity· Natural adjuvants·
Polyphenols
Introduction
Colorectal cancer, also known as bowel cancer, is the third
most common diagnosis making up about 10% of all type
of cancers, and second lethal malignancy due to old age
with both strong environmental associations to lifestyle and
genetic risk factors (Eom etal. 2021). Surgical resection for
localized early stages is commonly executed. In addition,
standard treatments include chemotherapy with anticancer
drugs and target therapy (monoclonal antibodies as well as
angiogenesis and protein kinase inhibitors). Recently, adju-
vant therapy with antioxidant natural products, such as flavo-
noids, has proven to increase the chance of cure on high-risk
patients with colon cancer (Namdeo etal. 2020).
Flavonoids are secondary metabolites with widespread
presence in different herbal medicinal matrices, vegetables,
and fruits, as essential nutraceuticals, where they exert pro-
tection to plants against UV radiation, microbe infections,
and oxidative stress. In addition, comprehensive research
has showed the valuable roles of flavonoids in human health,
including anticancer, antihypertensive, or antithrombotic
effects. Especially, their anticancer potential has been docu-
mented and commonly attributed to their ability to regulate
oxidative stress as therapeutic agents via suppressing reac-
tive oxygen species (Slika etal. 2022).
In the viewpoint of colorectal cancer treatments, all fla-
vonoids could have effectiveness, as antiproliferative agents,
via diverse mechanisms of action, which include carcinogen
inactivation, cell cycle arrest by induction and differentiation
of apoptosis, inhibition of angiogenesis, acting as chemosen-
sitizers for reversal of multidrug resistance in cancer cells,
or reducing the oxidative stress caused by pharmacological
drug treatments (Kapoor etal. 2021).
Salvigenin (1) or 5-hydroxy-4′,6,7-trimethoxyflavone
(C18H16O6) is naturally occurring in various plant fami-
lies, mainly including Lamiaceae (Ayatollahi etal. 2009)
and Asteraceae (Noori etal. 2013; Serino etal. 2021). This
flavone has demonstrated effective cytotoxicity through
* Mabel Fragoso-Serrano
mabelfragoso@unam.mx
1 Departamento de Farmacia, Facultad de Química,
Universidad Nacional Autónoma de México, Ciudad
Universitaria, 04510MexicoCity, Mexico

Revista Brasileira de Farmacognosia
induction of apoptosis in human cancer cell, such as colon
adenocarcinoma (HT-29), breast adenocarcinoma (MCF-7),
glioblastoma (SF-268), and human kidney epithelial cells
(Sarvestani and Sepehri 2016). Salvigenin reduces tumor
cell growth in vivo and enhanced cellular immune responses
(Noori etal. 2013). Recently, it has been shown that co-
administration of 1 with doxorubicin induced apoptotic
effects via mitochondrial disfunction in colorectal HT-29
and SW948 cancer cell lines (Sarvestani etal. 2018). There-
fore, the present investigation evaluated the combinatory
effect of salvigenin from Asterohyptis stellulata Epling,
Lamiaceae, with the potential to induce apoptosis and cell
cycle arrest and synergize the activity of therapeutical anti-
tumor drugs to offer an improvement for the treatment of
human colon carcinoma cells (HCT-116) by drug dose
reduction and the concomitant decreasing of side effects
(Araújo etal. 2011; Patel 2021).
Material andMethods
Aerial parts of Asterohyptis stellulata Epling, Lamiaceae
(Fig.S1) were collected in the locality of Otates, Municipal-
ity of Actopan, State of Veracruz, Mexico (Lat, 19.532963
N; Long, − 96.717062 W; Alt, 488 masl) on January 14,
2023, by A.C. Hernández-Rojas and M. Kilian. Samples
of the species were identified by Dr. Hernández-Rojas and
deposited at the Herbarium XAL with duplicates (accession
number 152242) of the Instituto de Ecology A.C. (INECOL,
Xalapa, Veracruz). The plant material (1.4kg) was extracted
by maceration 4 × 24h each at room temperature with petro-
leum ether. A yellowish-white solid precipitated (250mg)
from the petroleum ether solution (Fig.S3). This solid was
washed with MeOH (3 ×) to remove polar impurities and
pigments, as the solid was insoluble in this protic solvent.
Subsequently, the clean solid was subjected to recrystalliza-
tion. Initially, it was dissolved in CH2Cl2 (3.5ml) and, to
facilitate a controlled crystallization, a few drops of petro-
leum ether (0.5ml) were added. The solution was filtered
and allowed to cool at room temperature, resulting in the
formation of pale-yellow crystals (125mg). Further recrys-
tallization (50mg) with CH2Cl2-petroleum ether (9:1)
yielded 40mg of pure salvigenin (1). This compound was
identified by comparison of its physical constants (Morad-
khani etal. 2012) and spectroscopic properties, such as 1H
and 13C NMR (Fig.S4), as well as HRMS (Fig.S5), with
published values (Ayatollahi etal. 2009).
Salvigenin (1): pale yellow crystals, mp 185–187°; 1H
NMR (600MHz, CDCl3) δ 12.77 (s, 1H, C5-OH), 7.82
(d, J = 9.0Hz, 2H, H-2′ and H-6′), 7.00 (d, J = 9.0Hz, 2H,
H-3′ and H-5′), 6.56 (s, 1H, H-3), 6.53 (s, 1H, H-8), 3.96
(s, 3H, C-7,-OMe), 3.92 (s, 3H,C-6,-OMe), 3.88 (s, 3H,
C-4′,-OMe); 13C NMR (CDCl3, 150MHz) δ 182.8 (C-4),
164.1 (C-2), 162.7 (C-4′), 158.8 (C-7), 153.3 (C-4a), 153.2
(C-8), 132.8 (C-6), 128.1 (C-3′, C-5′), 123.7 (C-1′), 114.6
(C-2′,C- 6′), 106.3 (C-5), 104.2 (C-3), 90.7 (C-8a), 61.0
(C-7, -OMe), 56.4 (C-6, -OMe), 55.7 (C-4′, -OMe). HR
APCI-TOF–MS m/z 329.1016 [M + H]+ (calcd. for C18H17O6
m/z 329.1019, δ= − 0.9 ppm), 314.0778 [M + H– CH3]+,
296.0664 [314– H2O]+, 268.0723 [296– CO]+.
Cytotoxicity and drug combination assays were con-
ducted with salvigenin (1) and using human colon carci-
noma cells (HCT-116). The cells were cultured in fetal
bovine serum medium, 100 U/ml penicillin G, and 100μg/
ml streptomycin at 37°C under 5% CO2 atmosphere and
100% relative humidity. Cells were used when they reached
60–70% confluence and were maintained in the logarithmic
growth phase. A suspension of 104 cells was used. From
this suspension, 190µl was seeded in 96-well plates and
10µl of different concentrations of test samples in DMSO
(10%) was added and the experiments were performed in
triplicate. The microplates were incubated for 72h, and the
sulforhodamine B (SRB) method was used. Cell density was
determined using an ELISA plate reader at 564nm. For the
combination assays, cells were exposed to test compounds
for 72h. The clinical drugs vinblastine (0.003µM), podo-
phyllotoxin (0.008µM), colchicine (0.008µM), ellipticine
(1.6µM), and doxorubicin (0.7µM) were individually tested
at sublethal concentrations in combination with salvigenin
(1), which was evaluated at final concentrations of 50, 30,
20, 10, 3, and 1µM, followed by SRB method. The growth
percentage was plotted along with their respective concen-
trations using Prisma v. 8.01 to obtain the IC50 (Moreno-
Velasco etal. 2024).
Results andDiscussion
The name for the genus Asterohpytis was derived from the
Greek Aster (star) due to the calyx found at the base of the
flowers with a stellar-like lobes, a character used to distin-
guish the genus which, first proposed by Epling, was segre-
gated from the large genus Hyptis. It belongs to the subtribe

Revista Brasileira de Farmacognosia
Hyptidinae that encompasses approximately 19 genera and
around 400 species distributed mainly in tropical America
(Pastore etal. 2021). Asterohyptis is also distinguished from
Hyptis by its numerous small flowers (reduced white corol-
las) which are arranged in axillary elongate clusters or spike-
like inflorescences, composed of few-flowered verticillasters,
in axils of reduced bracts, corolla lobes not thickened, and
non-explosive anthers (Figs.S1and S2). The calyx lobes
are subulate or filamentous, often rigid, spreading, corollas
weakly 2-lipped with 5 subequal lobes, with the thickened
hinge at base of anterior corolla lip (Turner 2011).
Asterohyptis stellulata is a shrub that grows primarily in
the seasonally dry tropical biome, frequently in open habi-
tats (Turner 2011). Biogeographical data indicates that its
native range is mainly in Mexico, as an endemic species, but
its presence is also reported in Central America and Brazil
(accessions: IPNI 2024 and GBIF 2024, respectively). In
Mexico, its presence in the Pacific slope is remarkable while
in the Gulf of Mexico is rare, occurring only in the state of
Veracruz (Turner 2011) where populations are not frequently
observed, not only because of its restricted natural distribu-
tion, but also because of the intensive agricultural and live-
stock activities in the region. The population studied here
consists of few individuals (woody, 5m high, no recruit-
ment observed), and collected on an abandoned property for
almost 15years (Fig.S1A).
From the ethnobotanical perspective, there are few
reports of A. stellulata, mainly as a healing plant. Maximino
Martínez (1989), on his impressive book—first published
in 1939—about the medicinal plants of Mexico, reported
the common names and usages known so far, registered
as “Cordón de San Antonio,” “hierba del becerro” o “bar-
retero” in the state of Guerrero, and “hierba del ahito” o
“té maravilloso” (wondrous tea) in Michoacán. Decoctions
of the leaves are used for wound healing;thus, the crude
drug isknown as “hierba del golpe” (herb to heal bruises)
in Morelos (Monroy-Ortíz etal. 2013) where it is alsoused
against indigestion and stomach spasms. The activity of A.
stellulata was evaluated by Álvarez-Santos etal. (2022)
finding antibacterial and antioxidant activity of its phenolic
content and promoting closure speed of wounds confirm-
ing the traditional use of A. stellulata for wound healing.
No common name or usage was recorded in the collection
locality for A. stellulata even though other members of the
subtribeHyptidinae have been used there traditionally for
generations, e.g., “hierba del burro”; Mesosphaerum sua-
veolens (L.) Kuntze is commonly used macerated in alcohol
mainly to treat gastrointestinal disorders, frequently culti-
vated in local gardens.
Combinatory antiprolifetarive and palliative effects have
been reported for flavonoids on clinic symptoms associated
with all therapeutical antitumor drugs, such as nausea, vom-
iting, diarrhea, mucositis, kidney problems, and peripherial
neuropathic pain (Uebel etal. 2019; Fernández etal. 2021).
In addition, the protective effect of flavonoids in radiother-
apy has also been demonstrated (Wang etal. 2020; Wu etal.
2023). Therefore, these active redox antioxidant polyphenols
could provide a double effect in drug combination or co-
administration of active agents, potentiating the antitumor
effect of clinical chemotherapeutic agents and radiotherapy
by controlling oxidative stress and, concurrently, preventing
important side effects due to their anti-inflammatory poten-
tial and for maintaining the genomic stability (prevention of
DNA damage) of normal fast-growing cells, like those in the
skin and digestive tract of cancer patients (Slika etal. 2022).
Consequently, for drug combination assays with salvi-
genin (1), the cytotoxicity of five clinical antitumor drugs in
human colon carcinoma cells HCT-116 was initially evalu-
ated (Fig.1). Table1 summarizes the half maximal inhibitory
concentration (IC50) values for the tested clinical drugs in
this cell line as well as the cell viability in their combination
assays with salvigenin by using the sulforhodamine B colori-
metric assay (Moreno-Velasco etal. 2024). Vinblastine had
a IC50 of 0.23 µM, podophyllotoxin 0.97 µM, colchicine 0.2
µM, ellipticine 9 µM, and doxorubicin 3.2 µM. Salvigenin
Fig. 1 Cell viability assays in human colon carcinoma cells (HCT-
116 line) with clinical antitumoral drugs
Table 1 Cytotoxicity (IC50) for clinical drugs and combination assays
with salvigenin (1) in human colon carcinoma cells (HCT-116 line)
by using the sulforhodamine B colorimetric assay
IC50 for salvigenin alone: > 50 µM; Combination assay: vinblas-
tine 0.003 µM, colchicine or podophyllotoxin 0.008µM, ellipticine
1.6µM, doxorubicin 0.7µM, and 1–50μM salvigenin for IC50 calcu-
lations (tested compound 1 + antitumor drug)
IC50 (μM)
Drug Salvigenin + drug
Colchicine 0.20 ± 0.02 1.5 ± 0.1
Podophyllotoxin 0.97 ± 0.06 1.8 ± 0.2
Vinblastine 0.23 ± 0.02 4.7 ± 1.3
Ellipticine 9.00 ± 0.05 5.9 ± 0.7
Doxorubicine 3.20 ± 0.13 17.3 ± 1.7

Revista Brasileira de Farmacognosia
showed no effects as a cytotoxic agent with a IC50 > 50μM
(Fig.2), in agreement with previous results where flavonoids
displayed low cytotoxicity in the HCT-116 line (Fernández
etal. 2021). This is an important requirement for the execu-
tion of the proposed combination assays with clinical drugs
to identify any potentiation effect of salvigenin with the com-
bined antitumor drugs in this HCT-116 line (Moreno-Velasco
etal. 2024). Therefore, the potentiation of the cytotoxicity
with the individual isolated compound 1 at the concentra-
tions of 50, 30, 20, 10, 5, 3, and 1μM was investigated with
sublethal doses of the tested clinical drugs (0.003 µM for
vinblastine, 0.008 µM for colchicine and podophyllotoxin,
1.6 µM for ellipticine, and 0.7 µM for doxorubicin).
A dose–response curve was obtained and the IC50 value
for the combination of salvigenin and the five tested antitu-
mor drugs was calculated (Fig.2). The combination assays
in HCT-116 cell line exhibited statistically important dif-
ferences with all tested drugs with respect to single treat-
ment of salvigenin (Fig.2). The number of surviving cells
was compared with an untreated control of salvigenin after
48h. A significant enhancement for salvigenin cytotoxicity
even at 3μM was observed with all drugs. For instance,
while podophyllotoxin at 0.003 µM produced no cell death,
supplementation with 3 and 30μM of salvigenin induced
an inhibition of cell viability to 10% and 20%, respectively
(Fig.S6). The best IC50 values for salvigenin with the tested
samples were 1.8 µM for the combination with podophyl-
lotoxin and 1.5 µM for the combination of with colchicine,
in contrast to the IC50 value of 4.7 µM for the combination
with vinblastine, 5.9 µM for the combination with ellipti-
cine, and 17.3 µM for the combination with doxorubicin.
The combinations of a subinhibitory dose of podophyllo-
toxin and colchicine increased the cell death about 30-folds
as compared to salvigenin alone. Similar results were previ-
ously described for the combination of apigenin (IC50 0.98
µM) and luteolin (IC50 0.99 µM) in combination with the
clinical drug 5-fluorouracil in HTC-116 colon carcinoma
cells (Fernández etal. 2021). The antiproliferative effect of
salvigenin-induced cell death in combination assays, due
to reactive oxygen species scavenging, could be associated
with the potentiation of apoptotic pathways as previously
described for flavonoids (Namdeo etal. 2020; Kapoor etal.
2021; Sarvestani etal. 2018; Patel 2021).
In conclusion, a combination of salvigenin (1) with an
antitumoral drug induces antiproliferation activity and
enhances cell death on colorectal cancer cells which might
allow a reduction of malignant side effects by dose lowering
of therapeutic drugs.
Supplementary Information The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s43450- 024- 00549-0.
Acknowledgements Adriana C. Hernández-Rojas was a postdoctoral
fellow (PAPIIT: IN212813), Programa de Becas Posdoctorales (POS-
DOC), Dirección General de Asuntos del Personal Académico, UNAM.
Author Contributions BARC: isolation, chemical analysis, cytotoxicity
assays, and writing of the first draft; ACHR: collection of plant mate-
rial, botanical identification, preparation of dried herbarium specimens,
and field ethnobotanical observations and notes on the plant material;
MFS: cytotoxicity assays; RPM and MFS: conceptualization of the
project and technical supervision. All authors have read the final manu-
script and approved its submission. This article was taken from the M.
Sc. thesis of Briand André Rojas-Castaño, Programa de Maestría y
Doctorado en Ciencias Químicas, UNAM.
Funding Financial support was provided by Dirección General de
Asuntos del Personal Académico, UNAM (DGAPA: IN202123).
Data Availability Data and material will be made available on request.
Declarations
Ethics Approval Not applicable.
Competing Interests The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
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permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
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