The ROS-dependent stimulation of cell survival and proliferation has been extensively studied. The most compelling accomplishment is the confirmation that ROS are secondary messengers involved in growth factor activation via the PI3K/Akt/mTOR and MAPK/extracellular regulated protein kinase (ERK) proliferation survival-related signaling cascades (Moloney and Cotter, 2018). Moreover, regulation of the NF-κB activation pathway and mutations in transcription factors and oncogenes, including Nrf2 and p53, are also involved.

The Akt pathway, through the phosphorylation and inactivation of its target proteins, consists of proapoptotic Bad, Bax, and Foxo transcription factors, which are responsible for their role in cell survival (Limaye et al., 2005; Moloney and Cotter, 2018). Numerous studies have shown that the ROS-induced PI3K/Akt survival pathway is activated in most cancer types. Phosphatases, such as PTEN and PTP1B, contain cysteine active sites that act as negative regulators of the PI3K signaling pathway and are oncogenic agents that are inactivated by increased H₂O₂ oxidation, thereby affecting cell survival. Considering the importance of PI3K/Akt in the mitogenic signaling cascade, excessive activation of this pathway by the destructive oxidation upstream of PTEN/PTP1B is a hallmark of malignancy (Pérez-Ramírez et al., 2015). Consistent with this finding, we found that PTEN was inactivated and the ROS-induced PI3K signaling pathway was activated in various cancers. NOXs in neuroblastoma lead to the inactivation of the oncogene PTEN and activation of the PI3K/Akt signaling pathway in an ROS-dependent manner (Calvo-Ochoa et al., 2017). Similarly, in breast cancer cells, the accumulation of transient H₂O₂ by CXCL12-activated NOX2 leads to the oxidation of PTEN and PTP1B, regulating the activation of the PI3K/Akt signaling pathway and leading to the maintenance of cell cycle protein D expression, which, in turn, stimulates cell proliferation (Deng et al., 2018).

Activation of the MAPK/ERK 1/2 pathway, as a function of increased cell proliferation, can be associated with the stimulation of growth factors and K-Ras (Khavari and Rinn, 2007). Mitochondrial ROS regulate the K-Ras-induced anchorage-independent growth of lung cancer cells through the MAPK/ERK pathway (Weinberg et al., 2010). The proliferative actions of ovarian cancer cells in the presence of high levels of endogenous ROS are facilitated by sustained ubiquitination and inactivation of endogenous mitogen-activated protein kinase phosphatase 3 (MKP3) and increased ERK1/2 activity (Chan et al., 2008). Identical results were obtained when breast cancer cells were treated with ROS scavengers/inhibitors targeting ERK1/2 or its upstream kinase MAPKK (Zhou et al., 2008). In addition to initiating its upstream signaling pathway, the MAPK phosphoenzyme is directly oxidized and inactivated, sustaining JNK activation via the reversible oxidation of cysteine to sulfenic acid at the catalytic site and the inhibition of JNK-inactivating phosphatase (Kamata et al., 2005; Son et al., 2011). As is well known, ERK1/2 not only plays a proliferative role but also functions in the survival, anchorage-dependent growth, and motility of a variety of cancer cells (Liou and Storz, 2010; Moloney and Cotter, 2018).

ROS contribute to cancer cell survival and proliferation by activating NF-κB and Nrf2. Studies identified that the formation of pancreatic precancerous lesions was attributed to K-Ras-derived mtROS activating NF-κB via PKD1 to upregulate proliferative EGFR signaling (Liou et al., 2016). Increased mitochondrial ROS levels would also induce the upregulation of antioxidant proteins, such as MnSOD, and antiapoptotic proteins through the aforementioned pathways (Storz et al., 2005), thus helping in cancer survival and proliferation. Studies have also shown that the occurrence of various cancers is strongly correlated with mutations in Nrf2 (Rojo de la Vega et al., 2018). These findings suggest that the upregulation of Nrf2, either through increased Nrf2 mRNA production by oncogenic gene transcription (DeNicola et al., 2011) or the inhibition of its blocker KEAP1 upregulation by ROS (Suzuki et al., 2019), promotes preneoplastic nodules in the liver (Zavattari et al., 2015). Furthermore, differential activation of Nrf2, caused by the previously mentioned factors, is linked to cancer recurrence and unfavorable prognosis (Wu et al., 2019).

Cancer metastasis is a complex multistep process, being one of the grounds for poor patient prognosis and treatment discouragement. The complex regulatory effects are reinforced by the fact that ROS function in cancer metastasis, allowing the regulation of key steps in cancer-increased migration, invasive potential, regulation of metabolism, epithelial–mesenchymal transition (EMT), and neovascularization (Liou and Storz, 2010).

The modulation of hypoxia contributes to the development of a malignant phenotype and aggressive cancer progression. PPP-dependent NADPH output is compromised by low glucose availability; subsequently, carcinoma cells accommodate glucose deprivation and protect against H₂O₂-induced apoptosis through the Warburg effect. Furthermore, the AMPK signaling pathway is activated to facilitate NADPH production and prevent anabolic processes that require NADPH depletion to optimize ROS yields, which significantly promotes the emergence of an aggressive phenotype (Aykin-Burns et al., 2009; Jeon et al., 2012; Ye et al., 2014; Vander Heiden and DeBerardinis, 2017).

The hypoxia-inducible factor-1 (HIF-1), composed of two subunits, HIF-1α and HIF-1β, potentially mediates cancer angiogenesis, metabolism, and metastasis, enhancing cancer survival and progression (Harris, 2002; Al Tameemi et al., 2019). ROS stabilize oxygen-sensitive HIF-α subunits by inhibiting PHD2 in the hypoxia signaling pathway (Bell et al., 2007), thereby enhancing cancer cell migration and invasion. Similarly, interest has been expressed in the increased expression of vascular endothelial growth factor (VEGF) genes and the activation of HIF-1α associated with metastatic disease (Semenza, 2012). The stability and activation of HIF-α through ROS-dependent mechanisms are strongly correlated with poor prognosis, increased cancer incidence (Horak et al., 2010), and aggressiveness in certain cancer cells. Furthermore, HIF-1 is responsible for the upregulation of glycolysis-related genes, such as lactate dehydrogenase and pyruvate dehydrogenase kinase 1, downregulation of GSH-based antioxidant gene expression (Lu et al., 2015; Stegen et al., 2016), and reduction of mitochondrial ROS production. It is equally intriguing to note that HIF-1 elicits increased lactate and carbon dioxide formation, and prevents intracellular acidification (Pouysségur et al., 2006), in both cases favoring extracellular matrix degradation and cell invasion (Rofstad et al., 2006).

EMT is the initial event in cancer cell metastasis. ROS promote metastasis by accelerating HIF-dependent angiogenesis through the stimulation of matrix metalloproteinase (MMP)-dependent ECM protein degradation (Chatterjee and Chatterjee, 2020; Aboelella et al., 2021). Another study also showed that ROS trigger the transcription factors NF-κB and FOXO3a and Rac-1, AP-1 (activator protein 1), or the p38 signaling pathway, to alter the expression of MMPs (Westermarck and Kähäri, 1999). It has also been reported that cancer cells induce the secretion of MMPs, such as MMP-1, via the upregulation of ROS to enhance vascular growth in the cancer microenvironment (Wartenberg et al., 2003). Angiogenesis, mediated by growth factors such as VEGF, can be accomplished through a coordinated signal transduction cascade by HIF-1α (Choudhry and Harris, 2018).

ROS have been proven to be excellent signaling molecules in the apoptotic process that directly induce cellular damage and activate caspase family protein-dependent activation of endogenous mitochondrial pathways and exogenous death receptor pathways (Redza-Dutordoir and Averill-Bates, 2016). ROS generate pressure against the open MPTP, causing a reduction in the mitochondrial transmembrane potential, thus contributing to the loss of membrane permeability and allowing the release of proapoptotic factors such as cytochrome c (Cyt-c) into the cytoplasm. Subsequently, once Cyt-c is released into the cytoplasm, its interaction with apoptosis protease-activating factor 1 (APAF-1) and pro-caspase-9 forms an apoptotic complex, simultaneously triggering a caspase-9 signaling cascade that breaks DNA and ultimately triggers apoptosis (Simon et al., 2000; Redza-Dutordoir and Averill-Bates, 2016; Moloney and Cotter, 2018). Furthermore, damaged mitochondria enable the production of more ROS, paradoxically accelerating apoptosis. In addition, ROS can modulate related signaling pathways and consequently cause apoptosis. Studies suggest that JNK, a subclass of the MAPK signaling pathway augmented by ROS, can respond by catalyzing the phosphorylation and downregulation of antiapoptotic proteins (Cadenas, 2004), increasing the expression of Bax, creating Bax homodimers, and ultimately destroying mitochondrial membrane integrity (Zhang et al., 2008). P38, another subclass of the MAPK signaling pathway, enthusiastically embraces apoptotic signaling enhanced by ROS production, and coincidentally, both of these can promote cell death through the involvement of apoptotic signal-regulated kinase 1 (Ask-1) (Saitoh et al., 1998; Liou and Storz, 2010). Moreover, it remains to be determined whether the ROS-mediated activity of the JNK and p38 signaling pathways is responsible for cell cycle arrest and inhibiting cancer cell growth and division (Wagner and Nebreda, 2009). Nevertheless, several other signaling proteins like P53 are also involved in ROS-induced apoptosis, and ROS above threshold levels initiate P53-induced genes, resulting in impaired mitochondrial function and triggering apoptotic effects (Safdar et al., 2016).

The extrinsic apoptotic pathway is triggered by the splicing of death-inducing ligands such as the Fas ligand (FasL) with their cognate receptors (FasR). After binding to the two receptors, the apoptotic message is transmitted to the cell interior, activating the linked death-inducing signaling complex (DISC), whose members include DD, DED, FADD (TRADD), and pro-caspase-8. Caspase-8 initiates a downstream caspase cascade that actively drives apoptosis. Cellular Fas-associated death domain-like interleukin 1β-converting enzyme inhibitor protein (c-FLIP) is a death receptor-mediated antiapoptotic factor. It has been shown that under conditions of threonine 166 phosphorylation and lysine 167 ubiquitination, the ROS-dependent degradation of the proteasome of c-FLIP reinforces the exogenous apoptotic pathway (Wilkie-Grantham et al., 2013). Additionally, in the case of N-acetylcysteine (NAC) pretreatment, the c-FLIP protein was efficiently stabilized and accelerated the initiation of apoptosis, confirming the role of ROS as an apoptosis-inducing factor (Moloney and Cotter, 2018). Moreover, ER stress and the regulation of energy metabolism triggered by ROS are indispensable for apoptosis.

Rather than acting as a mechanism for normal cell self-protection and survival, autophagy suppresses cancer and is referred to as type II programmed cell death. Ample evidence suggests that autophagy is directly mediated in malignancies and controlled by ROS levels (Poillet-Perez et al., 2015). The H₂O₂-dependent inactivation of autophagy-associated gene 4 (ATG4) leads to an increase in LC3-associated autophagosomes (Perillo et al., 2020), whereas oxidative stress in H₂O₂ and 2-ME-treated cancer cells also leads to autophagy-induced death (Chen et al., 2008). mTORC1, a negatively regulated regulator of autophagy (Moloney and Cotter, 2018), is suppressed by AMPK activation and contributes to autophagy induction. Autophagy in human bronchial epithelial cells is prevented by arsenic-induced ROS production. Notably, phosphorylation of AMPKK due to oxidative stress and the consequent alteration of the AMPK pathway further cause an increase in ROS and, eventually, apoptosis (Poillet-Perez et al., 2015). Last but not least, transcription factors, such as NF-κB, equally regulate autophagy by controlling the expression of genes that predominantly induce ROS-related autophagy in cancer, consequently regulating cell death (Boyer-Guittaut et al., 2014).

Ferroptosis is regulated by cell death (RCD), evoked by ROS-induced iron-dependent lipid peroxidation (Dixon et al., 2012). Peroxidized polyunsaturated fatty acids (PUFAs), triggered by oxidative stress involving excessive iron levels and insufficient GSH, are the underlying features of ferroptosis (Stockwell et al., 2017). There is ample evidence that intracellular iron, rendering a free state with redox activity, occurs through Fenton chemistry to increase lipoxygenase activity and ROS production (Stockwell et al., 2017). In contrast, membrane phospholipid-PUFAs are oxidized, which shows tremendous potential to shift membrane pores and integrity (Dixon and Stockwell, 2019). Studies have suggested that GPX4 utilizes GSH to reduce lipid hydroperoxides, thereby limiting ferroptosis (Kuang et al., 2020). In recent years, a mounting stream of data have emerged demonstrating that ferroptosis, specifically mediated by small molecules, exerts dramatic suppressive effects on cancer growth. Erastin, a synthetic small-molecule drug inhibiting cystine uptake, lends itself to an impairment of the GSH-dependent GPX antioxidant system via cystine/glutamate reverse transporter protein (system XC⁻) mediation, allowing for higher ROS levels and altered permeability of the outer mitochondrial membrane, causing cell death through ferroptosis in cancer cells, thus bearing mutant RAS (Yagoda et al., 2007; Dixon et al., 2012). The other agent, RAS-selective lethal compound 3 (RSL3), reportedly stimulates ferroptosis by blocking GPX, rather than the XC system (Imai et al., 2017). In addition, ROS trigger p14ARF (a cancer suppressor), which subsequently reactivates P53 and inhibits Nrf2 to activate ferroptosis and allow the downregulation of SLC7A11 and xCT activity (Chen et al., 2017). Numerous studies have confirmed that ferroptosis curtails cancer cell progression by eliminating these factors.

Cancer metastasis is inhibited by ROS overload (Piskounova et al., 2015). Remarkably, cancer cells can escape cell death during metastasis through metabolic alterations that are mediated by modulating the level of antioxidant capacity (Reczek and Chandel, 2017). Jiang et al. suggested that human melanoma cells promote metastasis by relying on NADPH-generating enzymes that rely on folate-mediated metabolism of single carbon units (Piskounova et al., 2015). Somewhat more interesting is the discovery that blood itself likely functioned as a prooxidant environment, provoking oxidative stress and hindering metastasis (Nieto et al., 2016).

Unsuitable ROS levels reinforce cell death, and inverse signals for cell survival are heightened. The survival signal is mediated by the mitochondrial ROS activation of protein kinases and NF-κB, leading to the upregulation of antioxidant proteins (Cao et al., 2020). Apoptosis triggered by natural ginsenosides via the modification of ROS, involving but not limited to endogenous and exogenous apoptotic pathways, tends to come into vogue in the treatment of cancer. In addition, many researchers have emphasized the superior role of ROS in targeting ER- or energy metabolism-mediated pathways that trigger apoptosis in various cancer cell lines. Natural ginsenoside extracts that modulate the role of ROS (lower or higher) in the aforementioned apoptotic pathways in cancer therapy should not be underestimated (Kim et al., 2017; Seervi et al., 2018; Cao et al., 2020; Zheng et al., 2020).

It was discovered that ultrasound-treated ginseng berry extract (UGBE), containing multiple ginsenosides, including Rh1, Rg2, and ginsenosides Rg3 and Rh2, could activate the mitochondria-mediated apoptotic pathway in cancer cells through an ROS-dependent mechanism. The same conclusion was obtained in ginsenoside Rh2- and Rg3-treated human leukemia Jurkat cells (Park et al., 2012; Chen et al., 2015; Jung et al., 2016; Xia et al., 2017). Consistent with previous studies, Rg3 enhanced the level of ROS and led to the caspase 9/3 cascade, yet its induction of apoptosis was not significantly disturbed by the application of NAC, suggesting that the increased ROS associated with Rg3 was not the culprit of apoptosis (Kim B.-M. et al., 2013). The underlying mechanism behind this process still requires further exploration. Several studies have uncovered a specific mechanism by which Rk1 induces mitochondria-dependent apoptosis by mediating the PTEN/PI3K/Akt/mTOR signaling pathway via elevated ROS levels in MCF-7 cells (Hong and Fan, 2019b). However, ginsenoside-induced reduction of ROS, leading to the activation of signaling pathways, is also an effective treatment for the induction of apoptosis (Huynh et al., 2021), which is consistent with the finding that diminished ROS-mediated upregulation of JNK activation plays an integral role in the ginsenoside-mediated mitochondrial apoptosis pathway (Ham et al., 2006; Mao et al., 2014). However, Chu et al. demonstrated that Rg1 exerts cytoprotective effects in MPP + -treated SHSY5 cells by reducing the ROS-mediated regulation of JNK (Chu et al., 2020).

Ginsenoside-mediated dysregulation of antioxidant enzyme activity is associated with endogenous apoptosis. Choi et al. identified that ginsenoside Rg3 regulates CAT activity and inhibits the MEK signaling pathway to mediate apoptosis (Choi et al., 2013). Rg5 and Rk1 mediate apoptosis in lung cancer cells through the regulation of GSH (Kwak and Pyo, 2016). Furthermore, Lu et al. found that Rk1 could promote apoptosis in cervical cancer cells by reducing GLS1 and GSH and inhibiting glutamine metabolism (Lu et al., 2022). However, one study pointed out that Rg1 could inhibit DMBA-mediated carcinogenesis by restoring antioxidant enzyme activity (Chu et al., 2020). FBG has cytoprotective functions by suppressing MAPK and lowering ROS levels caused by the induction of antioxidant enzyme activity (Bak et al., 2014). However, Rh2, by enhancing ROS, partially counteracts p53-induced apoptosis by activating AMPK and NF-κB signaling pathways to promote cancer survival and growth and can exert better anticancer effects when applied in combination with antioxidants (Li et al., 2011).

Rh2 and compound K evoke apoptosis in a cystathionine- and p38 MAPK-dependent manner in astrocytoma cells, and combined treatment with Fas ligands exerts synergistic cytotoxic effects by reducing intracellular ROS (Choi and Choi, 2009). Lee et al. found that the combination of Rg3 and TRAIL resulted in a noticeable improvement in ROS production to either one alone. Although the antioxidant NAC effectively inhibited ROS production, it failed to suppress apoptotic cell death induced by Rg3 combined with TRAIL, suggesting that ROS may not be required for Rg3 sensitivity to TRAIL (Lee et al., 2013).

ER stress-mediated apoptosis cannot be minimized by ginsenoside treatment. Ginsenoside Rh2 has been shown to facilitate apoptosis in lung cancer cells, especially through the induction of ROS production, stimulating the upregulation of ATF4 and CHOP, with ER stress further inhibiting cell proliferation (Ge et al., 2017). Similarly, Wu K. et al. found that ATF4 knockdown attenuated the proapoptotic effect of Rg3 in gallbladder cancer cell lines by inhibiting ROS (Wu K. et al., 2018). As such, it has been suggested that Rh2 enhances ROS, inhibits ETC complex formation, affects energy stress, upregulates VDAC1, and interferes with glycolytic pathways to promote apoptosis (Liu et al., 2020; Liu et al., 2021).

The dual role of autophagy in cancer progression and inhibition remains controversial. Natural ginsenosides can promote or inhibit autophagy by regulating ROS for cancer therapeutic effects.

It has become more unambiguous that Rg3, as an inhibitor of autophagy, can mediate the production of ROS, decrease the mitochondrial membrane potential, and consequently induce apoptosis, all of which induce the release of AIF from the mitochondria and enable nuclear translocation that leads to HeLa cancer cell death (Bian et al., 2019). G-Rh2 showed a significantly stronger inhibition of autophagy than Rg3. The specific mechanism is to impair mitochondrial function through increased ROS, leading to defective/impaired lysosomal acidification/function and, ultimately, HGC-27 cell death (Han et al., 2020). The conclusion that Rh2 inhibits autophagy in cervical cancer cells was also drawn by Wang et al. in cervical cancer cells (Wang J. et al., 2020). Furthermore, by the preapplication of N-acetyl-l-cysteine (NAC) to esophageal cancer cells, Bian et al. identified that ginsenoside Ro-induced elevated expression of autophagy-associated proteins, such as LC3B-II, was significantly reversed, precisely through the modulation of the ESR2-NCF1-ROS axis. Importantly, the study also observed that Ro enhanced the cytotoxicity of 5-fluorouracil (5-Fu) by delaying CHEK1 (checkpoint kinase 1) degradation and downregulating the DNA replication process, which strongly suggests that G-Ro can be used as an effective anticancer agent to overcome chemoresistance in combination therapy (Zheng et al., 2016). However, growing evidence suggests that the promotion of autophagy plays a critical role in cancer treatment. Hwang et al. demonstrated that the activation of mitochondrial autophagy is essential for combating lung cancer in Rg3-enriched red ginseng, which is initiated by the increase in ROS (Hwang et al., 2022). Likewise, several native ginsenosides exert anticancer effects through the ROS-mediated regulation of signaling pathways. Rh4 mediates ROS production to induce the upregulation of p53 signaling, thereby activating autophagy and positively regulating iron death to promote colorectal cancer cell death (Wu et al., 2022). However, Wu et al. revealed that Rh4 induces autophagy by facilitating the ROS/JNK/P53 pathway, and interestingly, the upregulation of autophagy-associated proteins ATG7 and Beclin-1 is involved in the regulation of autophagy (Wu Q. et al., 2018). Rg5 and Rh1 promote ROS production, and trigger MAPK activation and the PI3K/Akt signaling pathway, respectively, to promote autophagy and cell cycle arrest, inhibit cancer cell proliferation, and promote the onset of apoptosis (Liu and Fan, 2019).

Numerous studies have suggested that natural ginsenoside products display pronounced anticancer activity at different stages of cell cycle arrest. Lu et al. found that ginsenoside Rk1 effectively arrests the cell cycle in the S-phase and induces apoptosis in breast cancer MCF-7 cells. Moreover, increased p53 and p21 proteins and the downregulation of cyclin A and CDK2 might contribute to the anticancer effects of Rk1. Rk1 may regulate the proteins via the upregulation of the ROS-mediated PTEN/PI3K/Akt/mTOR signaling pathway, sequentially inhibiting proliferation and apoptosis (Lu et al., 2022). Hong et al. observed identical alterations in ROS and proteins in MDA-MB-231 triple-negative breast cancer cells, with the difference being that the cells blocked the cell cycle in the G0/G1 phase (Hong and Fan, 2019a). Huynh et al. revealed that the accumulation of the G0/G1 phase in cancer cells incubated with Rh1 was enhanced, along with marked improvement in phosphorylated Rb protein levels and p27 protein expression; meanwhile, the expression of cycle-related proteins—including cyclin D1, cyclin D3, CDK2, CDK4, and CDK6—diminished. Moreover, the mentioned reaction coincided with the ROS-mediated PI3K pathway (Huynh et al., 2021), and these results are similar to the findings of Jin et al. (2022). A decrease in ROS levels exerts an aggressive effect on cell cycle arrest. Shui et al. showed that Rg3 has promising anticancer activity against lung cancer by decreasing reactive oxygen levels, activating cell cycle-associated proteins, and controlling MAPK relevant to proliferation (Sun et al., 2016). Conversely, Jeon et al. applied NAC to counteract the G1-S phase arrest due to Rg2 via the activation of AMPK and the regulation of cell cycle regulators induced by increased ROS, implying that increased ROS can also exhibit excellent anticancer effects by promoting cell cycle arrest (Jeon et al., 2021). Comparably, Rg1 exerts apparent cancer-fighting actions on paclitaxel-resistant nasopharyngeal carcinoma cells by upregulating ROS to block the PI3k/Akt signaling pathway (Li et al., 2019). Rg18, in a similar manner, or at least in part, downregulated the JNK/NF-κB signaling pathway to lead to G1-phase cell arrest to curb cancer cell proliferation of A549 cells to combat cancer (Leem et al., 2018). It has, therefore, been abundantly demonstrated that ginsenosides can exhibit exceptional therapeutic anticancer abilities at different stages of the cell cycle via the modulation of ROS.

Targeting cancer metastasis by interfering with angiogenesis and reducing invasiveness is an important aspect of ginsenoside therapy. Previous research revealed that G-Rh2 shows both high antioxidant activity and low toxicity by decreasing the production of ROS and subsequently repressing MMP-2 and VEGF expression, thereby suppressing the invasion and metastasis of oral squamous cell carcinoma cells (Ping et al., 2020). Nonetheless, Jin et al. concluded that Rh1 repressed cancer cell angiogenesis, metastasis, and invasion by boosting MtROS-mediated inhibition of the STAT3/NF-KB signaling pathway (Jin et al., 2021). Additionally, the ginsenoside Rg1 may suppress the progression of DMBA-induced breast cancer via a concentration-dependent increase in ROS production and by modulating the activation of molecules involved in cell proliferation, apoptosis, invasion, angiogenesis, and EMT conversion (Chu et al., 2020). Targeting senescence is also a more promising approach to treat cancers, as suggested by Sin S et al., who delivered chronic treatment with sub-apoptotic concentrations of 20(S)-Rg3 to induce ROS production via Akt activation and p53/p21-dependent senescence-like growth arrest in glioma cells (Sin et al., 2012). This study provides valuable insights into the future development of 20(S)Rg3 as a novel anticancer agent.