# Oridonin: A natural terpenoid having the potential to modulate apoptosis and survival signaling in cancer

Abhishek Chauhan, Hemant Joshi, Divya Kandari, Diwakar Aggarwal, Ritu Chauhan, Hardeep Singh Tuli, Arpit Mehrotra, Abhilasha Sood, Ujjawal Sharma, Darin Mansor Mathkor, et al.

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## To cite this version:

Abhishek Chauhan, Hemant Joshi, Divya Kandari, Diwakar Aggarwal, Ritu Chauhan, et al. "Oridonin: A natural terpenoid having the potential to modulate apoptosis and survival signaling in cancer. phytomedicine Plus, 2025, 5, 10.1016/j.phyplu.2024.100721. hal-05484901

HAL Id: hal-05484901

https://univ-reunion.hal.science/hal-05484901v1

Submitted on 30 Jan 2026

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# Oridonin: A natural terpenoid having the potential to modulate apoptosis and survival signaling in cancer

Abhishek Chauhan<sup>a</sup>, Hemant Joshi<sup>b</sup>, Divya Kandari<sup>b</sup>, Diwakar Aggarwal<sup>c</sup>, Ritu Chauhan<sup>d</sup>, Hardeep Singh Tuli<sup>e,*</sup>, Arpit Mehrotra<sup>e</sup>, Abhilasha Sood<sup>e</sup>, Ujjawal Sharma<sup>f</sup>, Darin Mansor Mathkor<sup>g</sup>, Shafiul Haque<sup>g,h</sup>, Naveen Chandra Joshi<sup>i</sup>, Laurent Dufossé<sup>j,*</sup>

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## ARTICLE INFO

**Keywords:**
Oridonin
Terpenoids
Cancer
Apoptosis
Cell signaling

## ABSTRACT

**Background:** Oridonin, a diterpenoid lactone derived from medicinal plants, has drawn considerable attention due to its therapeutic potential, particularly its anticancer properties. It demonstrates efficacy in inducing apoptosis, suppressing cancer cell proliferation, and sensitizing cells to conventional chemotherapeutics by modulating key signaling pathways like PI3K/AKT, MAPKs, and NF-κB.

**Purpose:** This article investigates the apoptotic mechanisms and anticancer potential of oridonin, including its modulatory effects on signaling pathways and its derivatives' enhanced efficacy against drug-resistant cancer cells.

**Methods:** A systematic literature search was conducted using Scopus, PubMed, SpringerLink, ScienceDirect, Wiley Online, and Web of Science databases, covering the period from 2007 to 2024. Keywords such as "Oridonin," "Apoptosis," "Cancer Cell Signaling Pathways," "PI3K/AKT," "ROS," and "Nanotechnology" were used, yielding 96 relevant studies.

**Results:** Oridonin induces apoptosis through intrinsic and extrinsic pathways, involving ROS amplification and mitochondrial membrane potential regulation. It modulates proteins like Bax, Bcl-2, cytochrome c, and caspases, leading to DNA fragmentation. Its derivatives, such as 13p, exhibit enhanced potency by arresting the G2/M phase and targeting drug-resistant cells with minimal toxicity. Advanced nano-delivery systems and combination therapies further enhance oridonin's therapeutic potential.

**Conclusion:** Oridonin demonstrates robust anticancer activity by modulating signaling pathways and inducing apoptosis. Its derivatives and novel delivery systems offer promising avenues for overcoming drug resistance and optimizing its therapeutic efficacy. Further research, including clinical trials, is necessary to fully harness its potential as a cancer treatment alternative.

## 1. Introduction

Improper cell signaling is an essential property of cancer that

promotes tumor growth and progression. The cellular signaling pathways form an interconnected network, receiving and transforming information as per cellular requirements and conditions, thereby

<footnote><sup>a</sup> Amity Institute of Environmental Toxicology, Safety and Management, Amity University, Noida, 201303, India</footnote>

<footnote><sup>b</sup> School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India</footnote>

<footnote><sup>c</sup> Department of Biotechnology, Maharishi Markandeshwar Engineering College, Maharishi Markandeshwar (Deemed to Be University), Mullana, Ambala 133207, India</footnote>

<footnote><sup>d</sup> Department of Biotechnology, Graphic Era (Deemed to be University), Dehradun 248002, Uttarakhand, India</footnote>

<footnote><sup>e</sup> Department of Allied Health Sciences, Chitkara School of Health Sciences, Chitkara University, Punjab, India</footnote>

<footnote><sup>f</sup> Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Punjab, Bathinda, 151401, India</footnote>

<footnote><sup>g</sup> Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan-45142, Saudi Arabia</footnote>

<footnote><sup>h</sup> Gilbert and Rose-Marie Chagoury, School of Medicine, Lebanese American University, Beirut 1102 2801, Lebanon</footnote>

<footnote><sup>i</sup> Amity Institute of Microbial Technology, Amity University, Noida 201313, India</footnote>

<footnote><sup>j</sup> Chemistry and Biotechnology of Natural Products, CHEMBIOPRO, Université de La Réunion, ESIROI Agroalimentaire, 15 Avenue René Cassin, CS 92003, CEDEX 9, F-97744 Saint-Denis, France</footnote>

<footnote>* Corresponding authors.</footnote>

<footnote>E-mail addresses: hardeep.biotech@gmail.com (H.S. Tuli), laurent.dufosse@univ-reunion.fr (L. Dufossé).</footnote>
regulating cell synthesis and breakdown. Apoptosis and cell survival are two such sides of a coin, wherein one regulates the other with the help of signaling molecules. Apoptosis, also known as programmed cell death and survival signaling both play essential roles in cancer chemistry (Ali et al., 2024). Resistance to apoptosis is an important feature of many aggressive cancers, leading to treatment resistance (Hsieh et al., 2019; Sobral et al., 2023). Mutations in apoptotic proteins such as p53 and the over-expression of certain anti-apoptotic proteins like Bcl-2, are the key players that can disrupt the apoptotic pathway, and hence act as contributing factors in cancer progression (Chan et al., 2024). On the other hand, survival signaling pathways such as PI3K/Akt, NF-κB, IGF-1/IGF-1R, and Hedgehog Pathways are also activated in cancer to promote cell survival and growth (Lilhore et al., 2022). Thus, the dys-regulation of apoptosis and survival signaling pathways can reasonably be considered for their involvement in tumor progression. The uncon-trolled growth in cancerous cells is probably due to their ability to elude programmed cell death and enhance the survival of the cancerous cells. Cancer cells initiate mechanisms to prevent apoptosis despite DNA damage or other abnormalities. Various natural compounds possessing essential antioxidant, and anti-inflammatory properties have been explored for their anticancer effects, with certain positive outcomes as well (Hashem et al., 2022; Chauhan et al., 2023). Terpenoids are a group of organic compounds that have shown potential effects in preventing tumor progression in different types of cancer. Many terpenoids have shown beneficial anticancer effects through their ability to promote the induction of apoptosis or through the inhibition of apoptosis resistance in cancer cells. This is possible due to their ability to interfere with certain cell signaling pathways. Terpenoids like lupeol, resveratrol, etc., have been reported to prevent cancer through modulation of the Bcl2 family proteins or inhibition of the PI3K/Akt and the MAPK signaling pathway. Oridonin is one such compound of terpenoid origin, which has been under extensive investigation in recent years owing to its potential benefits in cancer research (Liu et al., 2021; Li et al., 2024). The present review will focus on the potential of oridonin in the modulation of apoptosis and survival signaling in cancer.

## 2. Methodology

### 2.1. *Search strategy*

A comprehensive search of electronic databases was conducted to identify relevant studies for this review, including Scopus, PubMed, SpringerLink, ScienceDirect, Wiley Online, and Web of Science. The search covered literature from 2007 to 2024, utilizing the following keywords and combinations:

* "Oridonin" paired with terms such as "Apoptosis," "Cancer Cell Signaling Pathways," "PI3K/AKT," "MAPK," "NF-κB," "Reactive Oxygen Species (ROS)," "Mitochondrial Pathways," "Tumor Growth Inhibition," "Cell Cycle Arrest," "Synergism," "Chemotherapy," "Nanotechnology," "Drug Resistance," "Complementary Therapy," and "Pharmacokinetics."

* Additional combinations included: "Terpenoid," "ROS-Induced Apoptosis," "Intrinsic Pathways," "Extrinsic Pathways," "Anticancer Properties," "Drug Delivery Systems," and "Therapeutic Potential."

### 2.2. *Inclusion and exclusion criteria*

*Inclusion criteria*

Studies focusing on the pharmacological and biological activities of oridonin in various cancers, including gastrointestinal, liver, pancreatic, bladder, and esophageal cancers. Research using in vitro and in vivo models examining oridonin's effects on cancer cell proliferation, apoptosis, and signaling pathways. Investigations into oridonin's chemical properties, its derivatives (e.g., 13p), and their impact on mitochondrial pathways, ROS generation, and cell cycle arrest. Studies

evaluating oridonin's synergistic effects with chemotherapeutics, its safety profile, and its potential as a complementary or alternative therapy. Research exploring novel drug delivery systems for oridonin, such as nanotechnology-based delivery mechanisms.

*Exclusion criteria*

Studies on compounds unrelated to oridonin or derived from mon-oterpenoid sources. In vitro studies with duplicated data or whose titles and abstracts do not meet the inclusion criteria. Research on unrelated topics or with insufficient focus on apoptosis or cancer signalling path-ways involving oridonin. Articles written in languages other than En-glish. Studies for which full texts are unavailable. Nonprimary research articles, such as case reports, letters, and editorials.

## 3. Chemistry and pharmacokinetics of oridonin

Chemically, oridonin is a diterpenoid lactone that can be isolated from medicinal herbs. Its major source is *Rabdosia rubescens*. Belonging to the labdane class, this diterpenoid is a 20-carbon molecule with the molecular formula $C_{20}H_{28}O_6$ (Fig. 1). Being hydrophobic in nature oridonin shows poor absorption in the gastrointestinal tract. Its distribution to the other body parts is highly influenced by its lipophilicity and the rate of blood flow. Although the exact metabolic pathway for oridonin in the living system is still not clear, a previous LC-MS-MS based study in rodents suggested that oridonin is primarily metabolized in the liver (Li et al., 2021). On the other hand, it has been reported to exhibit multiple metabolic pathways under in-vitro conditions consisting of hydroxyl-ation, dehydrogenation, rehydration, etc. It is known to possess impor-tant pharmacological properties such as anti-cancer, anti-inflammatory effects, etc. (Huang et al., 2020; He et al., 2024). Owing to its pharma-cological properties and related benefits, significant advancement has been reported in its beneficial effects in previous years. However, due to low bioavailability, significant research has been focusing on improving its delivery strategies by employing delivery/transport agents such as liposomes, nanoparticles, etc. that can enhance the elimination half-life of the molecule. High doses and prolonged supplementation have been reported to show pharmacological as well as toxic effects, hence demanding further investigations (Sun et al., 2020). Oridonin exhibits dual efficacy through Cancer Stem Cell (CSC) differentiation induction as well as cytotoxic effect, which disassembled tumorspheres and reduced CSC markers. It increased TP53 expression, suppressed tumor stemness, PD-L1 expression, and hypoxia, thus promoting strong anti-cancer immune responses. Oridonin showed significant pro-apoptotic effects with commendable biosafety, targeting tumor progression effectively (Li et al., 2024b; Ye et al., 2023). The pharma-cokinetics of oridonin might be significantly affected due to its chemical interaction with certain substrates and enzymes such as Liver Cyto-chrome P450 as previously reported (Li et al., 2021). Hence, chemical modifications in its structure are being eyed as ideal approaches to

<figure><img src="image_5.png" /><figcaption>Fig. 1. Chemical structure of oridonin.</figcaption></figure>
improve its pharmacology and bioavailability.

# 4. Apoptotic and survival signaling modulation in cancer

## 4.1. The Fas-FasL pathway by oridonin

One of the primary mechanisms in the course of modulating apoptotic and survival signaling in cancer by oridonin is via the Fas-Fas ligand (FasL) pathway, which is recognized as a crucial regulator of apoptosis during cancer (Liu et al., 2012). The pathway comes into action whenever Fas (also known as CD95) present on the surface of a cell binds to its ligand (FasL, also known as CD95 L), thus triggering a multitude of signaling events that eventually leads to progression of apoptosis (Shi et al., 2016). The FasL pathway is fundamental in maintaining tissue homeostasis and removing damaged or impending harmful cells. It is well known that, during cancer an equilibrium between pro-survival and pro-apoptotic signals can be interrupted, thereby permitting cancerous cells to escape apoptosis and continue proliferating. However, oridonin has been reported to maintain this equilibrium in several ways, such as: by upregulation of Fas, stimulation of FasL, inhibition of pro-survival mechanisms, and induction of mitochondria-mediated apoptosis responses, etc. (Guan et al., 2021; Liu et al., 2021) (Fig. 2). The upregulation of Fas by oridonin increases the expression of Fas receptors on the surface of cancerous cells, thus making them more susceptible to being targeted by FasL-mediated apoptotic destruction (Table 1). Moreover, oridonin has demonstrated the propensity to initiate production of Fas-ligand (FasL) via specific immune cells or rather by cancer cells themselves. This mechanism upon initiation is reported to enhance the expression of Fas receptors on the surface of cancer cells and hence triggers apoptotic machinery (Shi et al., 2016). In addition, inhibition of several pro-survival signaling pathways by oridonin, including targeting of NF-κB pathway involved in promoting the survival of cancer cells is well known. Therefore, by inhibiting such mechanisms, oridonin can precisely augment the sensitivity of cancer cells via the ensuing Fas-FasL pathway (Qing et al., 2016). Furthermore, oridonin can regulate the apoptotic pathway by ensuing mitochondrial apoptosis by disrupting mitochondrial membrane potential with concomitant enhanced expression of apoptotic proteins (such as Apaf-1, caspase-3, and cytochrome c), thereby leading to activation of caspases (Sun et al., 2012) (Fig. 2). Altogether, these mechanisms contribute to imparting vital anti-cancer properties of oridonin. However, the precise mechanism/s and effectiveness of oridonin may

differ depending on the specific type of cancer, and therefore further investigation is suggested to elucidate its therapeutic potential.

## 4.2. Modulating the Bcl2-Bax pathway by oridonin

Oridonin has been widely investigated for its potential in modulating Bcl-2 (B-cell lymphoma 2) and Bax (Bcl-2-associated X protein) pathways involved in cancer progression (Li et al., 2018; Liao, Dong et al. 2021). Such Bcl-2 family of proteins are known to precisely execute apoptotic mechanisms by either influencing the expression of cell survival proteins (anti-apoptotic pathway via Bcl-2) or by directly inducing apoptotic proteins (pro-apoptotic pathway via Bax). Any, dysregulation in these pathways can contribute significantly to cancer development and thus resistance to treatment (Qian et al., 2022). In cancer, oridonin has been shown to influence the Bcl-2/Bax pathway by downregulating the expression of Bcl-2, upregulation of Bax expression, alteration of mitochondrial membrane permeabilization leading to caspases activation, and inhibition of Bcl-2 anti-apoptotic function, etc. (Fig. 2). Oridonin can simultaneously downregulate and upregulate the expression of Bcl-2 (an anti-apoptotic protein) and Bax (a pro-apoptotic protein), respectively. Such downregulation by oridonin is shown to potentiate cell death by preventing the release of pro-apoptotic proteins localized in mitochondria, thus by lowering Bcl-2 levels oridonin can shift the equilibrium in favor of apoptosis (Li et al., 2019). Conversely, upon upregulation of Bax by oridonin, an optimal threshold of mitochondrial membrane permeabilization is disrupted with concomitant release of cytochrome c, triggering an amalgamation of signaling events involved in activation of key effector caspases (such as caspase-3) and ROS/JNK/c-Jun pathway implicated in apoptosis regulation (Zhang et al., 2019). Furthermore, oridonin can directly interrupt the potent interaction between Bcl-2 and Bax, thus further enhancing the pro-apoptotic property of Bax (Cui et al., 2007). These properties of oridonin collectively contribute to its therapeutic potential as an anti-cancer agent by promoting apoptosis in cancer cells through modulation of the Bcl-2/Bax pathway. By favoring pro-apoptotic signals over pro-survival signals, oridonin can potentially inhibit the growth and survival of cancer cells.

## 4.3. Targeting the PI3K-Akt-mTOR pathway

An essential pathway in cancer development, the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR)

<figure><img src="image_6.png" /><figcaption>**Fig. 2.** Diagram showing how oridonin affects both the intrinsic and extrinsic apoptotic pathways to exert its anti-cancerous effect.</figcaption></figure>
<table><caption>**Table 1**
Anti-proliferative properties of oridonin based on in vitro studies.</caption><thead><tr><th>Tumor type</th><th>Cell culture</th><th>Effects</th><th>Mechanistic insight</th><th>Concentration</th><th>References</th></tr></thead><tbody><tr><td>Osteosarcoma</td><td>MG-63 and HOS</td><td>Induces apoptosis</td><td>↑Bax/Bcl-2 ratio, ↓MMP, ↑ROS generation, ↑caspase-3 and caspase-9, ↓Nrf2 pathway, ↓NF-κB, ↑PPAR-γ</td><td>0–20 µM</td><td>(Lu et al., 2018)</td></tr><tr><td rowspan="3">Laryngeal</td><td>HepG2 and TU212</td><td>Induces apoptosis</td><td>↓proliferation of laryngeal carcinoma, ↑cleaved caspase-3 and PARP, ↑GRP78, ↑P-ERK, ↑p-EIF2α, ↑CHOP</td><td>0, 20, 60 µM</td><td>(Kou et al., 2020)</td></tr><tr><td>HepG2 and Tu212</td><td>Apoptosis and autophagy</td><td>↑Apoptotic cells, ↑c-PARP, decreased p-mTOR increased, ↑p-AMPK, ↑MDC-positive ↑LC3II, ↑Beclin 1</td><td>Oridinol (24 µM for HEp-2 cells and 36 µM for Tu212 cells, respectively) and cetuximab (10 µg/mL)</td><td>(Cao et al., 2019)</td></tr><tr><td>HepG2</td><td>Induced apoptosis</td><td>↑membrane blebbing, ↑granular apoptotic bodies, chromatin condensation, ↓mitochondrial transmembrane potential, ↑Bax, ↑FADD, ↑caspase-8, ↑caspase-3, ↓Bcl2, ↓SIRT1, ↑ROS</td><td>0,10,7,16,24,36,54 and 81 µM</td><td>(Kang et al., 2010)</td></tr><tr><td rowspan="10">Esophageal Squamous</td><td>TE-8 and TE-2</td><td>Induced apoptosis</td><td>↓proliferation and colony formation, ↑DNA fragmentation, ↑sub-G0/G1, Evokes Phosphatidylinserse Externalization, ↓caspase-3, ↓LASP1 and PDLIM1, Hsp70 increased, ↓ENO1</td><td>0,5,10, 20 and 40 µM</td><td>(X. X. Zhang et al., 2023)</td></tr><tr><td>KYSE30, KYSE510, TE1, KYSE150, KYSE410 and EC109</td><td>Induces apoptosis</td><td>↓cancer cell proliferation and growth, ↓intracellular glutathione generation, ↑apoptotic rate, ↓migration and invasion, ↑ROS, ↑H2AX</td><td>5–80 µM of Cisplatin and oridonin</td><td>(Yang et al., 2022)</td></tr><tr><td>RKO, LoVo, HCT116, SW480</td><td>Apoptotic induction</td><td>↓tumor growth, ↓metastasis, ↑ER stress, ↑loose morphology of ER, ↑vesicles and irregular shape, ↑ATF4 and CHOP, ↓TCF4, ↑YOD1 and FYN, ↓CFTR ROS, ↑Ca2+, ↑TP53, ↑Wnt/β- catenin</td><td>0,5,10,15,20,25 and 30 µM</td><td>(Zhou et al., 2023)</td></tr><tr><td>DLD-1</td><td>Induced apoptosis and autophagy</td><td>↑cleaved caspase-3, ↑cleaved PARP, ↑Beclin1, ↑LC3-II, ↓LC3-I, ↓p62, ↑p-AMPK, ↓p-mTOR, ↓p-ULK1</td><td>0,5,10,15,20 and 25 µM</td><td>(Bu et al., 2020)</td></tr><tr><td>DLD1, RKO, LS174T, SW480, SW48, HCT116 and HCT-15</td><td>Induced apoptosis</td><td>↓proliferation of cancer cells, ↑G2/M arrest, ↓precursor form of caspase-3, ↑cleaved form of caspase-3, ↑cleaved PARP, ↓XIAP, ↑Bax</td><td>0–100 µM</td><td>(Zhang et al., 2019)</td></tr><tr><td>SW620</td><td>Induced apoptosis</td><td>↓proliferation of cancer cells, ↑Bad, ↓Bcl-2, ↑p53, ↑p-p53, ↑BMP7, ↑p-p38</td><td>0, 5, 10, 15, 20 and 25 µM</td><td>(Liu et al., 2018)</td></tr><tr><td>HCT116</td><td>Induced apoptosis</td><td>↓proliferation of cancer cells, ↑BMP7, ↑apoptotic cells, ↑Bad, ↓Bcl-2, p38 MAPK (p-p38)</td><td>0,5,10,15,20 and 25 µM</td><td>(Ren et al., 2016)</td></tr><tr><td>SW480 and SW620</td><td>Induced apoptosis</td><td>↓viability of cancer cells, ↑total apoptotic cells, ↓FAS and SREBP1, ↓FAS promoter transcriptional activity, ↓palmitic acid, and stearic acid</td><td>0,5,10,20,25 and 30 µM</td><td>(Kwan et al., 2013)</td></tr><tr><td>Hepatocellular</td><td>SMMC-7721, HepG2, Bel-7402, and Huh7</td><td>Induces apoptosis and suppresses metastasis</td><td>↓viability of cancer cells, ↓colony counts, ↓PCNA and Bel-2, ↑Bax, ↑cleaved PARP, C3, ↓Cell migration and invasion, ↑E-cadherin, ↑Snail, ↑Vimentin, ↓p-Akt</td><td>oridonin (0, 10, 20 and 30 µM), sorafenib (0, 2.5, 5 and 10 µM)</td><td>(Li et al., 2020)</td></tr><tr><td></td><td>SMMC-7721</td><td>Induces apoptosis</td><td>↓proliferation of cancer cells, ↑caspase-3, –8 and –9, ↓Bcl-2 and ↓Bcl-xL, ↑Bax, ↑p53, and p21, ↑EGF, ↑EGF receptor</td><td>20 µg/mL oridonin, Lentinan 200 µg/mL</td><td>(Xu et al., 2017)</td></tr><tr><td></td><td>HepG2</td><td>Induced apoptosis</td><td>↓cell viability, ↑p-JNK, ↑p-p38, ↑p-p53, ↑p21, ↑cyclin B1, ↓p-ERK, ↑caspase-9, ↑caspase-3</td><td>0,20,40,60,80 and 100 µM</td><td>(Wang et al., 2010)</td></tr><tr><td rowspan="2">Pancreatic</td><td>Panc-1 and Panc02</td><td>Induces apoptosis and autophagy</td><td>↓Pancreatic cancer cells, ↑LC3B II, ↑p62, ↑Beclin-1, ↑PI3 K, ↑p-JNK, ↑p-Erk, ↑p-p38MAPK, ↑PI3K</td><td>0, 5, 10, 20, 40, or 80 µM</td><td>(Zhao et al., 2021)</td></tr><tr><td>SW1990</td><td>Induced apoptosis</td><td>↑cytotoxicity towards cancer cells, ↑G0/G1 phase cells, ↓S and G2/M phase, ↑p-p53, ↑p21, ↑phosphor-p38 increased, ↑caspase-9 and –3</td><td>0, 10, 20, 40, 80, 160 µM</td><td>(Bu et al., 2014)</td></tr><tr><td>Bladder</td><td>T24</td><td>Induces apoptosis</td><td>↓proliferative, colony-forming, and migratory capacities, ↑apoptosis frequency, ↑p53 and cleaved caspase-3, ↑TRPM7, ↓p-AKT, ↓p-ERK</td><td>0, 2, 4, 6, 10, 15, 20, and 30 µM</td><td>(Che et al., 2021)</td></tr><tr><td rowspan="2">Murine fibrosarcoma</td><td>L929</td><td>Induces apoptosis and autophagy</td><td>↑intracellular NO production, ↑Bax, ↓cytochrome c release, ↓Bcl-2, ↑Beclin 1, ↑LC3 I to LC3 II, ↑ERK and p53</td><td>50 µM</td><td>(Ye et al., 2012)</td></tr><tr><td>L929</td><td>Induces apoptosis</td><td>↑G2/M phase cell percentage, ↓cdc2, ↓cdc25c and ↓cyclin B, ↑p21 and p-cdc2, ↑p-p5, ↓Ras and Raf, no change in JNK level, ↓p-JNK</td><td>50 µM</td><td>(Cheng et al., 2009)</td></tr></tbody></table>

pathway, is involved in controlling proliferation, differentiation, and apoptosis. Growth factors and particular extracellular signals can activate it. Multiple cancer types have been linked to dysregulation of this pathway (Yang et al., 2019; Rascio et al., 2021). A new era for cancer-targeted therapy has begun with the development of PI3K/AKT pathway inhibitors. Since idelalisib's initial approval confirmed the PI3 K pathway's druggability, more and more PI3 K inhibitors have been developed (Jiang et al., 2020). Oridonin can effectively reduce the viability of a variety of tumor cells by, among other things, promoting apoptosis and inhibiting cancer cell proliferation (Che et al., 2021; Zhao et al., 2021).

Yang and others established that oridonin inhibits AMPK/Akt/mTOR-dependent autophagy to have anti-lung cancer pharmacological

activity (Yang et al., 2019) (Fig. 3). The modulation of this pathway is how oridonin exerts its therapeutic effects in squamous cell carcinoma (Ghafouri-Fard et al., 2022). Additionally, oridonin suppressed the PI3K/AKT pathway, significantly reduced proliferation, and increased apoptosis in oral squamous cell carcinoma cells as well as in xenografted nude mice (Table 2). This was accomplished by preventing the phosphorylation of PI3 K and Akt (Yang et al., 2018). According to (Wang and Zhu, 2019), oridonin reduced the activity of the mTOR signaling pathway, increased the level of FOXP3, and prevented the metastasis of human ovarian cancer cells. Furthermore, by interacting with the ATP-binding pocket of AKT, Oridonin repressed the signaling pathway of PI3K/Akt/mTOR in esophageal cancer cells (KYSE-150, KYSE-3, and EC9706) and significantly inhibited the growth of tumors in the
<figure><img src="image_7.png" /><figcaption>**Fig. 3.** Oridonin's chemopreventive effects through the modification of several signaling cascade's molecular actors. Oridonin's suppressive effect is shown by the red arrow.</figcaption></figure>

<table><caption>**Table 2**

Anti-tumor actions of oridonin using in vivo experiments.</caption><thead><tr><td>Tumor types</td><td>Animal models</td><td>Effects</td><td>Mechanisms</td><td>Dosage</td><td>Duration</td><td>References</td></tr></thead><tbody><tr><td>Laryngeal</td><td>BALB/C nude mice xenografted with HepG2 cells</td><td>Induces apoptosis</td><td>↓tumor size and volume, ↓proliferation of laryngeal carcinoma, ↑cleaved caspase-3 and PARP, ↑GRP78, ↑P-ERK, ↑p-eIF2α, ↑CHOP</td><td>10 mg/kg</td><td>28 days</td><td>(Kou et al., 2020)</td></tr><tr><td>Colorectal</td><td>BALB/c-nude mice xenografted with LoVo and RKO</td><td>Induces apoptosis and prevents cell metastasis</td><td>No significant histological differences between the oridonin and control groups in the hearts, livers, spleens, lungs, and kidneys, ↑YOD1 and FYN, ↓CFTR, ↓ROS, ↓intracellular Ca2+ concentration, ↓Ki-67, ↓CD31-positive microvessel score</td><td>160 mg/kg</td><td>28 days</td><td>(Zhou et al., 2023)</td></tr><tr><td>Colon</td><td>Nude mice. Xenografted with DLD-1</td><td>Induced apoptosis and autophagy</td><td>↑p-AMPK, ↑LC3-II, ↑caspase-3, ↓p-mTOR, ↓p-ULK1 protein</td><td>5 and 10 mg/kg</td><td>14 days</td><td>(Bu et al., 2020)</td></tr><tr><td>Colon</td><td>Athymic nude mice xenografted with SW620 cells</td><td>Induces apoptosis</td><td>↑antiproliferative effects, ↓growth rate of tumors in mice</td><td>50 or 100 mg/kg</td><td>21 days</td><td>(Liu et al., 2018)</td></tr><tr><td>Pancreatic</td><td>C57BL/6 mouse model</td><td>Induces apoptosis and autophagy</td><td>↓tumor formation, ↑apoptosis- and necrosis associated pathologic changes, ↓Ki-67 and VEGF,</td><td>20 mg/kg</td><td>14 days</td><td>(Zhao et al., 2021)</td></tr><tr><td>Hepatocellular</td><td>BALB/c nu/nu mice xenografted with HepG2 cells</td><td>Induces apoptosis</td><td>↓tumor growth, ↓p-Akt, ↓Ki67, ↓Vimentin, ↓Bcl-2</td><td>oridonin (30 mg/kg), sorafenib (20 mg/kg)</td><td>28 days</td><td>(Li et al., 2020)</td></tr></tbody></table>

xenograft mice model of esophageal cancer (Song et al., 2018; Jiang et al., 2019). By inhibiting the PI3 K pathway, oridonin abridged the growth of pancreatic carcinoma cells and triggered their apoptosis both in vitro and in vivo (Zhao et al., 2021). Inducing extensive apoptosis in vitro and inhibiting tumor growth in vivo by targeting TRPM7 through inactivating AKT signaling in bladder cancer, oridonin has demonstrated therapeutic anticancer potential (Che et al., 2021). By preventing the biosynthesis of valine, leucine, and isoleucine in breast cancer cells (4T1, MCF-7, and MDAMB-231), oridonin significantly decreased the expression of mTOR, PI3 K, and AKT, as well as prevented the mTOR activity (Sun et al., 2018; Zhang et al., 2023) (Fig. 3). Thus, oridonin should be considered for clinical use as a potent and long-lasting cancer therapeutic agent.

### 4.4. Targeting the JAK-STAT3 signal pathway

STAT3 (Signal transducer and activator of transcription 3) is a member of the Janus kinase (JAK)/STAT signaling pathway that is phosphorylated in response to extracellular signals (Ren, Ghoorun et al. 2020; Hu et al., 2023). Bcl-xL and survivin are two examples of

anti-apoptotic proteins which are transcribed under the influence of STAT3 (Chen et al., 2014). In many cancers, inappropriate activation of JAK/STAT signaling pathway plays an integral role in tumor growth, metastasis and oncogenesis (Ashrafizadeh et al., 2020). STAT3 activated p21 as well as cyclins (A, B1, and D), cell cycle control factors that are repressed by inhibiting active STAT3. This inhibition also decreased VEGF as well as MMP-2 expression related with cell metastasis (Tolomeo and Cascio, 2021). The administration of oridonin reduced the levels of STAT3, phospho-STAT3, p21, cyclins (A, B1, and D), VEGF and MMP-2 thereby inhibiting the activity of this pathway. As such apoptosis was induced and G2/M phase arrest established for cells derived from leukemia (K562), breast cancer cells (MCF-7), hepatocellular carcinoma cells (Bel7402), lung adenocarcinoma cells (A549), prostate adenocarcinoma cells (PC-3), uterine cervix epithelioid carcinoma cells (HeLa) and gastric adenocarcinoma epithelial cells (BGC823) (Bose et al., 2020). Yet another derivative termed CYD0618 among them has been tested to bind Cys542 on STAT3 thus irreversibly blocking ovarian cancer through allostery inactivation. This reduces STAT3 dimerization and nuclear translocation, decreasing oncogene expression that is targeted by STAT3 (Shen et al., 2019). Inhibition of the STAT3 signaling
pathway by oridonin suppressed human osteosarcoma cell proliferation, migration and invasion ability (Du et al., 2019). Accordingly, JAK/STAT signaling pathway has been established to be associated with Epithelial-Mesenchymal Transition (EMT). It was demonstrated that among other things oridonin inhibited JAK2/STAT3 signalling pathway thereby suppressing angiogenic metastatic phenotype and altering EMT in thyroid cancer cells (Liu et al., 2022). Consequently, anticancer drugs with multiple targets could be designed using oridonin and its derivatives.

### 4.5. Inducing apoptosis via autophagy by oridonin

Oridonin is a natural compound derived from the traditional Chinese medicinal plant, *Rabdosia rubescens*. Over its ability to induce apoptosis (programmed cell death) and autophagy (cellular recycling process), oridonin has been regarded in cancer research. Some studies have revealed that oridonin affects apoptosis and autophagy in cancer cells via different mechanisms (Zhao et al., 2021). Oridonin causes initiation of various pathways leading to apoptosis in cancer cells. In the case of Bel-7402, SGC-7901, HL-60, PC-3, A549, K562, L-02 cell lines, it was shown that mitochondrial pathway or intrinsic pathway are involved in regulating apoptosis (Xu et al., 2008; Wang et al., 2012; Hu, Bai, et al., 2019). This mitochondria pathway triggers disruption of mitochondrial membrane potential by the oridonin thus releasing cytochrome c as well as activating caspases (such as 3 and 8) which cause cellular death (Li et al., 2023). Moreover, this compound also influences HepG2, MCF-7, HCT-116, B16 and K562 as far as extrinsic pathway via death receptors is concerned among other effectors like L-02 cell lines (Liu et al., 2021). These mechanisms include cascade events of caspase family, Bcl-2 family, p53, MDM2, NF-κB, PI3K/Akt/mTOR, MAPK-p38 and JAK/STAT (Chen et al., 2016). Additionally it leads to degradation of essential cellular components hence initiating cellular stress ultimately resulting into cell death (Zhao et al., 2021).

### 5. Synergistic action of oridonin in cancer

In cancer treatment, the synergistic effect involves combining oridonin and other drugs to increase its anticancer potency while reducing the side effects that may arise and defeating drug resistance. Oridonin was associated with increased cytotoxicity of conventional chemotherapy drugs used in treating gastric cancer cells such as paclitaxel or cisplatin by upregulating PTEN and down-regulating PI3K/Akt signaling pathways (Wang et al., 2016). In A549 cells, similarly, oridonin sensitized cisplatin induced apoptosis through AMPK/Akt/mTOR-dependent autophagosome accumulations (Yang et al., 2019). Similarly, different studies have shown that in cancers such as MCF-7, A549, etc., a combination of oridonin along with chemotherapy can cause synergistic effect for inducing apoptosis and inhibiting proliferation of cancer cells (Li et al., 2019; Liu et al., 2021). Combining oridonin with targeted therapy against a specific kinase or signaling pathway in this manner could be more effective in disrupting cancer cell signal pathways (Rath et al., 2022; Singh Tuli et al., 2022; Tuli et al., 2022, 2023; Sethi et al., 2023). Some MUM-2B and C918 choroidal melanoma cell lines treated with TRAIL together with Oridonin exhibited significantly high levels of apoptotic rate due to G2/M arrest induction, increased levels of caspase-3 and BAX and suppressed BCL-2 (Hua et al., 2021). An example is combining oridonin with immunotherapy approaches such as immune checkpoint inhibitors or cancer vaccines, may enhance the immune system's ability to recognize and attack cancer cells (Kleponis, Skelton and Zheng, 2015; Kumar and Das, 2023).

Bioactive natural products and their nanocarriers have therapeutic efficacy against hepatocellular carcinoma because of targeted and responsive drug delivery (Chauhan et al., 2023). Further, more comprehensive safety and efficacy evaluations are needed for clinical applications (Rahman et al., 2021). Nanodelivery systems for oridonin employ nanoparticles (NPs) to incorporate or encase oridonin into a

carrier at nano scale (Liu et al., 2024). This method has a number of advantages as compared to conventional drug delivery systems such as increased solubility, improved stability, controlled release, targeted delivery and reduced systemic toxicity (Khosa, Reddi and Saha, 2018). A study on Oridonin-loaded poly (d,l-lactic acid) NPs (ORI-PLA-NP) synthesized NPs having an average size of 137.3 nm with 87.2 % of them being distributed between the range of 107–195 nm (Xing, Zhang and Tan, 2007). Improved solubility and enhanced bioavailability have been observed in Oridonin-NPs (Zhang et al., 2020). ORI-NPs tested on in-vitro and in-vivo tumors demonstrated that they significantly decreased the cancerous effects on the K562 cells and also reduced the tumor volume of S – 180 tumor-bearing mice than free ORI did (Lou et al., 2009). Similarly, ORI-NPs are created for targeting specific cancer cells or tissues such as liver-targeted delivery for instance (Li et al., 2013). ORI-NPs were found to accumulate in targeted tumor tissues thereby improving their permeability and retention effect (Liao et al., 2021). A more recent study reported that absorption of ORI-Gal-PT-NPs endocytosis increased by HepG2 cells upto 4 – 5.6 fold was detected as earlier than free ORI solution through flow cytometry analysis showing apoptosis rate increase by 4 – 5.6 % when compared to free ORI solution (Wang et al., 2016; Wu et al., 2019). Nanodelivery systems enabled controlled and sustained release of oridonin over a longer duration. This allowed for a more consistent and prolonged therapeutic effect, reducing the need for frequent dosing (Hu, Wang, et al., 2019; Zhang et al., 2020).

### 6. Safety aspects

However, its safety should also be taken into account. Oridonin also causes stomach problems, liver issues, and reversible changes in the blood (Li et al., 2021; Liu et al., 2021). Hepatotoxicity and nephrotoxicity can both result from high dosages e.g., 10mg/kg (Xu et al., 2020; Li et al., 2021). So caution must be exercised when combining this drug with others due to its potential to affect cytochrome P450 enzymes (Zhang et al., 2018, 2020). Indigestion, hepatotoxicity and changes in the blood may follow the use of Oridonin (Iskusnykh et al., 2021; Yao et al., 2023). Zhang et al. (2014) investigated systematically the growth-inhibitory activities of oridonin in human glioma. The MTT assay performed in the in vitro experiments showed the inhibition of cell proliferation by oridonin in a dose-dependent and time-dependent manner wherein U251 cells are more responsive than U87 cells to oridonin. LD50 values for the U87 cells were 20 µM at 24 h, 10 µM at 48 h, and 5 µM at 72 h, respectively; while for the U251 cells, LD50 was observed to be 5 µM at 48 h All these results strongly highlighted the therapeutic potential of oridonin. Mitigating safety issues during application of oridonin in therapy requires appropriate dose determination, monitoring and consideration for possible interactions. These authors advised professional medical advice before using it (Kleponis, Skelton and Zheng, 2015; Wang et al., 2016; Li et al., 2019).

### 7. Conclusion and future perspectives

Oridonin, an anticancer agent derived from the herbs of the *Rabdosia rubescens* plant, has shown promise in causing cell death (apoptosis) and self-digestion (autophagy) in cancer cells. What is still needed are strong clinical trials that take into account its safety, efficacy, and most suitable dosages for various types of cancer. One has to use nanotechnology or similar strategies to increase water-insoluble oridonin's solubility and improve its therapy success. Chemotherapy, targeted therapy and immunotherapy could be more powerful when oridonin is added but this needs further investigation to determine how best they can be combined for maximum effect. Furthermore, an inquiry into the synergistic activities of oridonin together with such other anticancer phytochemicals like cucurbitacin, luteolin, wogonin, silydianin, quercetin e.t.c would offer a new area for scientific research. To surmount these obstacles and turn them into opportunities for investigation in future endeavors that will include expanding the clinical trials scope through more studies
conducted in this area, development of further nano delivery strategies and investigations on combination therapies for maximal exploitation of its cancer inhibitory potential as an alternative mode of therapy.

## Ethical approval

Not applicable.

## CRediT authorship contribution statement

**Abhishek Chauhan:** Writing – original draft. **Hemant Joshi:** Writing – original draft. **Divya Kandari:** Writing – original draft. **Diwakar Aggarwal:** Writing – original draft. **Ritu Chauhan:** Writing – original draft. **Hardeep Singh Tuli:** Writing – review & editing, Conceptualization. **Arpit Mehrotra:** Writing – review & editing, Conceptualization. **Abhilasha Sood:** Writing – review & editing, Conceptualization. **Ujjawal Sharma:** Writing – review & editing, Conceptualization. **Darin Mansor Mathkor:** Writing – review & editing, Conceptualization. **Shafiul Haque:** Writing – review & editing, Conceptualization. **Naveen Chandra Joshi:** Writing – review & editing, Conceptualization. **Laurent Dufossé:** Writing – review & editing, Conceptualization.

## Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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