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. 2025 Jul 27;39(9):4046–4059. doi: 10.1002/ptr.70051

Current Insights of the Potential Plant Bioactive Compounds on Modulating the mTOR Signaling Pathway in Regulating Oncological Disorders

Sonali Khanal 1, Manjusha Pillai 1, Md Shimul Bhuia 2, Muhammad Torequl Islam 2,3, Onkar Sharma 1, Rachna Verma 4,5,✉, Eugenie Nepovimova 5,6, Kamil Kuca 5,7,8,✉, Dinesh Kumar 1,5, Raihan Chowdhury 2
PMCID: PMC12423487  PMID: 40717210

ABSTRACT

Deregulation of the mechanistic target of the rapamycin (mTOR) pathway plays an important role in cancer genesis and progression, making it an attractive target for cancer treatment. Disrupting the mTOR pathway contributes to uncontrolled cell growth, increased proliferation, and enhanced cell survival, all of which are hallmarks of cancer. The findings imply that the deregulation of the mTOR pathway in cancer provides a compelling basis for therapeutic treatments. Phytochemicals such as flavonoids and polyphenols have been shown to play a key role in suppressing different kinases implicated in PI3K/AKT/mTOR signaling cascades. A thorough study of the molecular connections between bioactive substances, mTOR signaling, and autophagy activation can lead to the creation of personalized treatments that work better and have fewer side effects. Finding out how important it is to target the mTOR pathway and how to use bioactive chemicals from plants to treat cancer are both important discoveries that could lead to more precise medicine and the development of effective cancer drugs. Finally, targeting mTOR pathways using plant‐derived chemicals may be a promising therapy strategy for cancer. This review tries to summarize putative plant bioactive chemicals that act on malignancies via mTOR signaling pathways. Furthermore, the paper discusses the role of the mTOR pathway in cancer, specifically its influence on cell growth, proliferation, and survival.

Keywords: apoptosis, autophagy, mTOR signaling pathway, oncology, pharmacology, plant bioactive compounds

1. Introduction

A crucial regulator of cell growth and metabolism, the mammalian target of rapamycin (mTOR) is a highly conserved protein kinase (Boutouja et al. 2019). It is an extensively conserved enzyme that governs crucial cellular processes like growth regulation, autophagy, and metabolism. This protein kinase is a common kind of enzyme that specifically targets the amino acids serine and threonine. It belongs to a group of kinases called phosphoinositide 3‐kinase‐related kinases (PI3K), which are found in all eukaryotic organisms. This kinase is located on a chromosome (Girodengo et al. 2022; Jhanwar‐Uniyal et al. 2024). Since it was discovered in the early 1970s, rapamycin, also produced by Streptomyces hygroscopicus , fundamentally targets mTOR (Brown et al. 1994). T regulatory cells, tumor‐associated macrophages (TAMs), CD4, CD8, myeloid‐derived suppressor cells (MDSCs), endothelial cells, and cancer‐associated fibroblasts (CAF) have all been shown to be modulated by mTORC1/2 in various studies (Thomson et al. 2009; Weichhart et al. 2015). Additionally, through TAMs, T cells, activation, and the development of antigen‐presenting cells, mTOR is connected to the control of the immune system (Mafi et al. 2022). Numerous physiological processes, including metabolism, motility, transcription, apoptosis, autophagy, cell cycle progression, and differentiation, are regulated by the PI3K/AKT/mTOR signaling pathway (Saxton and Sabatini 2017). It has been found that several pharmaceuticals, both natural and artificial, are effective in inhibiting mTOR and regulating the growth of cancer. Apigetron, dihydromyricetin, piperlongumine, thymoquinone, glycyrrhizic acid, cryptotanshinone, cannabisin B, licochalcone A, and curcumin are a few of the compounds that have demonstrated promise as anticancer medications (Kim et al. 2020). Herbal medications are one of the most trustworthy sources of phytonutrients, and they have the potential to be a natural therapy and a green alternative to the widely used radioactive treatment for numerous cancers. Worldwide recognition has been accorded to these conventional herbal remedies for their anti‐proliferative, anti‐angiogenic, anti‐inflammatory, anti‐oxidant, anti‐mutagenic, and anti‐invasive characteristics (Yu et al. 2013). Around 35,000 bioactive chemicals derived from plants, seaweed, and other sources have been identified to inhibit pathogenic signaling linked with cancer start, with no detrimental or adverse effects (Tao et al. 2018).

Alkaloids, terpenoids, quinones, saponins, flavonoids, volatile oils, and phenolics, for example, have a possible cytotoxic effect against colorectal cancer cells while posing fewer dangers and side effects (Gupta et al. 2022). Phytochemicals such as flavonoids and polyphenols have been shown to inhibit different kinases implicated in the PI3K/AKT/mTOR signaling cascades (George et al. 2017). Traditional herbal remedies, on the other hand, are not widely used due to a number of important issues, including the poor solubility and bioavailability of these substances. Other reasons for plant‐based medications include drug synergism, intellectual property difficulties, variety in extraction processes and sources, and lack of drug‐likeness (Esmeeta et al. 2022). The dysregulation of the PI3K/AKT/mTOR pathway is recognized as a key driver of cancer growth and progression. PI3K/AKT/mTOR pathway abnormalities are present in about 50% of malignancies and are the most frequently activated pathways in human cancer. Subsequent investigation has shown that mTOR is often active in neoplasms and governs cancer cell metabolism by regulating crucial metabolic enzymes. As a result, it has been focused on as a potential therapy for cancer. Furthermore, rapamycin hinders the growth of endothelial cells and safeguards against the worsening of the condition by the use of drug‐eluting stents administered into the artery (Glaviano et al. 2023; Zhang et al. 2023). Furthermore, monitoring mTOR activity is critical in cancer care. The status of mTOR signaling gives important information about disease progression and therapy response. Several methods are used to monitor mTOR in cancer, including molecular profiling, biomarker analysis, imaging techniques, and so on. Techniques like liquid biopsy and biosensing have recently emerged, providing a better assessment of mTOR monitoring. These techniques aid in identifying abnormal mTOR activity, predicting therapy effects, and guiding therapeutic decisions (Meric‐Bernstam and Gonzalez‐Angulo 2009; Bouquier et al. 2020; Moldogazieva et al. 2021; Marafie et al. 2024).

This review study discusses the effects of plant bioactive compounds on altering mTOR signaling and their possible use in cancer treatment. It also outlines the methods that are currently available for detecting mTOR activity. It investigates the role of mTOR in various oncological illnesses as well as how plant bioactive substances can control its action. It also examines the potential for combining natural therapies with a nanotechnology‐mediated inflammatory cascade to treat a variety of chronic and acute disorders. The study highlights the importance of knowing and monitoring mTOR in cancer treatment throughout the discussion and investigates various methodologies and procedures used for this aim.

1.1. mTOR Signaling Pathway in Cancer

Protein kinase mTOR is divided into two signaling complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), and is a member of the phosphoinositide‐3‐kinase (PI3K) family (Laplante and Sabatini 2012). Though they phosphorylate distinct downstream substrates and exhibit varying biological functions, these two protein kinases share the same catalytic‐TOR component. In addition, there are three equivalents of mTORC1: mTOR, raptor (mTOR‐associated regulatory protein), and mLST8 (mammalian lethal protein 8 with Sec13, also referred to as GL). It also contains two inhibitory subunits, PRAS40 (proline‐rich AKT substrate of 40 kDa) and DEPTOR (mTOR‐interacting protein including DEP domain). Proton‐1/2 (found with rictor protein composition‐1/2), mSIN1 (mammalian stress‐activated protein kinase interaction protein 1), mTOR, mLST8, rictor (an mTOR‐independent raptor partner), and DEPTOR comprise mTORC2 (Battaglioni et al. 2022). While mTORC2 phosphorylates AKT on the primary phosphorylation site at Ser473, mTORC1 activity can be determined by examining the phosphorylation of ribosomal subunit S6 or the direct downstream target ribosomal subunit S6K1 on Thr389. AKT is activated by PI3K, and this leads to the phosphorylation of mTOR, which enhances cell survival and proliferation. VEGF, c‐myc, and survivin are among the oncogenes and growth factors that have been demonstrated to be upregulated with activation of the PI3K/AKT/mTOR signaling pathway. One cytokine that tumor cells release is called VEGF, and it plays a key role in angiogenesis, which is crucial for the prognosis and progression of cancer (Mafi et al. 2023) (Figure 1).

FIGURE 1.

FIGURE 1

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mTOR signaling pathway in cellular process and regulation of various cellular functions.

In endometrial cancer cells, it has been demonstrated that natural drugs like epigallocatechin gallate (EGCG) decrease the secretion of vascular endothelial growth factor A (VEGFA). This, in turn, inhibits the PI3K/AKT/mTOR/hypoxia inducible factor‐1 (HIF‐1) pathway and suppresses cancer angiogenesis (Gao et al. 2015). Based on these data, it seems sensible to assume that blocking PI3K/AKT signaling results in hyperactivation of the mTOR pathway, which encourages cell division and triggers the cell cycle transition in some cells (Laplante and Sabatini 2013). This eventually develops into a cancer prognosis, according to many publications on human cancer (Murugan 2019). Some typical causes of mTOR hyperactivation include loss of function due to mutations in tumor suppressors such as neurofibromin 1/2 (NF1/2), oncogenic mutations in KRAS, PIK3CA, phosphatase and tensin homolog (PTEN), AKT, or tuberous sclerosis 1/2 (TSC1/2) (Grabiner et al. 2014). Moreover, there is a strong correlation between the activation of the PI3K/AKT/mTOR pathway and the acquisition of Epithelial‐Mesenchymal Transition (EMT) in cancer cells (Guo et al. 2016; Chang et al. 2013). The PI3K/AKT/mTOR signaling pathway may also affect cancer cells and host immunity.

2. Mechanism of mTOR Regulation in Cancer Pathways

2.1. Autophagy

Autophagy, which plays crucial roles in cellular homeostasis and cell survival in both healthy and pathological conditions, is the product of the evolution of the conserved catabolic process (Boya et al. 2013). According to White (2015) and Kimmelman and White (2017), it is also thought of as a survival‐promoting route that regulates cancer cells and has a complicated role in the growth, development, and propagation of cancer cells. Reactive oxygen species (ROS) buildup and hunger trigger the induction of autophagy (Yun et al. 2020). Two main complexes trigger autophagy: the Unc‐51‐like kinase 1 (ULK‐1) complex and the class 3 phosphoinositide 3‐kinase (PI3K) complex, which comprises Beclin‐1 (Birgisdottir et al. 2019). Activation of the PI3K/AKT/mTOR signaling pathway inhibits it. Growth hormones, amino acids, and ROS may all promote the inhibition of autophagy by activating protein kinases such as mTOR (Lamb et al. 2013; Russell et al. 2014). Moreover, class 1 PI3K diminishes autophagic flow by activating the mammalian rapamycin (mTOR) target, which lowers ULK‐1 (Kim et al. 2011).

The process of macroautophagy results in the emergence of double‐membrane‐bound vesicles called autophagosomes. Transforming a cytosolic truncated protein (LC3‐I) into a phosphatidylethanolamine‐conjugated variant (LC3‐II) results in the formation of an autophagosome. When a lysosome and an autophagosome combine, an autolysosome is created. The autophagic cargo in the autolysosome destroys the autophagy substrates LC3B‐II and p62 (ubiquitin binding protein). The formation of p62 and LC3B‐II aggregates is thought to be a trustworthy sign of a reduction in autophagic flux. Recently, autophagy and TLR signaling were connected (Into et al. 2012). TLR4 inhibition has the potential to decrease cell proliferation; nevertheless, the autophagy‐induced survival mechanism is a conserved catabolic system that has evolved over time and is engaged in a variety of physiological processes, including host protection, cellular metabolism, and longevity (Kuballa et al. 2012; Tey and Khanna 2012).

Most nanoparticles have been shown to aggregate in acidic vesicular organelles such as endosomes and lysosomes, and lysosomes play a crucial role in amino acid‐induced mTORC1 activation (Nel et al. 2009; Parveen et al. 2012; Lunova et al. 2019). Because mTOR signaling is modulated, targeting cancer cell lysosomes with nanoparticles may be a practical strategy for chemotherapeutic treatment. It could be possible to improve the curative benefits of selective mTOR inhibitors by combining them with nanoparticles. Moreover, modifying the surface of nanomaterials could impact mTOR signaling in a unique way. For example, polystyrene nanoparticles with carboxyl groups stimulate mTOR, while those with amino groups inhibit mTOR signaling.

Research on the molecular mechanisms underlying the modification of mTOR signaling by nanoparticles is necessary to maintain the targeted therapeutic effect on cancers. Moreover, as the lysosome is the site of both mTORC1 activation and nanoparticle accumulation, more research is required to understand the relationship between lysosome‐mTORC1 and nanoparticles in cancer cells. Research on the use of mTOR inhibitors in conjunction with tailored nanoparticles to treat certain cancers is essential (Allemailem et al. 2021). The autophagic mechanisms by regulating mTOR signaling pathways in various cancers are displayed in Figure 2.

FIGURE 2.

FIGURE 2

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The autophagic mechanisms by regulating mTOR signaling pathways in oncological disorders.

2.2. Apoptosis

Apoptosis, which is triggered by many anticancer medications, is another crucial mechanism in the therapy of cancer (Pistritto et al. 2016). Two major molecular pathways are involved: extrinsic (mediated by death receptors) and intrinsic (mitochondrial) (Putcha et al. 2002; Elmore 2007). The Bcl‐2 and caspase families are the main groups affected by the intrinsic pathway (Putcha et al. 2002). TNF activates caspase‐8 by interacting with TNF receptor 1 (TNFR1) and cleaving procaspase‐3 into its active form (Elmore 2007). By activating caspases through the mitochondrial pathway or releasing cytochrome C, phytochemicals can induce apoptosis. An apoptosis‐inducing factor (AIF) is produced as a result of them (Jung et al. 2007; Fernández‐Lázaro et al. 2024). It has been demonstrated that several of these compounds suppress anti‐apoptotic factors while increasing the production of pro‐apoptotic proteins such as caspase‐3 and BAX (Wang et al. 2015). Figure 3 depicts the apoptotic mechanism in tumors that is mediated by mTOR signaling pathways.

FIGURE 3.

FIGURE 3

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The mechanism of apoptosis by regulating mTOR signaling pathways in oncological disorders.

2.3. Inhibition of Proliferation

Cancer cells change their metabolism to have access to nutrients, which helps them grow and proliferate. Pathways that promote food absorption control have a similar alteration in cancers, notwithstanding the variety of genetic alterations that lead to carcinogenesis (Pazhooh et al. 2021). Therefore, restricting the intake of nutrients and other essential materials (such growth hormones) can prevent the development and metabolism of malignant cells, making this a potentially effective therapeutic approach for the treatment of cancer (Feitelson et al. 2015; Zhu and Thompson 2019). According to Mayer and Arteaga (2016), hyperactivation of mTOR signaling promotes cell proliferation and metabolism, both of which are involved in the genesis and growth of tumors. According to Watanabe et al. (2011), the signaling pathway is mainly involved in cell growth, survival, metabolism, production of proteins, and homeostasis. Through SGK1 kinase, the mTOR signaling system synchronizes anabolic processes with energy, oxygen, and food availability as well as external stimuli to control cell growth and proliferation (Dibble and Manning 2013; Mori et al. 2014). Consequently, natural mTOR signaling system inhibitors can decrease the growth of malignant cells, making this a prominent therapeutic target in the management of cancer.

3. Effect of Plant‐Derived Bioactives on mTOR Pathway

Plant bioactive substances are second‐generation metabolites that have pharmacological or toxicological effects on both humans and animals. These plant‐derived bioactives interact with the mTOR pathway through various mechanisms, modulating subsequent cellular processes. Plant bioactive compounds have the potential to significantly impact the mTOR pathway, offering promising treatment approaches for disorders characterized by mTOR dysregulation (Fakhri et al. 2022). Several plant bioactive compounds have been identified to affect the mTOR pathway. The widely recognized plant bioactive ingredient resveratrol, which is present in grapes and red wine, stimulates AMP‐activated protein kinase (AMPK), a cellular energy gauge. The tuberous sclerosis complex (TSC) proteins are phosphorylated and activated during AMPK activation, hence inhibiting mTOR function and suppressing the mTOR pathway. Resveratrol may have curative properties because of its activation of AMPK and reduction of mTOR signaling, which reduce protein synthesis and promote autophagy (Brockmueller et al. 2021). Curcumin, a bioactive component of turmeric, has an effect on the mTOR pathway as well. It controls the production of microRNAs linked to mTOR signaling and inhibits the PI3K/AKT pathway, a major upstream activator of mTORC1. Furthermore, curcumin modifies mTOR activity by activating AMPK. By inhibiting mTOR‐mediated processes, curcumin exhibits potential anti‐inflammatory and anticancer effects (Khan et al. 2020). EGCG, a green tea catechin, has been demonstrated to reduce mTOR signaling by activating AMPK and decreasing AKT, a prominent mTORC1 activator. This results in decreased cell proliferation and the activation of autophagy. EGCG's mTOR inhibitory actions are linked to its anti‐cancer chemo‐preventive properties (Seok et al. 2019). Berberine, an isoquinoline alkaloid found in plants like Goldenseal and barberry, inhibits mTORC1 activation through the AMPK‐dependent pathway, thereby suppressing mTOR signaling. Berberine's potential therapeutic benefits against various conditions such as cancer, diabetes, and cardiovascular diseases may be influenced by its ability to modulate the mTOR pathway (Rauf et al. 2021). Triterpenoids such as celastrol and ursolic acid also impact the mTOR pathway. Celastrol, derived from Tripterygium wilfordii, inhibits mTOR signaling by reducing mTORC1 activity and inducing autophagy. Ursolic acid, found in plants like rosemary and apple peels, inhibits mTORC1 signaling by reducing the phosphorylation of downstream targets. These compounds have implications for cancer prevention and treatment (Gill et al. 2016). Sulforaphane, derived from cruciferous vegetables like broccoli and cauliflower, has demonstrated mTOR inhibitory effects and is associated with the mechanisms involved in reduced cancer cell proliferation (Xie et al. 2022). Table 1 shows different bioactive compounds extracted from various plants to target pathways regulating cancers.

TABLE 1.

Plant‐derived bioactive compounds acting through mTOR pathways to treat various oncological disorders.

Plant bioactive compounds Plant source Target pathway Type of cancer References
Resveratrol Grapes, red wine AMPK, tuberous sclerosis complex (TSC) proteins Breast cancer, prostate cancer, colorectal cancer Alayev et al. (2015)
Curcumin Turmeric Phosphoinositide 3‐kinase (PI3K)/AKT pathway, AMPK Breast, colorectal, pancreatic Hamzehzadeh et al. (2018)
Epigallocatechin gallate (EGCG) Green tea AMPK, AKT Breast, prostate, lung Singh et al. (2011)
Quercetin Onions, apples, berries, tea PI3K/AKT pathway, mTORC1 Lung, breast, colon Mirza‐Aghazadeh‐Attari et al. (2020)
Caffeic acid Coffee, fruits, vegetables PI3K/AKT pathway, mTORC1 Liver, colon, breast Narayanankutty (2021)
Ursolic acid Apple peels, rosemary mTORC1 downstream targets (S6 kinase, 4E‐BP1) Breast, colorectal, prostate Zhao et al. (2020)
Berberine Goldenseal, barberry AMPK, mTORC1 Breast, gastric liver, colorectal, pancreatic Zhu et al. (2022)
Celastrol Tripterygium wilfordii (Thunder God Vine) mTORC1, autophagy Lung, pancreatic, breast, colon, leukemia Haroon and Kang (2020)
Kaempferol Chinese medicinal plants, herbs, fruits, beans mTORC1, mTOR‐related gene expression Lung, liver, colon Imran et al. (2019)
Genistein Soybeans, legumes PI3K/AKT pathway, mTORC1 Breast, prostate, ovarian Sharifi‐Rad et al. (2021)
Fisetin Strawberries, apples, onions PI3K/AKT pathway, mTORC1 Breast, prostate, ovarian Rengarajan and Yaacob (2016)
Pterostilbene Blueberries, grapes PI3K/AKT pathway, mTORC1 Breast, lung, liver, prostate, colorectal Levenson and Kumar (2020)
Olive leaves Olive leaves (Olea europaea L.) PI3K/AKT pathway, mTORC1 Breast, lung, colorectal, prostate Albogami and Hassan (2021)
Sulforaphane Cruciferous vegetables (broccoli, cauliflower) AMPK, mTORC1 Breast, bone, lung, colorectal, bladder, prostate Esteve (2020)
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4. Effect of Plant Bioactives Against mTOR Pathways Mediated Oncological Disorders

4.1. Oral Cancer

The anticancer properties of lycopene (LP) on oral cancer (OC) cells indicate that it may stimulate the PI3K/AKT/mTOR signaling pathway, which would suppress EMT and boost OC cell death. Wang et al. (2020) found that the anti‐cancer properties of LP were linked to a dose‐related rise in apoptosis and a reduction in the growth, building of colonies, movement, and penetration of OC cells. To understand the mechanism underlying the regulatory effect of LP on OC, western blot was used to analyze the EMT markers (E‐cadherin and N‐cadherin) and important proteins associated with the PI3K/AKT/mTOR signaling pathway. In OC cells, LP treatment increased the ratio of EMT markers while decreasing the expression ratios of p‐PI3K/PI3K, p‐AKT/AKT, and p‐mTOR/mTOR. Cinnamomum zeylanicum extract (CZE) and its active component cinnamaldehyde (CIN) have demonstrated anti‐tumor properties against oral cancer. Laboratory studies indicated that both CZE and CIN effectively reduced the growth and proliferation of oral cancer cells, triggered apoptosis, and promoted autophagy. Additionally, they were found to inhibit the invasion and movement of NF‐κB into the cytoplasm, while also lowering the expression of several pathways related to PI3k‐AKT–mTOR (Aggarwal et al. 2022). Artonin E (AA2) and artobiloxanthone (AA3) induce apoptosis in oral cancer cells because they activate both caspase‐3 and caspase‐9, integral proteins in apoptosis. Both inhibited the expression of oncogenic proteins Bcl‐2, COX‐2, VEGF, and MMP‐9 connected with the survival of tumors, inflammatory, angiogenetic, and metastatic diseases. Moreover, AA2 and AA3 affect the Akt/mTOR and STAT‐3 signaling pathways by inhibiting the key cellular processes of cell proliferation, survival, and tumor growth (Aswathy et al. 2024).

4.2. Breast Cancer

It is well known that epidermal growth factor (EGF) phosphorylates mTOR and the associated mitogen‐activated protein kinase, which subsequently synthesizes genes linked to apoptosis, including hypoxia‐triggered factor 1‐alpha (HIF1). Jiang and Liu (2008) reported that the activation of the mTOR‐mediated HIF1 factor enhances several activities of endothelial and cancer cells, including the production of proteins, blood vessel development, the spread of cancer cells, emigration, division, and the death of cells. Park et al. (2016) investigated this pathway and found that pomolic acid prevents mTOR from being phosphorylated by EGF. HIF1 is also an important modulator of VEGF synthesis and a critical regulatory protein downstream of mTOR signaling. Tsai and Wu (2012). Increased HIF activation, which controls carcinogenesis, angiogenesis, and tumor expansion via VEGF, is generally associated with increased mTOR stimulation of following proteins, such as 70S6K and 4E‐BP1 (Guru et al. 2015). It has been found that pomolic acid inhibits the phosphorylation of mTOR and subsequent proteins, such as p70S6K and 4E‐BP1, in cells of breast carcinoma, which is triggered by EGF.

Muhammad et al. (2017) found that bitter melon ( Momordica charantia ) extract (BME) blocks mTOR/AKT signaling, which in turn promotes autophagy. Several investigations have demonstrated the therapeutic potential of mTOR kinase in the management of cancer. Moreover, BME stimulated AMPK in breast cancer cells, which controls cellular metabolism in an ATP/AMP ratio‐dependent approach to assist in maintaining a proper equilibrium for energy (Mihaylova and Shaw 2011).

Khan et al. (2021) investigated if the activity of important indicators, such as the tumor suppressor p53, pro‐apoptotic Bax, anti‐apoptotic Bcl‐2, and effector caspase‐3, increased in response to ethanolic Ajwa Dates Pulp Extract (ADPE). To gain more insight into the intracellular signaling system, the regulation of mTOR and AKT molecules was also investigated. After 48 h of ADPE treatment, the MDA‐MB‐231 cancer cell line underwent apoptosis as a result of decreased p‐AKT and p‐mTOR levels. According to these results, ADPE inhibits the AKT/mTOR signaling pathway, which is important for controlling the development and division of breast cancer cells.

It has been discovered that the effects of ursolic acid (UA) on cell survivability and mortality are modulated via the PI3K/AKT and MAPK cellular signaling pathways (Achiwa et al. 2007). Two higher dosages of UA (0.10% and 0.25%) were investigated by De Angel et al. (2010) on MMTV‐Wnt‐1 breast tumors. The results showed a significant reduction in ribosomal protein S6 (Ser265/569), phosphorylation of AKT, and MAPK cellular signaling. These findings validate UA's capacity to alter the AKT/mTOR pathway, inducing apoptosis and so impeding the growth of tumors. Comparably, it has been demonstrated that flavonoids and isoflavones extracted from Tephroseris kirilowii and Astragalus membranaceus cause cell death in various breast cancer in humans cell types by obstructing the PI3K/AKT/mTOR pathway (Zhang et al. 2018; Zhou et al. 2018). It has been shown that extracts of rosemary ( Rosmarinus officinalis ) reduce AKT and mTOR phosphorylation/activation, suggesting potential anticancer benefits (Jaglanian and Tsiani 2020). Resveratrol effectively suppressed the growth of breast cancer cells by causing developmental suspensions through the disruption of mTORC1 signaling networks and targeting AKT, as reported by Alayev et al. (2017).

Ganesan et al. (2024) evaluated the role of ononin, an isoflavonoid, on lung metastasis in triple‐negative breast cancer, showing very encouraging results. Ononin resulted in 50% inhibition of the proliferation of TNBC cells and decreased colony formation by 60% as measured in colony‐forming assays. The invasion and motility of TNBC cells decreased by 40% as determined using Transwell and wound healing assays. Ononin also resulted in a 45% reduction in tumor growth in TNBC xenograft models and decreased lung metastasis by 50%. It further reversed epithelial‐mesenchymal transition (EMT), downregulated EMT markers, and matrix metalloproteinases by 30% as assessed by western blotting. It also inhibited EGFR phosphorylation by 40%, which resulted in the inhibition of PI3K/Akt/mTOR signaling pathways with a 35% reduction. It was nontoxic to the liver and kidneys; thus, it is not toxic to the body system, and these findings make ononin a therapeutic agent for targeting the pathways mediated by EGFR in the metastasis of TNBC.

4.3. Lung Cancer

The transcription levels of AKT and mTOR mRNA in cells were assessed by Liu, Gao, et al. (2018) after curcumin therapy. They identified a substantial decrease in the transcription levels of AKT and mTOR mRNA in the treated sample as contrasted to the standard. The researchers used mTOR and PI3K/AKT inhibitors, such as rapamycin and LY294002, to evaluate curcumin in order to validate its inhibitory effect on these pathways. Key signaling molecules like mTOR, p‐mTOR, AKT, and p‐AKT were expressed in comparison to the reference cell line using western blotting, as mRNA does not accurately reflect protein expression. Curcumin therapy, in conjunction with prior treatment with rapamycin and LY294002, enhanced starvation and death in cancer cells by inhibiting mTOR signaling. Ahmad et al. (2023) explored the anticancer properties of two plant‐derived bioactive compounds, curcumin and plumbagin, focusing on their impact on the PI3K/AKT/mTOR pathway. Molecular docking analysis revealed that the combination of curcumin and plumbagin was more effective in inhibiting this pathway than either compound alone. In particular, the binding free energy analysis indicated that the complexes formed by PI3K, AKT, and mTOR with the combination of curcumin and plumbagin exhibited significantly higher binding free energy levels, suggesting a more effective synergistic approach to targeting the pathway.

4.4. Leukemia

Using gene expression and protein immunoblotting assays, Tlili et al. (2021) examined the impact of Rhus tripartita extracts on the PI3K/AKT/mTOR signaling pathways in acute monocytic leukemia THP‐1 cells. The findings suggest that R. tripartita extracts induce cell cycle arrest and apoptosis via the PI3K/AKT/mTOR signaling pathway by reducing phosphorylation of mTORC1 substrate S6Ser2040‐244 and mTORC2 downstream target AKT‐Ser473 in acute monocytic leukemia THP‐1 cells. Moreover, it is known that gallic acid inhibits AKT/mTOR signaling, which leads to mitochondrial dysfunction, an energy crisis, and the death of acute myeloid leukemia cells (Gu et al. 2018). Targeting key components of tumor suppressors, such as phosphatase and tensin homolog (PTEN), tuberous sclerosis 1/2 (TSC1/2), neurofibromin 1/2 (NF1/2), or oncogenic mutations in KRAS, PIK3CA, or AKT, may represent an effective treatment to kill acute myeloid leukemia and leukemia stem cells, according to growing evidence (Grabiner et al. 2014). Al‐Rawashde et al. (2022) examined the potential anti‐leukemic properties of thymoquinone (TQ), a compound derived from Nigella sativa , specifically on acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) cells by targeting the JAK/STAT and PI3K/Akt/mTOR signaling pathways. Treatment with TQ in FLT3‐ITD positive MV4‐11 AML cells and BCR‐ABL positive K562 CML cells led to a dose‐ and time‐dependent reduction in cell proliferation, significant downregulation of PI3K, Akt, and mTOR, and an increase in PTEN expression at both mRNA and protein levels. TQ effectively inhibited both the JAK/STAT and PI3K/Akt/mTOR pathways, resulting in a decrease in leukemia cell proliferation. These results indicate that TQ may be a promising therapeutic option for AML and CML, highlighting the need for further in vivo studies and clinical trials to assess its molecular mechanisms and effectiveness.

4.5. Gastric Cancer

It has been demonstrated that Thymoquinone, a bioactive lactone produced by N. sativa seed oil (black cumin), stimulates death in gastric cancer cells through disrupting the PI3K/AKT/mTOR signaling system. The treatment of thymoquinone induced a dose‐dependent decline in the concentrations of total AKT, mTOR1, mTOR2, and pI3K, but not in the levels of p‐AKT (S473), p‐AKT (T308), p‐mTOR1, p‐mTOR2, or pPI3K. Moreover, thymoquinone suppressed the production of mesenchymal genes such as N‐cadherin, Vimentin, and TWIST and hindered the spreading of gastric cancer cells. However, in gastric cancer cells given thymoquinone, there was a substantial increase in the regulation of epithelial marks like cytokeratin‐19 and E‐cadherin. Wu et al. (2024) investigated the therapeutic effects and mechanisms of gypenoside, a natural extract from Gynostemma pentaphyllum, on gastric cancer. Gypenoside was found to induce apoptosis in HGC‐27 and SGC‐7901 gastric cancer cells in a dose‐ and time‐dependent manner by targeting the PI3K/AKT/mTOR signaling pathway, as confirmed through network pharmacology, molecular docking, and western blot analyses. Mechanistically, gypenoside inhibited the phosphorylation of STAT3, which led to a reduction in PD‐L1 transcription in gastric cancer cells. This inhibition enhanced the antitumor activity of CD8+ T cells, as shown in coculture experiments. In vivo studies further supported gypenoside's antitumor effects, revealing significantly downregulated PD‐L1 expression in tumors treated with gypenoside. These findings suggest that gypenoside induces apoptosis through PI3K/AKT/mTOR inhibition and boosts T‐cell‐mediated immunity by suppressing STAT3 phosphorylation and PD‐L1 expression, making it a promising candidate for gastric cancer immunotherapy.

4.6. Hepatic Cancer

Dihydromyricetin, a flavonoid compound derived from Ampelopsis grossedentata, lowers mTOR by altering its precursor signaling channels, according to Xia et al. (2014) in an additional study. The western blot approach was used to investigate the class III phosphatidylinositol 3‐kinase/phosphoinositide‐dependent protein kinase 1/protein kinase B (PI3K/PDK 1/AKT) and extracellular signal‐regulated kinase (AMPK) pathways, which are mTOR‐related upstream signaling molecules. These processes have been connected to the hepatic cancer (HepG2) cells' activation of autophagy. Dihydromyricetin treatment increased PI3K expression while decreasing AKT and ERK1/2 phosphorylation. One master kinase that might hinder autophagy is PDK 1. Furthermore, by reducing the induction of AKT as well as subsequent targets of mTOR, cannabisin B, a naturally occurring substance isolated from the hempseed ( Cannabis sativa L.) hull, restricts cell growth and leads to cell death in human (HepG2) hepatocarcinoma cells (Chen et al. 2013). Prunetrin (PUR), which is derived from Prunus species, shows anti‐cancer properties in Hep3B liver cancer cells. It halts the cell cycle at the G2/M phase by lowering the levels of Cyclin B1, CDK1/CDC2, and CDC25c, and it triggers intrinsic apoptosis via the mitochondrial pathway. This is supported by the increased presence of cleaved caspase‐3, caspase‐9, PARP, and Bak, along with a reduction in Bcl‐xL levels. PUR also inhibits the AKT/mTOR signaling pathway and activates p38‐MAPK in a dose‐dependent manner, leading to reduced cell proliferation and increased apoptosis. These results indicate that PUR could be a promising therapeutic agent for hepatocellular carcinoma (Abusaliya et al. 2023).

4.7. Cervical Cancer

A flavonoid called licochalcone A (LiclA), which was isolated from the Batalin root of Glycyrrhiza inflata, inhibits the PI3K/AKT/mTOR signaling pathway in human cervical carcinoma lineages, triggering autophagy and cell death. LiclA decreased the expression of phosphor‐mTOR (ser2448), phosphor‐mTOR (ser2481), Raptor, and Rictor in a dose‐ and time‐dependent manner, according to Tsai et al. (2015). Moreover, rapamycin, a mTOR inhibitor, pretreatment in cancer cells showed a synergistic effect with LiclA in causing death, cancer prevention, and autophagy induction. Chrysotoxine (CTX) has two mechanisms through which it accomplishes an anti‐cervical cancer effect; it is inducing ferroptosis and preventing the PI3K/AKT/mTOR signaling pathway. CTX induces ferroptosis by elevating reactive oxygen species (ROS) and lipid peroxides, causing oxidative bumb. CTX causes this via the p53/GPX4/SLC7A11 axis, in which p53 is activated by CTX and the expression of its inhibitor SLC7A11, and functionally, CTX blocks GPX4, a master regulator of cellular defense against lipid oxidation. Excessive lipid peroxides and ROS drive ferroptotic cell death. Finally, CTX also suppresses the PI3K/AKT/mTOR axis, which is crucial for cell maintenance and survival in addition to phosphatidylinositol metabolism. CTX inhibits cellular metabolic activity and protein synthesis by interfering with this pathway, thus inducing cell death that limits tumor development (Zhou et al. 2024).

4.8. Urinary Bladder Cancer

Gartanin, a xanthone that occurs naturally in Garcinia mangostana , has shown promise as a tumor suppressor against human urinary bladder cancer. Studies have shown that gartanin therapy inhibits downstream activities of the mTOR process (p70S6 and 4E‐BP1) by two processes including AMPK stimulation as well as AKT suppression, accordingly (Liu et al. 2013). These studies also showed that phosphorylation degrees of mTOR and AMPK in RT4 cells were not significantly changed, yet it led to a dose‐dependent decrease in both phospho‐AKT and overall AKT levels.

Furthermore, Kavalactones, a type of lactone compound found in the roots of the kava plant ( Piper methysticum ), consist of docetaxel, yangonin, and flavokawain A. These compounds have a tendency to hinder the mTOR pathway by altering its downstream (rpS6, p70S6K, and 4EBP1) and upstream (LKB1, AKT signaling, and PRAS40) instances. This is compatible with the dropped viability of human bladder cancer cell lines (Liu et al. 2017). By modifying the AKT/mTOR signaling pathway through microRNA regulation, resveratrol promotes autophagy in bladder cancer cells (Zhou et al. 2014). By targeting the PI3K/AKT/mTOR pathway, paclitaxel and curcumin reduce autophagy in the bladder cancer cells (Khan et al. 2020).

Sulforaphane, an isothiocyanate in cruciferous vegetables, has potent anticancer effects mostly against bladder cancer. It causes apoptosis, cell‐cycle arrest, and suppresses bladder cancer cell proliferation, invasion, and metastasis. Sulforaphane also inhibits gluconeogenesis in bladder cancer and enhances chemotherapeutic drug action. It modulates its targeted basal molecular cascades, including the PI3K/AKT/mTOR pathway, MAPK, NfκB ZO‐1, NCAT, Nrf2, and miR‐124/IL‐6R/STAT3, which are major in bladder cell multiplication. It also affects bladder cancer stem cells and thus could be important in overcoming chemoresistance (Zuo et al. 2023).

G. pentaphyllum, by its active compound gypenosides, showed strong anticancer activity against bladder cancer. Bioactive ingredients of 10 compounds and 163 gene targets were identified using network pharmacology. VEGFA, STAT3, and PI3KCA were found to be critical candidates. The PI3K/AKT/mTOR signaling pathway is inactivated by the mechanism of action. Molecular docking confirmed the high binding affinity of gypenosides to PI3K, AKT, and mTOR. In vitro, the gypenosides caused the disruption of the signaling pathway through which bladder cancer cells underwent apoptosis, thus bringing about reduced proliferation and colony formation. In vivo studies further corroborated these results as gypenosides greatly inhibited tumor growth (p < 0.05), largely by promoting apoptosis through the PI3K/AKT/mTOR pathway suppression (Li et al. 2022).

4.9. Colon Cancer

The Ras protein is oncogenically activated in tumor cells, and this can be regulated by chemical compounds to reduce the proliferation of cancer cells. Kumar and Agnihotri (2019) combined only one intraperitoneal 1,2‐dimethylhydrazine (DMH) with a week‐long exposure to the inflammatory agent dextran sulfate sodium (DSS) to synthetically induce colorectal cancer (CRC) in mice. This resembled the unusual crypt foci–adenoma–carcinoma sequence that occurs in human CRC. It has been identified that the Ras oncoprotein connects with PI3K to phosphorylate and stimulate AKT. An alkaloid termed piperlongumine (PL), which is extracted from Piper longum Linn, substantially suppressed PI3K levels and Ser473 phosphorylation of AKT, thereby assessing the activity of both AKT/mTORC1 and mTORC2.

Additionally, after receiving DMH, DSS, and PL together, there was a decline in the gene transcription factor of NF‐kB, which has been proposed to promote a defense against apoptosis by enhancing levels of anti‐apoptotic proteins like Bcl‐2. Liu, Zhao, et al. (2018) found that the stimulated portion of clove produces apoptosis in colorectal cancer HCT‐116 cells by a PI3K/AKT/mTOR‐mediated autophagic route. The key component in cloves, oleanonic acid, diminished phospho‐Akt levels, downregulated phospho‐mTOR, and blocked PI3K phosphorylation in a dose‐dependent approach. Its combination activity using the PI3K regulator LY294002 proved more obvious in decreasing the relative amounts of p‐AKT/AKT and p‐mTOR/mTOR.

Atractylodin (ATD) suppresses mTOR and p38MAPK phosphorylation and elevates Beclin‐1 expression to stimulate autophagy in a cholangiocarcinoma cell line (Acharya et al. 2021). Atractylodes lancea is the principal origin of ATD. The influence of ATD on PI3K phosphorylation was dose‐dependent. According to Corti et al. (2019), AKT is a PI3K subsequent regulator protein that modulates angiogenesis, cell growth and multiplication alongside controlling the activity of the downstream mTOR protein. By inhibiting AKT, which either actively phosphorylates mTOR or slowly lowers the tuberous sclerosis complex, a negative regulator of mTOR, ATD substantially enhanced autophagy. Moreover, relative to the untreated control group, as the amount of ATD increased, so did the level of total mTOR and p‐mTOR.

In human colon tumor cells HCT116 and HT29, the curative impacts of curcumin combined with 5‐Fluorouracil (5‐Fu) on cellular autophagy have been investigated (Zhang et al. 2017). In order to discover the molecular process that activates the autophagic reaction, this research explored alterations produced to the fundamental autophagic machinery, particularly ULK1 and its upstream triggers AKT, mTOR, and AMPK. The findings suggested that mono‐5‐Fu, without altering AMPK signaling, regulated P‐ULK1(Ser317) and suppressed AKT/mTOR phosphorylation, causing autophagy in HCT116 and HT29 cells. Nevertheless, it was found that the combined administration of curcumin and 5‐Fu reduced all rates of serine/threonine kinases, including P‐AKT, P‐mTOR expressions, P‐AMPK, and P‐ULK1(S317). El‐Wetidy et al. (2024) investigated the apoptotic pathway by which Urolithin A (UA) exerts its inhibition of colorectal cancer (CRC) cells. Treatment with UA of HT29 cells was associated with apoptosis and suppressors of death, such as U0126 and LY294002, markedly protected the cells from death. Conversely, these suppressors showed little inhibition toward metastatic SW620 cells and indicated that the p‐AKT/PI3K/mTOR pathway was involved in CRC. Western blotting confirmed that the effects of UA on p‐AKT/PI3K/mTOR signaling are related to its effect on increasing the phosphorylation of ERK and AMPK in HT29 cells. UA lowered p‐AKT and mTOR but enhanced p‐c‐RAF and PTEN in SW620 cells, thus proposing a defense mechanism against apoptosis induced by UA. All these results illustrate that UA is potentially able to modulate the pathways of CRC progression and metastasis.

5. Monitoring of mTOR Signaling

Evaluating mTOR activity is essential to comprehending the intricate signaling network governing cell division, development, and metabolism. Numerous physiological and pathological processes, such as cancer, metabolic issues, and neurological illnesses, depend on the mTOR pathway. Scientists have come to understand that tracking mTOR activity is essential for gaining understanding of the underlying causes of illness and developing tailored treatments (Swiech et al. 2008; Yu et al. 2011).

Since 2000, scientists have been attempting to create trustworthy stand‐in indicators to gauge how well mTOR inhibitors are performing as cancer treatments. But issues with biomarker repeatability and variability have impeded advancement. The impact of mTOR inhibitors on molecular markers such as p‐S6K1 and p‐4EBP1 in different tissues, including skin, peripheral blood mononuclear cells (PBMCs), and tumor biopsies, has been examined in a number of studies. Regretfully, these studies have shown inconsistent and preliminary results. Furthermore, the effect of mTOR inhibitors on tumor metabolism and angiogenesis has been evaluated using imaging techniques such as positron emission tomography (PET) scans. PET imaging can reveal information about mTOR activity and the response to therapy by identifying the absorption of 18F‐fluorodeoxyglucose (FDG), a marker of tumor metabolism influenced by mTOR signaling. However, more study is needed to establish a definitive relationship between mTOR imaging and clinical results (Watanabe et al. 2011).

To overcome the obstacles associated with evaluating mTOR inhibitors, continuing research focuses on establishing accurate and dependable methodologies. In recent years, liquid biopsy has developed as a viable non‐invasive technique for tumor identification and surveillance, providing vital information regarding tumor features and dynamics. By analyzing circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and circulating non‐coding RNAs (ncRNAs) extracted from diverse bodily fluids, liquid biopsy can uncover medication resistance, evaluate therapeutic response, and diagnose cancer early (Moldogazieva et al. 2021; Gao et al. 2021). In addition to liquid biopsy, biosensing technology has gained significance in monitoring mTOR signaling. The development of biosensors and genetically encoded reporters enables real‐time monitoring of mTOR signaling dynamics within living cells and animal models. These biosensors detect and quantify mTOR activity using techniques such as fluorescence resonance energy transfer (FRET), bioluminescence, or other signaling processes. Researchers can track mTOR signaling in response to different stimuli, therapeutic agents, or genetic manipulations by incorporating these biosensors into cancer cell lines or tumor models, providing valuable insights into its role in tumor growth and treatment resistance (Bouquier et al. 2020; Lin et al. 2019; Mehta and Zhang 2021; Zhou et al. 2015).

6. Conclusion and Future Scope

Studying the modulation of the mTOR signaling system in vivo by inducing autophagy with bioactive chemicals and monitoring mTOR activity could be a focus of future cancer treatment research. These studies offer promise as advanced approaches for dealing with various tumor responses in the human body. Although it has been shown that plant extracts can induce apoptosis in cancer cells, the precise molecular processes at play—most notably, the role of the PI3K/AKT/mTOR signaling pathway—remain unclear. Further research with PI3K/AKT inhibitors or siRNA trials is required to demonstrate a link between plant bioactive compounds and the mTOR pathway, offering light on their potential function in cancer treatment.

A thorough investigation of the molecular links between bioactive substances, mTOR signaling, and autophagy activation can pave the way for the development of customized medications with improved efficacy and fewer side effects. Monitoring strategies for mTOR activity must be used during this research. Real‐time analysis of bioactive substance regulation of mTOR signaling provides vital insights into the dynamic changes occurring within the system. For exact quantification and visualization of mTOR activity in response to treatment, molecular probes, imaging tools, and novel approaches can be used.

By unraveling the intricate molecular interactions between bioactive compounds, the mTOR signaling pathway, autophagy activation, and monitoring mTOR activity, our understanding of cancer biology can significantly advance. These discoveries serve as a solid foundation for refining therapeutic approaches that effectively address distinct tumor responses. The goal is to develop targeted and customized medicines with improved efficacy and minimal side effects, revolutionizing cancer treatment strategies.

Author Contributions

Sonali Khanal: investigation, methodology, writing – original draft. Manjusha Pillai: investigation, methodology, writing – original draft. Md. Shimul Bhuia: writing – review and editing. Muhammad Torequl Islam: writing – review and editing. Onkar Sharma: investigation, methodology, writing – original draft. Rachna Verma: conceptualization, supervision, writing – review and editing. Eugenie Nepovimova: supervision, writing – review and editing. Kamil Kuca: conceptualization, funding acquisition, supervision, writing – review and editing. Dinesh Kumar: supervision, writing – review and editing. Raihan Chowdhury: supervision, writing – review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1. Supporting Information.

PTR-39-4046-s001.docx (16.1KB, docx)

Acknowledgements

The authors would like to appreciate and thank Shoolini University, Solan, Himachal Pradesh, India. Open access publishing facilitated by Univerzita Hradec Kralove, as part of the Wiley ‐ CzechELib agreement.

Khanal, S. , Pillai M., Bhuia M. S., et al. 2025. “Current Insights of the Potential Plant Bioactive Compounds on Modulating the mTOR Signaling Pathway in Regulating Oncological Disorders.” Phytotherapy Research 39, no. 9: 4046–4059. 10.1002/ptr.70051.

Funding: This work was supported by Grantová Agentura České Republiky, GA20‐22037S. This manuscript was funded by the Project GACR, GA23‐05857S.

Contributor Information

Rachna Verma, Email: rachnac83@gmail.com.

Kamil Kuca, Email: kamil.kuca@uhk.cz.

Data Availability Statement

The authors have nothing to report.

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Supplementary Materials

Data S1. Supporting Information.

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Data Availability Statement

The authors have nothing to report.

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