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CTMJ | traditionalmedicinejournals.com Chinese Traditional Medicine Journal | 2023 | Vol 6 | Issue 3 

 

    ISSN : 2693 6356 

2023 | Vol 6 | Issue 6 

 

 
 

 
 
 
 
 
 

A new horizon for the steroidal alkaloid cyclovirobuxine D 

(huangyangning) and analogues: Anticancer activities and mechanism 

of action 

Christian a, *, Jihong b 

a Oncowitan, Lille (Wasquehal), 59290, France 
b Medical School, Kunming University of Science and Technology, Kunming, 650500, China 

 
 

 

 

 

Introduction 
 

An evergreen shrub endemic to Southern China, 

Buxus microphylla var. Sinica (Chinese Boxwood, 

Buxaceae, 小収黄杨) is beneficial for absorbing 

and containing air pollutants, such as tiny 

particulate matter PM2.5.1 The Aside from being a 

popular decorative tree, it has a long history of 

usage in traditional Chinese medicine (Huang 

Yang Mu Ye, xiaoyehuangyang) for the treatment 

of cardiovascular diseases in China.2 The buxmi-

crophyllines and other cycloartane type alkaloids 

are present in B. microphylla extracts, among other 

triterpenoid alkaloids.Three to five different cancer 

cell lines have been shown to be significantly 

cytotoxic by buxmicrophylline B and R.four, six 

Other chemicals have been extracted from the 

plant's roots and leaves.as well as 

cyclomicrobuxinine and buxbodine B found in 

plants. However, cyclovirobuxine D (Cvb-D, Fig. 

1), the principal alkaloid derived from B. 

microphylla, has been in use for over 30 years in 

 
 

   Abstract— For a long time, huangyangning was a standard therapy for cardiovascular and cerebrovascular 

illnesses in China. Its active ingredient is the steroidal alkaloid cyclovirobuxine D (Cvb-D). It is on the Chinese 

pharmacopeia list. This little-known alkaloid has recently come to light as having anticancer effects in both 

laboratory and animal models. The medicine inhibits phosphorylation of proteins such as EGFR, ERK, Akt, 

and mTOR, among others, by activating several signaling pathways. Consequently, Cvb-D has anti-metastatic 

and anti-proliferative effects. Cvb-D and similar natural compounds derived from Buxus species have been 

studied for their potential anticancer properties in this review. Current knowledge on the molecular targets of 

Cvb-D is limited; nevertheless, theories have been developed by examining the drug's effects on signaling 

pathways and drawing comparisons to other drugs. Potential upstream targets of Cvb-D include the proteins 

EGFR and CTHRC1, which are involved in its anti-proliferative effect. As a further, more audacious 

hypothesis, the metastasis-associated protein S100A4 is proposed as a possible co-target for Cvb-D. With its 

well-established anti-cardiovascular effectiveness and promising safety profile, Cvb-D has the potential to be 

the subject of more mechanistic investigations into its anticancer effects. 
 

 



 

 

medicine since its discovery in 1964,7 and 

thorough characterization in 1979,8.10 Cvb-D is a 

pregnane-derived steroidal alkaloid that has a low 

water solubility but a satisfactory bioavailability 

when made into disintegrating tablets.11 The 

CFDA of China authorized huangyangning 

dispersible tablets (Fig. 1) in 2009 to treat various 

cerebrovascular and cardiovascular diseases, 

including coronary heart disease, angina pectoris, 

arrhythmia, heart failure, hypertension, and cardiac 

neurosis. Cvb-D is the active ingredient in these 

tablets.12 The 2015 Chinese Pharmacopoeia 

includes it. Cvb-D modulates blood pressure by 

expanding blood vessels and increasing coronary 

flow. In addition to lowering oxygen consumption 

by the heart, it has an antiarrhythmic action. This 

medicine has a lengthy history of usage in 

preventing acute cerebral ischemia and myocardial 

ischemia.Multiple pharmacological investigations 

in animal models (13–15) and clinical trials have 

shown Cvb-D's therapeutic impact on heart failure 

caused by myocardial infarction.2 The compound 

known as JLX001, which is the Cvb-D 

dihydrochloride salt The drug is now in 

development by Zhejiang Jingxin Pharmaceutical 

Co. of Shaoxing, China, with the goal of treating 

ischemic stroke.16 Just recently, research has 

shown that JLX001 may effectively reduce 

cerebral ischemia damage by blocking platelet 

activation and thrombus formation.17 As its 

principal route of action, JLX001 inhibited 

oxidative stress and inflammation in animal models 

via modulating the TLR2/4-NF-kB and AMPK-

ULK1 signaling pathways. The brain is protected 

against ischemia damage by this investigational 

medication.18, 19 When it comes to human clinical 

trials, JLX001 is an intriguing candidate.  

Cancer therapy is one of many new possible 

therapeutic indications for Cvb-D that has emerged 

in recent years. This article provides a summary of 

Cvb-anticancer D's characteristics and the current 

understanding of its action mechanism.  

Anticancer activity of cyclovirobuxine D 

 

Human breast cancer cells were used in an in vitro 

investigation to establish that Cvb-D had an 

anticancer impact. At an IC50 of 10 mM, the drug 

was discovered to decrease MCF7 cell viability. 
After 24 hours of treatment, it was discovered to 

induce autophagy, which is marked by the 

appearance of autophagosomes/autolysosomes and 

the up-regulation of autophagy markers like 

microtubule-associated protein LC3-II and 

autophagy protein ATG5.20 Because Cvb-D at low 

concentrations (1e10 mM) reduced Akt 

phosphorylation and suppressed mTOR 

phosphorylation without altering their intracellular 

expression levels, it was hypothesized that this 

inhibition of the Akt/mTOR axis was responsible 

for autophagic activation.20 Another in vitro 

investigation using two gastric cancer cell lines 

found that Cvb-D dose- and time-dependently 

decreased cell proliferation of MGC-803 and 

MKN2 cells; nevertheless, rather high doses (about 

50–60 mM at 72 h) were necessary to achieve a 

50% reduction in cell growth. Concentrations 

lower than 10 mM were more effective in 

inhibiting colony development. At very high doses 

(i.e., 30–120 mM), the effect was followed by a 

disruption of the cell cycle and the activation of 

apoptosis as shown by mitochondrial damages, 

caspase-3 cleavage, Bcl-2 down-regulation, and 

Bax up-regulation.21 In their study, the scientists 

used a murine macrophage RAW264.7 cell line—

which does not contain tumors—to demonstrate 

that the medication blocks the JAK-STAT 

pathway.22  

There has been an analogous in vitro investigation 

with glioblastoma cell lines.23 Cvb-D caused 

apoptosis, cell cycle arrests (in the S and G0/G1 

phases), and inhibition of glioma cell growth in 

T98G and Hs683 models. However, drug doses 

ranging from 100 to 200 mM were required to 

induce a significant amount of apoptosis. The 

sensitivity of these glioma cells to Cvb-D seems to 

be low. Nevertheless, this provides more evidence 

that the medication may inhibit cell proliferation 

and promote cell death in response to aggressive 

malignant cells. Using hepatocellular carcinoma 

(HCC) cells, researchers have recently shown that 

Cvb-D may inhibit cell proliferation and induce 

cell death.24 With an IC50 of around 15–17 mM, 

Cvb-D treatment inhibited the proliferation of 

HepG2 and HCCLM3 cells in a dose-dependent 

manner, whereas lower drug concentrations 

resulted in impaired colony formation. At doses 

ranging from 10 to 40 mM, Cvb-D was seen to 

trigger a significant death of HCC cells, just as it 

did in the gastric cell line. The potency is moderate. 

However, the fact that the research also 



 

 

documented the drug's action in living organisms 

makes it noteworthy. Mice with HepG2 tumors 

showed an increase in the rate of tumor cell death 

and a significant decrease in tumor volume after 

receiving intraperitoneal administration of Cvb-D 

(10 mg/kg, every two days, for 14 days). The 

medicine effectively reduced tumor development 

in mice and seemed to be well-tolerated (treated 

animals did not lose weight). Thus, the anticancer 

effect is associated with a medication-induced 

suppression of the EGFR-FAK-AKT/ERK1/2-

Slug signaling pathway, as shown by biochemical 

tests indicating the drug could diminish 

phosphorylation of EGFR, Akt, and ERK1/2 in 

HCC cells in vitro.24 

A comparable study using cells from colorectal 

cancer was reported not long ago.Cell colonies are 

formed and DLD-1 and LoVo cell proliferation is 

reduced by 25 Cvb-D with an IC50 of 23–26 mM. 

Vimentin and N-cadherin are important indicators 

of the drug-induced epithelial-mesenchymal 

transition (EMT), and the medication decreased 

their expression in both cell types in a dose-

dependent manner while boosting E-cadherin's 

expression. In order to decrease tumor cell invasion 

and dissemination via blood and lymphatic vessels, 

the medication protects the extracellular matrix. By 

inhibiting matrix metalloproteinases MMP2 and 

MMP9 and downregulating effector proteins 

including Snail, Slug, and ZEB, Cvb-D can control 

EMT. Cvb-D also decreased cancer cell motility 

and induced cell death by changing the expression 

of the up-regulated Bax protein and the down-

regulated Bcl-2 protein, respectively. There was a 

clear reduction in Akt and Erk-1/2 

phosphorylation, which points to the 

PI3K/AKT/ERK signaling pathway as the primary 

mechanism by which the medication exerts its 

anticancer effects. It is worth noting that a key 

protein involved in the anticancer effect was 

identified: CTHRC1, which stands for collagen 

triple helix repeat containing 1. This protein is 

often overexpressed in cancerous cells. Cancer cell 

motility, colony formation, invasion, and 

proliferation are all facilitated by this protein, 

making it an important mediator of 

oncogenesis.Cvb-D can significantly downregulate 

CTHRC1 expression in DLD-1 and LoVo cells, 

which in turn causes phospho-AKT and phospho-

ERK to disappear. Cvb-D may have an upstream 

target in CTHRC1, according to the authors' 

findings.25 This anticancer  

 

 

 



 

 

 
 

Fig. 1. Structure of cyclovirobuxine D (Cvb-D) isolated from Buxus microphylla. Cvb-D is the active pharmaceutical ingredient of the drug Huangyangning tablets used in China 

to treat cardiovascular diseases. Cvb-D is also known as cyclovirobuxinum D or bebuxine (C26H46N2O) and is listed in the Pharmacopoeia of the People ’s Republic of China 

(edition 2015). 



 

 

 

Cvb-D's activity was studied in vivo by xenografting DLD-1 cancer cells into mice. The tumor volume was 

significantly decreased and the residual tumor showed evident symptoms of drug-induced apoptosis after four 

weeks of intraperitoneal injection of Cvb-D (15 mg/kg/day). This new research not only backs up Cvb-D's 

anticancer claims in colon cancer, but it also lays out crucial molecular details, such as how the secreted 

glycoprotein CTHRC1 is a potential target for Cvb-D and a major driver of its anticancer impact. It may also 

function as an effector, changing its state in reaction to Cvb-D's influence on a target farther upstream.  

So far, five separate investigations have shown that Cvb-D has anticancer effects in various animal models 

(Table 1). Two in vitro + in vivo investigations with hepatocellular and colorectal cancer cells, as well as three 

in vitro investigations with gastric, breast, and glioma cell lines20,21,23.24,25 Although more research is 

needed, the current findings support the idea of Cvb-D as a potential new cancer treatment. But details of how 

it works are all over the place. Specifically, Cvb-D's probable molecular targets are still mostly unknown (see 

below). Different things that Cvb-D does 

To treat or prevent many cardiovascular illnesses, Cvb-D is an effective medicine. Cardiomyocytes damaged 

by oxidation or hypoxia are more likely to survive after taking this medicine.27 Additionally, it activates an 

antioxidant response mediated by Nrf 2 that protects against diabetic cardiomyopathy. Based on a molecular 

modeling investigation, it has been suggested that Cvb-D directly binds to Nrf2, a transcription factor. This 

might explain why drugs can increase Nrf2's nuclear translocation and reduce oxidative stress.28 Similarly, 

doxorubicin, an anticancer medication, may cause cardiotoxicity; however, Cvb-D can protect against this. In 

vitro, it decreased cardiac oxidative damages and mitochondrial biogenesis impairment by doxorubicin-

induced myocardial cell death.29 Cvb-D is not the only one with this quality. Cyclobuxine and buxaustroines 

A-N, two other alkaloids derived from the Chinese shrub Buxus austro-yunnanensis, have shown 

cardioprotective effects (Fig. 2).30  

 
Other anticancer Buxus natural products 

 

In vitro studies have shown that extracts from many Buxus plants, including Buxus papillosa, Buxus 

hildebrandtii, and Buxus sempervirens, have substantial antiproliferative activity against various cancer 

cells.no. 31  

 

33 The ability of an acetonic B. sempervirens extract to suppress the growth of cancer cells and to induce 

apoptosis and autophagy in cancer cells is particularly noteworthy.33 While alkaloids and cyclovirobuxines 

are present in these extracts, they are far from the only natural compounds they contain.  

 

More than 250 members make up the enormous and diverse Buxus alkaloid family to which Cvb-D belongs; 

these members all have a core structure that is triterpenoid-steroidal pregnane tetracyclic (Fig. 2).34 The 

members of this family may be categorized into two groups based on the number of B rings they contain: 

those with a 7-membered ring and those with a 6-membered ring. The first group consists of derivatives of the 

9(10e19)-abeo-4,4,14a-trimethyl-5a-pregnane system.Similar to the other natural products shown in Figure 2, 

including cyclovirobuxeine A, buxandrine, and E-buxenone, Cyclovirobuxines A–D belong to the second 

category. Buxmicrophylline B and N-acetyldihydrocyclomicrophylline F, both derived from B. microphylla, 

have shown cytotoxic effects on cancer cells, such as HL60 leukemia cells and human tumor HepG2 cells 

(with sub-micromolar activity against both types of cells).5  

 

Not all Buxus alkaloids are cytotoxic; nevertheless, those that are either mildly or Additional beneficial 

characteristics may be shown by non-cytotoxic chemicals. One such cycloartane alkaloid is O-

tigloylcyclovirobuxeine-B, which has a strong anti-parasitic action against the malaria parasite Plasmodium 

falciparum but very mild cytotoxic effects on L6 rat cells.36,37 It has also been shown to have anti-leishmanial 

and anti-fungal bioactivities.38 A number of Buxus alkaloids, including buxamine C, have been shown to 

inhibit acetyl-cholinesterase (AChE), an enzyme critical to the breakdown of the neurotransmitter 



 

 

acetylcholine. Molecular modeling has led to the hypothesis that the drug interacts directly with this 

enzyme.39 However, in several instances, the level of 40AChE inhibition is low; for example, buxidine and 

buxandrine have IC50 values more than 100 mM.40 Although buxmicrophylline C and buxbodine B, both 

derived from Buxus macowanii, are more effective AChE inhibitors, their IC50 values remain quite high, 

exceeding 10 mM.41  

Two chemicals with anticancer properties are isolated from the compound family. One of them is KBA01, a 

triterpenoid alkaloid derived from B. microphylla that has shown promising antiproliferative effects against 

several cancer cell lines. It was much more effective than other cancer cell lines against the highly sensitive 

HT29 colon cancer cells (CRC; IC50 = 5 mM).The p53 protein has an oncogenic mutation (R273H mutation) 

in 42 HT29 cells. Similar to Cvb-D in structure (Fig. 2), KBA01 was discovered to engage in a chaperone-

mediated cascade that ultimately leads to the death of tumor suppressor protein p53.  
Table 1 

Anticancer activities of cyclovirobuxine D in different models. 
 

Cancer models [cell lines] Cyclovirobuxine D activities References 

Breast cancer [MCF7] - Inhibition of cell proliferation 20 

- Inhibition of Akt/mTOR axis 

- Induction of autophagy 

Gastric cancer [MGC-803, MKN2] - Inhibition of cell proliferation and colony formation 21 

- Blockade of the JAK-STAT pathway 

- Cell cycle arrest and induction of apoptosis 

Glioblastoma [T98G, Hs683] - Inhibition of cell proliferation 23 

- Cell cycle block and induction of apoptosis 

Hepatocellular carcinoma [HepG2, HCCLM3] - Inhibition of cell proliferation and colony formation 24 

- Inhibition of the EGFR/AKT/ERK1/2 signaling pathway 

- Cell cycle arrest and induction of apoptosis 

- Reduction of tumor in vivo 

Colorectal cancer [DLD-1, LoVo] - Inhibition of cell proliferation and colony formation 25 

- Regulation of the epithelial-mesenchymal transition 

- Reduction of cancer cell mobility (with reduced expression of CTHRC1) 

- Induction of apoptosis in vitro and in vivo 

- Inhibition of tumor growth in vivo 



 

 

 

 
 
Fig. 2. Structures of several Buxus alkaloids and other natural products cited in this review. 

 

drug-induced degradation of the mutant p53 

protein was not seen, despite the aided mechanism. 

An attractive anticancer strategy that works in 

tandem with existing medications is to target the 

proteasomal degradation of the tumor suppressor 

protein p53. When combined with anticancer drugs 

like doxorubicin and 5-fluorouracil, the natural 

product lipoic acid leads to the synergistic killing 

of colorectal cancer cells in a p53-dependent 

manner. It also induces ubiquitination and 

proteasomal degradation of p53 in various 

colorectal cancer cell lines.43 The anticancer 

effects of other medications that may cause the 

mutant p53 protein to degrade are encouraging.44 

A number of malignancies, including colorectal 

and osteosarcoma, have shown promise when 

treated with therapeutic strategies that target 

mutant p53.45  

Another alkaloid from Buxus that deserves 

particular notice for its biological activities is E-

buxenone, which is derived from Buxus hyrcana. It 

has been shown to inhibit the proliferation of T 

cells triggered by phytohemagglutinin. Curiously, 

a molecular modeling research suggested that E-

buxenone and its analog buxidin directly interact 

with IL-2, and both compounds were discovered to 

reduce IL-2 and IL-4 production in a dose-

dependent manner (Fig. 2).46 Although 

experimental confirmation of this in silico 

prediction is still pending, E-buxenone and 

buxidin's immunosuppressive characteristics may 

be therapeutic in a variety of diseases.  

 

 

Cvb-D molecular targets? 

 

The cyclovirobuxine literature review and 

associated  

 

product brought attention to an underappreciated 

category of all-natural goods. Cvb-D seems to have 

helpful anticancer characteristics in addition to its 

well-known vascular protective benefits. Several 

supplementary in vitro and in vivo experimental 

models have now shown its anti-tumor efficacy. 

Although the amount of activity is not very high, it 

is noticeable in models of colon and liver 

cancer.24, 26 To fully understand the drug's 

potential, more in vivo trials using other models 

and in conjunction with current anti-tumor 

medications are necessary. In order to guide the 

selection of medication combinations and develop 

optimum protocols, however, a better 

understanding of its mechanism of action and its 

targets is required. As of right now, this is the only 

restriction on this newly revealed anticancer drug. 

Where does Cvb-D aim its molecular attacks?  

 

We may go to research in an effort to shed light on 

this mystery.  

 

carried out using Cvb-D or other naturally 



 

 

occurring compounds belonging to the same 

chemical class. In the first scenario, target 

suggestions obtained from in silico research are our 

exclusive option because to the lack of drug-target 

structural investigations. Above, we noted that the 

drug's protective impact against oxidative stress in 

cardiomyocytes might be explained by a modeled 

direct interaction of Cvb-D with the Nrf 2-Keap 1 

complex.28 The medication may be able to fit into 

a binding pocket in the Nrf2- Keap1 complex, as 

revealed by the docking research. This would lower 

the complex's binding free energy and disrupt the 

connection between Nrf2 and Keap1. 

Consequently, Cvb-D would encourage Nrf2 

nuclear translocation and activate its downstream 

signaling pathways, resulting in oxidative stress 

attenuation.28 Additional tiny compounds that can  

 

There are known compounds that disrupt Nrf2-

Keap1 complexes, such as quercetin (3,40-  

 

Such compounds as diglucoside, esculin, and 

salvianolic acid A)47 do not have strong  

treatments for cancer. We think that Cvb-D's 

anticancer activity can't be explained by this target 

interaction alone; other targets are required.  

The anticancer impact was shown to be mediated 

in part by the secreted protein CTHRC1 (Collagen 

triple helix repeat containing-1), according to 

another research (Fig. 3).25 The antiproliferative 

action of Cvb-D was diminished when CTHRC1 
was knocked down using siRNA. Several studies 

shown that Cvb-D inhibited colorectal cell 

proliferation via a CTHRC1-dependent pathway. 

Even while this doesn't prove that CTHRC1 is a 

molecular target of Cvb-D, it does show that it is 

involved in its action.25 Recent research has 

identified this protein as a key regulator of both 

primary tumor development and the metastasis of 

cancer cells to other tissues.48 out of 49 Colorectal 

cancer, 50 osteosarcoma, 51 HCC, and 

endometriosis are among the diseases for which it 

is being evaluated as a potential predictive 

biomarker and a potential therapeutic target.53 

Intriguingly, a cervical cancer model showed a 

strong decrease of tumor cell metastasis when a 

particular monoclonal antibody was used to 

directly block CTHRC1.54 Similarly, a xenograft 

model revealed that the protein enhanced the 

metastatic spread of epithelial ovarian cancer 

cells.55 Undoubtedly, CTHRC1 promotes 

metastasis; hence, it may be very beneficial to 

enhance cancer therapies by down-regulating it 

using antibodies or medications such as Cvb-D. At 

this time, no medication has been identified that 

interacts directly with CTHRC1. Cvb-D may be the 

first small molecule ligand for this receptor. 

The second strategy involves searching for 

complementary natural substances in  

 

the same class of chemicals and the targets that they 

interact with. The structural and functional 

diversity of saponins is astounding. Of the various 

subclasses, there are as many as eleven primary 

classes (dammaranes, tirucallanes, lupanes, 

hopanes, ole-ananes, taraxasteranes, ursanes, 

cycloartanes, lanostanes, cucurbitanes, and 

steroids).56 Together, these classes provide a wide 

range of potential applications.  
 

many substances that may be compared to Cvb-D. 

Anthracite, argentatin A, actein, (23 R, 24 E)-23- 

acetoxymangiferonic acid, and many other 

anticancer drugs are members of the cycloartanes, 

the saponin class most closely related to Cvb-D. 

Regrettably, the majority of these drugs have had 

their anticancer effects studied, but not their 

molecular targets. An example of a rare situation 

where a target has been suggested is the derivative 

cycloartane-3,24,25-triol. It was discovered that 

out of 451 kinases tested, MRCKa (myotonic 

dystrophy protein kinase-like alpha) inhibits 

serine/threonine protein kinase activity with a 

Kd50 of 0.26 mM.60 Because of its function in 

p53-dependent autophagy, this target is 

intriguing.61, 62 Aiming to combat cancer, 

researchers are diligently seeking small-molecule 

inhibitors that specifically target Cdc42-binding 

MRCK kinases.63 Examining Cvb-D's action on 

this kinase may provide some intriguing insights.  

There are likely several targets involved in the 

action mechanism of Cvb-D, and it is challenging 

to identify the target of any natural substance. The 

related cycloartane actein (from the medicinal plant 

Cimicifuga racemosa) was used in a recent target-

fishing investigation that used system chemical 

biology approaches. The analysis revealed eight 

possible targets, one of which being the metastasis-

associated calcium-binding protein S100A4.64.65 



 

 

dollars Hepatocellular carcinoma66 and colorectal 

cancers associated with herpes simplex virus have 

recently had S100A4 suggested as a potential 

therapeutic target.67, 68 Specifically, S100A4 

controls how polyploid large cancer cells migrate 

and invade.69 Cvb-D has shown significant action 

in vivo models of HCC and colon cancer, as 

previously mentioned. Hence, research into the 

possibility of Cvb-D binding to S100A4 is 

warranted. Although they share some structural 

features, the glycosylated cycloartane actein is 

structurally different from Cvb-D (Fig. 2). We 

should expect a comparable level of mechanical 

complexity, with several goals contributing to it.  

 

 

 
 

Figure 3 shows a schematic of the mechanism of 

action of cyclovirobuxine D (Cvb-D). Several 

proteins, including as ERK1/2, EGFR, mTOR, and 

Akt, are phosphorylated when exposed to Cvb-D. 

Because of these consequences, mitochondrial 

disturbances trigger the intrinsic apoptotic 

pathway. Additionally, it triggers the transcription 

of genes that play a role in regulating the cell cycle 

and promoting cell proliferation. Cvb-D also 

inhibits the Akt/mTOR axis, which allows certain 

cancer cells to initiate autophagy. Currently, Cvb-

D's upstream targets remain a mystery; 

nevertheless, there is talk of a possible direct effect 

on EGFR as well as the proteins S100A4 and 

CTHRC1.  

anti-cancer effects. Since S100A4 is an essential 

ligand of the EGFR receptor, an interaction 

between Cvb-D and S100A4 may account for the 

drug's subsequent effects, most noticeably the 

drug-induced suppression of EGFR 

phosphorylation seen in vitro.70, 71 The function 

of S100A4 in cancer metastasis72 has been shown, 

and a small poly- aromatic compound called 

amlexanox has been found to suppress cancer cell 

proliferation by disrupting the interaction between 

S100A4 and EGF.73 In addition, part of the p53-

dependent effects shown with Cvb-D may be 

explained by the fact that S100A4 forms complexes 

with p53,74. Therefore, we suggest looking into the 

possibility of Cvb-D interacting with S100A4 and 

the consequent EGFR antagonist effect. 

Additionally, it would be beneficial to study how 

Cvb-D may interact with EGFR, since this receptor 

has been shown to be directly occupied by a 

number of natural products that inhibit EGF 

binding to EGFR, such as cucurbitacin D and 

analogs, and protopanaxadiol.From 75 to 78  



 

 

 

In conclusion, it has been shown after a thorough 

literature review that proteins CTHRC1, S100A4, 

and EGFR are the three most promising anticancer 

target candidates for Cvb-D (Fig. 3). Naturally, 

there can be other ones. To find other proteins that 

Cvb-D can target, it might be helpful to use reverse 

screening methods79,80. However, it may result in 

a large number of contenders. To illustrate the 

point, twelve signal transduction pathways and 

thirty-three critical target proteins were uncovered 

when the anticancer medicine epigallocatechin-3-

gallate's potential targets were identified using a 

reverse docking approach.81  

 

Conclusion and prospects 

 

Historically, cyclovirobuxine D, a triterpenoid 

alkaloid, has been used to treat cardiovascular 

diseases in traditional Chinese medicine. The anti-

arrhythmia and vasodilatory actions of the 

medicine Huangyangning have made it famous. No 

organ damage or general toxicity was seen in rats 

fed for eight weeks continuously with a dose 50-to-

200 times higher than the human dosage, according 

to a recent toxicology research.18 Despite the lack 

of published clinical research supporting the 

charges, the medicine seems to be safe and 

effective, and it has been seen in Chinese hospitals 

for decades. But the Huangyangning pills' active 

pharmaceutical ingredient (API), cyclovirobuxine 

D, has a history of use in the treatment of 

cardiovascular disorders. Since 2009, the CFDA 

has authorized the medicine, and many 

pharmaceutical firms offer the active 

pharmaceutical ingredient (API). To speed up the 

drug's dissolving rate, researchers are creating new 

Cvb-D formulations including Cvb-D 

nanosuspensions.82  

Cvb-D has recently opened up new avenues of 

potential use outside the cardiovascular sector, 

namely in the fight against cancer. Preliminary 

evidence of activity in vivo has been reported 

lately, and other investigations have shown that the 

medication has antiproliferative effects against 

various cancer cell types in vitro. Though the 

activity level isn't very high, the antitumor effect—

which results in the death of cancer cells and the 
suppression of metastasis—is evident. Cvb-D 

regulates cell cycle progression, inhibits 

metastasis, and activates signaling pathways 

similar to those of other steroidal alkaloids. These 

pathways include up-or down-regulation of 

apoptotic (Bax, Bcl 2, caspases) and autophagic 

(LC3, AKT, mTOR) proteins.No. 83 

Unfortunately, the chemical effects that initiate 

these reactions remain mostly unknown. Little is 

known about the significance or molecular 

processes that underlie the anticancer action. 

However, other proteins might be suggested as 

possible targets; for example, EGFR and CTHRC1 

are known to be involved in Cvb-D activity, and 

here we make a more daring assumption about 

S100A4.  

 

This all-natural product needs to be promoted and 

studied immediately.  

 

enhance its anticancer efficacy and mode of action 

in living organisms. With any luck, this evaluation 

will serve as a catalyst for further Cvb-D testing in 

other models, perhaps with more suitable 

medication compositions and combinations. Cvb-

D has a lengthy history of usage and a high safety 

profile; it may one day be a cancer therapy 

medicine or a molecular tool to alter the activity of 

the proteins CTHRC1 and S100A4, neither of 

which have particular pharmacological effectors at 

this time.  

 
Funding 

 
This research did not receive any specific grant from 

funding agencies in the public, commercial, or not-for-profit 

sectors. 

 
Declaration of competing interest 

 
The authors declare no conflict of interest associated with 

this publication and there has been no significant financial 

support for this work that could have influenced its outcome. 

 
CRediT authorship contribution statement 

 
Christian Bailly: Conceptualization, investigation, project 

administration, supervision, writing ‒ original draft, and 

writing ‒ review & editing. Jihong Zhang: Writing ‒ review & 
editing. 

 
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