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J Cancer 2025; 16(14):4081-4098. doi:10.7150/jca.114837 This issue Cite

Review

From Herb to Hope: A Systematic Exploration of Medicinal Plants' Role in Cancer Therapy

Sahar S. Alghamdi^1,2,3 , Ruya Alshkrh¹, Afrah E. Mohammed^4,5, Shuroug A. Alowais^1,2,3

1. King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia.
2. King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.
3. Ministry of National Guard Health Affairs (MNGHA), Riyadh, Saudi Arabia.
4. Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
5. Microbiology and Immunology Unit, Natural and Health Sciences Research Center, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

✉ Corresponding author: Dr. Sahar Alghamdi, ghamdisaedu.sa.

Received 2025-4-1; Accepted 2025-7-8; Published 2025-9-27

Abstract

Medicinal plants play a critical role in drug development, serving as a valuable source of bioactive compounds. Cancer, characterized by uncontrolled cell proliferation, presents significant challenges in treatment due to its multifaceted nature. This study aims to evaluate the anticancer potentials of selected medicinal plants specifically focusing on in vitro and in vivo studies that evaluate therapeutic implications for cancer treatment. A systematic review was conducted to assess both in vitro and in vivo studies involving selected medicinal plants: Saussurea costus, Lepidium sativum, Rhus tripartite, Pyrus communis, Chenopodium murale, Erucaria hispanica, Trigonella hamosa, Argemone ochroleuca, and Galium odoratum. The review involved analyzing cancer cell lines, plant parts used, extraction methods, and mechanisms of action reported in the literature. A total of sixty-nine articles were identified that investigated the anticancer properties of the selected plants. Notably, S. costus, L. sativum, and R. tripartite exhibited significant anticancer potential. In contrast, P. communis, C. murale, E. hispanica, T. hamosa, A. ochroleuca, and G.odoratum had limited studies available. The predominant mechanism of action identified for the anticancer activity was the induction of apoptosis. The findings indicate that these medicinal herbs possess promising therapeutic potential as anti-cancer agents. However, further research is warranted for P. communis, C. murale, E. hispanica, T. hamosa, A. ochroleuca, and G. odoratum to enhance understanding of their anticancer activities and explore their full therapeutic capabilities.

Keywords: Saussurea costus, Lepidium sativum, Rhus tripartite, Pyrus communis, Chenopodium murale, Erucaria hispanica, Trigonella hamosa, Argemone ochroleuca, Galium odoratum, anticancer, in vitro, in vivo

1. Introduction

Medicinal plants have played an important role in the discovery of innovative treatments for a variety of diseases. Compounds derived from many herbal plants have demonstrated important therapeutic effects on human pathologies [1]. As a result, medicinal plants are increasingly recognized as a potential source for identifying candidate drugs, particularly in the search for cancer therapies and in efforts to minimize cancer cell resistance to treatment.

Cancer is one of the diseases that has been an obstacle in the scientific and medical fields due to its complex biological nature. The use of plants as potential cancer therapies has been a subject of interest throughout history [2]. Globally, approximately 20 million new cancer cases and 9 million cancer-related deaths were reported in 2022 [3]. The treatment of these diseases is becoming more challenging due to resistance to current treatments. In addition to resistance, the side effects of the cancer therapies impact the patient's quality of life. Thus, it is a global concern, as it can hinder treatment and has an impact on the prognosis of the disease, prompting researchers to pursue novel pharmacological solutions.

In recent years, there has been an ongoing quest for effective drugs as a preventive therapies for cancer, and to overcome the resistance issue [4]. In this context, medicinal plants are being studied as possible anticancer treatments. Recent findings on medicinal plants (Saussurea costus, Lepidium sativum, Rhus tripartite, Pyrus communis, Chenopodium murale, Erucaria hispanica, Trigonella hamosa, Argemone ochroleuca, and Galium odoratum) have increased the scientific interest in their bioactive compounds, particularly anticancer properties [5-13]. Traditionally, these plants have been used for a variety of purposes, including antimicrobial, antioxidant, and anticancer applications. They contain a variety of secondary metabolites, such as polyphenols, flavonoids, steroids, which enhance their ability to induce the cancer cell death via different mechanisms.

The main aim of this systematic review is to assemble all current studies that explore and analyze the anticancer activity of the extracted parts of the selected medicinal plants in both in vitro and in vivo models.

2. Methods

2.1. Research questions

This systematic review focuses on the analysis of the anticancer activity for the extracts or isolated compounds of selected plants (Saussurea costus, Lepidium sativum, Rhus tripartite, Pyrus communis, Chenopodium murale, Erucaria hispanica, Trigonella hamosa, Argemone ochroleuca, and Galium odoratum) and their effects on in vitro and in vivo models, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We included studies published within the past 24 years (2000-2024) to ensure adequate representation of historical and recent research findings regarding the selected medicinal plants (Figure 1).

2.2. Data sources

Google Scholar was utilized as a database to identify the studies that investigate the anticancer properties of the selected medicinal plants. As a search strategy, to conduct a comprehensive search, we utilized certain keywords and specific phrases, it involves “Saussurea costus" AND ("anticancer" OR "cytotoxic") AND ("in vitro" OR "in vivo"), " Lepidium sativum" AND ("anticancer" OR "cytotoxic") AND ("in vitro" OR "in vivo"), and so forth for each plant. The search is limited by the filter to include the articles that are published between 01/01/2000 to 01/08/2024 in English.

2.3. Inclusion criteria

Selected articles were required to investigate the potential anticancer effects for the chosen medicinal plants using in vitro or in vivo models, with plant extracts or isolated compounds tested against cancer cell lines or tumor-induced animal models.

2.4. Exclusion criteria

Articles were excluded if they did not evaluate anticancer activity or did not involve cancer cell lines or tumor models. Additionally, non-English articles, clinical trials, and non-original studies (e.g., systematic reviews or meta-analysis) were excluded.

 Figure 1 

The systematic review approach and scope. A systematic review focused on the anticancer activity of selected medicinal plants, including original studies such as in vitro and in vivo. Data selection was based on the study's title, language, and relevance objectives, with data sources determined by keywords and filters. Data extracted includes cancer cell type, extraction methods, IC₅₀ values, and proposed mechanism of action.

 Figure 2 

Flow chart illustrating the study selection process: A total of 15,018 records were identified, of which 14,950 were excluded due to irrelevant research questions or different plant species. After screening 72 records, 2 were excluded due to language barriers and one was retracted resulting in 69 studies included in the final analysis.

2.5. Study selection

The screening of the preselected articles, using the described search strategy, was conducted by a single author and initially based on title and abstract review (Figure 2). Duplicates, studies irrelevant to the research question, and those investigating different plant species were excluded. Subsequently, the studies that are written with different languages other than English were eliminated. The final selection of the eligible studies was carried out by a single author.

2.6. Data extraction

Data extraction was carried out by a single author for all included articles. The extracted information encompassed several key aspects: the type of cancer cells treated with the plant extracts, the specific plant name, the part of the plant utilized in the study, the extraction methods and solvents employed by researchers, and the results, including values for IC₅₀. Additionally, any proposed mechanisms of action suggested by the studies were recorded.

3. Results

To assess their anticancer activity and mechanism of action, a comprehensive review of in vitro and in vivo studies on nine plants— Saussurea costus, Lepidium sativum, Rhus tripartite, Pyrus communis, Chenopodium murale, Erucaria hispanica, Trigonella hamosa, Argemone ochroleuca, and Galium odoratum —was conducted. The selected medicinal plants have been investigated for their cytotoxic potential against a variety of cancers, including acute myeloid leukemia, breast cancer, lung cancer, colon cancer, tongue squamous cell carcinoma, colorectal cancer, liver cancer, prostate cancer, melanoma, cervical cancer, neuroblastoma, adenocarcinoma, ovarian cancer, esophageal cancer, gastric cancer, and skin cancer. Following a thorough examination for sixty-one in vitro and in vivo studies, the findings revealed that the S. costus, L. sativum, R. tripartite, C. murale, P. communis, E. hispanica, T. hamosa were investigated for their cytotoxic activity. No studies were found evaluating the anticancer properties of A. ochroleuca and G. odoratums' anticancer properties (Table 1).

The proposed mechanism of action is mostly related to generation of reactive oxygen species (ROS) and induction of apoptosis.

3.1. Saussurea costus

S. costus was the most extensively studied plant across diverse types of cancer, including breast cancer (MCF-7, MDA-MB-231, SK-BR-3, MDA-MB-453), colon cancer (HTC116, Caco2, LS174T, HT-15, HT-29), liver cancer (HepG-2, HuH-7, PLC/PRF/5, SMMC-7721), lung cancer (A549, SK-MES-1), gastric cancer (AGS), central nervous system (CNS) cancer (XF498, IMR-32, SH-SY5Y, Rat B103), prostate cancer (PC-3, LNCaP, DU145), leukemia (HL-60, Jurkat E6-1, THP-1), cervical cancer (HeLa), esophageal cancer (Eca109, KYSE150), ovarian cancer (SK-OV-3, OVCAR3), soft tissue sarcoma (SW-872, SW-982, TE-671) [14-33].

In vitro studies utilized different parts of S. costus; however; root was the most utilized part for the most cancer types, while a few studies tested leaves and fruits of S. costus for breast (MCF-7), colon (CaCo-2), liver cancer (HepG2) [22,25,29,34-38]. Other studies investigated isolated compounds, namely costunolide and dehydrocostuslactone [14-16,18,20,21,32,39-41].

Breast cancer was the most studied cancer type, with MCF-7 as the predominant cell line, in addition to MDA-MB-231, SK-BR-3, and MDA-MB-453, demonstrating the versatility of extracts and solvents. In a study conducted by Peng et al. (2013), the roots were extracted using liquid-liquid extraction with methanol and ethyl acetate and tested on MCF-7 cell lines, revealing IC₅₀ values ranging from 1.7 to 6.1 μg/mL[28]. Similar findings were reported by Bhushan et al. (2023), where liquid-liquid extraction was applied to root extracts and tested on the MDA-MB-231 cell line using additional solvents such as hexane, chloroform, ethanol, and butanol[37]. A similar trend was observed, where hexane and chloroform showed IC₅₀ values of 5.3-12.18 μg/mL, whereas ethanol and butanol exhibited higher IC₅₀ values, ranging from 20 to >100 μg/mL. Comparable results were observed for other plant parts, including leaves and fruits, as summarized in Table 2.

Additionally, other studies have explored alternative extraction techniques, such as nanoparticle synthesis and supercritical carbon dioxide extraction, to evaluate the antitumor potential of S. costus extracts [14,42,43]. One study optimized the extraction of S. costus oil using supercritical fluid extraction at different pressures, achieving significant inhibition with an IC₅₀ value of 0.46 μg/mL on MCF-7 cells [42]. In contrast, magnesium oxide nanoparticles synthesized from S. costus methanol extracts exhibited relatively lower antiproliferative effects on MCF-7 cells, with IC₅₀ values of 80 μg/mL and 26.7 μg/mL for magnesium oxide and palladium nanoparticles, respectively [14,42].

Choi, (2009) tested dehydrocostuslactone on MDA-MB-231, SK-BR-3, and MDA-MB-453 cell lines, reporting IC₅₀ values ranging from 25.6 to 43.2 μM/mL, while costunolide tested on MCF-7 cells showed an IC₅₀ value of 30.16 μM/mL [39].

A similar pattern of inhibition, depending on plant parts, solvents, and extraction methods, was observed in other cancer types, including colon, liver, gastric, esophageal, and pancreatic cancers [14,28,28,30,37,43,43-45]. Although hexane and chloroform extracts generally showed potent inhibition, one study found no significant cytotoxicity with hexane root extracts against colon (HCT-116, HCT-29) and prostate cancer (PC-3, LNCaP, DU145), as the hexane extracts did not affect cell viability [21,38].

However, neuroblastoma cell lines (XF498, SH-AY5Y, and B103) showed susceptibility to both methanol and ethanol extracts of S. costus, with IC₅₀ values ranging from 15-20 μg/mL and 0.43-1.70 μM/mL when exposed to ethanol and methanol extracts, respectively [29,46].

Other cancer types that demonstrated sensitivity to S. costus extracts include ovarian, colorectal, skin, and soft tissue cancers [15,22,24].

 Figure 3 

Proliferation inhibition: The mechanisms of action of S. costus involved the modulation of the PI3K/AKT/mTOR pathway, as well as the regulation of the MAPK/ERK pathway. Additionally, S. costus impacts the WNT/β-Catenin pathway by reducing β-catenin levels and depicts the inhibition of the NF-κB pathway. Furthermore, the regulation of cell cycle proteins, such as CDKs and cyclins leading to induction of cell cycle arrest.

The cytotoxic potential of S. costus has been extensively investigated, and it has been observed that its anticancer effects are mediated through multiple mechanisms (Figure 3), including the induction of apoptosis, cell cycle arrest, modulation of the androgen receptor and autophagy processes, decreased proliferation, and alterations in cellular signaling cascades by modulating phosphorylation processes. In particular, autophagy appears to be promoted through upregulation of LC3I and LC3II levels (high LC3II/LC3I ratio) and beclin1, while mTOR phosphorylation is inhibited [32,33,47]. The interplay between autophagy and apoptosis is notable; inhibition of one can stimulate the other, suggesting a dual mechanism of action.

Ten in vivo studies have evaluated the anticancer activity of S. costus. The investigated type of cancer included breast cancer (MCF-7, MDA-MB-231), liver cancer (SMMC-7721), lung cancer (LC-540), leukemia, laryngeal carcinoma, esophageal cancer, gastric cancer (MKN-28) [47-51] (Table 3). Most studies utilized either the roots or isolated compounds (costunolide and dehydrocostus lactone), with ethanol and hexane as organic solvents for the extraction.

One study found that hexane root extract of S.costus inhibited hepatocellular carcinoma (HCC) with an inhibition rate of 55.71% [52]. Likewise, ethanol extracts showed anti-leukemic effects by reducing white blood cell counts to normal levels [50].

The isolated compounds also exhibit anticancer activity, the lowest dose (costunolide at 10 mg/kg/day) was tested on immunodeficient female NCr nude homozygous mice with breast and colon cancer, showing reduction of the tumor volume. The highest dose (dehydrocostus lactone at 40 mg/kg/day for 28 days) was tested also for esophageal cancer in the Eca109-b mouse model, and the results showed inhibition of the tumor growth [27]. Several studies attempt to investigate the mechanisms, the in vivo anticancer activity of S. costus is related mainly to induction of apoptosis by activating pro-apoptotic proteins such as p53 and Bax, while inhibiting anti-apoptotic proteins like Bcl-2, leading to programmed cell death, cell cycle arrest, modulating certain signaling pathways, such as EGFR, which reduces the proliferation and invasion of cancer cells, and suppress PI3K/Akt and MEK/P38 pathways, reduction the inflammatory process by suppression the level of TNF-α and NF-κB, and induction of reactive oxygen species.

3.2. Lepidium sativum

Fourteen studies have investigated the anticancer activity of L. sativum on various cancer types, such as liver (HuH-7 and HEPG-2), breast cancer (MCF-7), colon cancer (DLD-1, HCT-116, HT-15, HT-29, SW480, HTB-38, and Caco2), cervical cancer (HeLA 2), lung cancer (A-549 cell line), prostate cancer cells (P-C3), endometrium cancer (ECC-1), tongue squamous carcinoma (CAL-27), melanoma cancer (A-375 cell line), neuroblastoma (IMR-32), ovarian cancer (OV17R), leukemia (Jurkat E6-1)[53-66]. The studies utilized various plant parts, including leaves, roots and seeds, with th most employed seeds being the most commonly used part.

Liver cancer was the most commonly studied cancer type. Studies reported similar IC₅₀ values across different cell lines, plant parts, and extraction solvents [58,64], particularly when polar solvents were used. This pattern was also observed in other cancer types, including breast, colon, cervical, lung, prostate, endometrial, tongue squamous cell carcinoma, and leukemia [54,55,57,60,66]. However, the results showed variability in cytotoxic activity.

In a study by Abd-elmegeed et al. (2023), phenolic compounds, such as rutin, benzoic acid, cinnamic acid, and vanillin were isolated and evaluated, revealing IC₅₀ values ranging from 28.8 μg/mL to 64.32 μg/mL [53]. Furthermore, Ibrahim et al. (2023) demonstrated that L. sativum ethanol extracts that are treated with glucosinolates showed inhibition of cancer cells, prostate cancer (PC-3), colon cancer (coca2), lung cancer (A-549), and liver cancer (HepG2) with IC₅₀ ranges 38.5-92.6 mg/mL, without effect normal cell lines [59].

Nanoparticles synthesis using L. sativum extracts has also been explored. Meer et al. (2022), and Efati et al. (2023) reported enhanced cytotoxic potential of L. ativum extracts against colorectal adenocarcinoma (SW480) and colon adenocarcinoma (HT-29 and Caco-2) at different degrees of temperature, the lowest IC₅₀ (13.14 µg/mL) was detected to SW480 with ZnO at 350 °C [57,63]. In contrast, Amina et al., (2021) study of Ag-MgO nanoparticles found no enhancement of L. sativum extracts [55].

Several studies have investigated the mechanism of action underlying the anticancer effects of L. sativum. These studies demonstrated that the anticancer activity is related mainly to induction of apoptosis and cell cycle arrest. L. sativum extracts showed upregulation of pro-apoptotic proteins such as BAX, p53, and caspases 3/7, alongside the downregulation of anti-apoptotic proteins like Bcl-2 (Figure 4) [57]. Additionally, upregulation of SMAD2 and SMAD3 expression has been observed in the live cancer cell upon exposure to L. sativum extracts. Moreover, L. sativum extracts showed induction of cell cycle arrest at the S phase, thereby inhibiting their proliferation (Table 4) [59].

3.3. Rhus tripartite

The cytotoxic potential of R. tripartite leaves and roots was examined in four studies, using diverse cancer cell lines, including acute myeloid leukemia (THP-1), myelogenous leukemia (K-562), colon cancer (DLD-1, Caco-2), breast cancer (MCF-7), lung cancer (A-549) (Table 6) [67-71]. The extraction process used butanol, methanol, ethanol, and ethyl acetate as organic solvents. The lowest IC₅₀ value (39.83 μg/mL) was reported for methanol extracts against colon adenocarcinoma DLD-1 cell line [68].

In contrast, aqueous extracts showed lower cytotoxic activity with IC₅₀ values 195.37 μg/mL and 200 μg/mL against A-549 and DLD-1) cell lines, respectively. Similarly, in Tlili et al. (2019) reported IC₅₀ values less than 50 μg/mL for methanol extracts against CaCo-2 and K-562 cell lines [71].

The mechanism of action for R. tripartite extractions is thoroughly explained by Tlili et al., 2021, which involves the inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT mammalian target of rapamycin (mTOR) pathway that eventually results in the induction of apoptosis and the suppression of tumor growth, as shown previously in Figure 4 [70].

 Figure 4 

Apoptosis and autophagy: S. costus and L. sativum activate p53, which leads to DNA damage response, cell cycle arrest, and apoptosis by upregulating pro-apoptotic proteins like Bax and Bak while down regulating anti-apoptotic proteins such as Bcl-2 and Mcl-1. Additionally, S. costus influences autophagy pathways, including Beclin-1 and the interaction of death receptors, leading to autophagic cell death. It includes also the apoptosis by ROS generation, which leads to mitochondrial dysfunction and apoptosis. R. tripartite is also involved in the modulation of the PI3K/AKT/mTOR pathway.

3.4. Pyrus communis

Cytotoxic potential of P. communis has been examined in two studies on various cancer types, including lung cancer (A549, WI-38), prostate cancer (LNCaP), urinary bladder cancer (HCV29T), kidney cancer (A-498), mouse myelogenous leukemia carcinoma (M-NFS-60), ovary cancer (CHO-K1) [72,73].

Both studies utilized the fruits of P. communis. The study that utilized hydroinstillation extraction method showed higher cytotoxicity, with IC₅₀ values ranging values: from 30.9 to 105 μg/mL. In contrast, the study employing the UPLC-PDA-MS extraction method showed lower cytotoxicity, with IC₅₀ values ranging from: 0.5 - to 3.2 mg/mL (Table 7) [72,73].

3.5. Chenopodium murale

Only one in vitro study has evaluated C. murale's anticancer activity in breast cancer (MCF-7) and liver cancer (HCAM), with leaves extracted using an ethanol solvent. The investigation found that the extraction had weak cytotoxic activity, with IC₅₀ of 1504 µg/mL for breast cancer and 1267 µg/mL for liver cancer cells (Table 8) [74].

3.6. Erucaria hispanica

E. hispanica was investigated in one study involving four different cancer cell lines, breast (MCF7), liver (HEPG2), cervix (HELA) and colon (HCT116) cancers, utilizing methanol extracts of aerial parts of E. hispanica [10].The results showed IC₅₀values 18 μg/mL, 20.8 μg/mL, 14.7 μg/mL and 21.4 μg/mL respectively (Table 9).

3.7. Trigonella hamosa

A single study has investigated to explore the anticancer activity of methanol extracts from T. hamosa aerial parts. The reported IC₅₀ values were 6.71 μg/mL for breast cancer (MDA-MB-231), 4.93 μg/mL for lung cancer (A549), and 13.74 μg/mL for colon cancer (HTC-166) (Table 10) [75].

4. Discussion

Medicinal plants have long served as a valuable source for the discovery of novel therapeutic agents, particularly in the treatment of diseases such as cancer [76]. Cancer remains a complex and life-threatening condition, contributing to rising mortality rates globally. Additionally, the development of resistance to existing treatments further complicates cancer management and presents significant challenges [77]. Consequently, there is a pressing need to identify new therapeutic agents that can enhance current treatment strategies and address resistance issues. Several medicinal plants have shown promising therapeutic properties, including anticancer activity.

This systematic review critically assessed the available evidence on the anticancer potential of selected medicinal plants. A total of sixty-nine studies were identified that investigated the anticancer effects of for S. costus, L. sativum, Rhus tripartite, C. murale, P. communis, E. hispanica, T. hamosa. In contrast, A. ochroleuca, and G. odoratum have not yet been evaluated for their anticancer potential.

Among these, S. costus was the most extensively studied. It has been tested against various cancer types, most notably breast (MCF-7, MDA-MB-231, SK-BR-3), liver (HepG2), and colon cancers (HCT-116, HT-29). The cytotoxic activity of S. costus varied depending on the extract type and cell line. For instance, non-polar organic solvents like hexane and chloroform demonstrated high potency, with IC₅₀ 0.4 µg/mL - 2.1 µg/mL [30]. However, this potency did not consistently extend to all cancers—prostate cancer cell lines (PC-3, LNCaP, DU145), for example, showed resistance to hexane extracts [21,38]. In comparison, extracts prepared with polar solvents (methanol, ethanol, butanol) generally showed lower potency (IC₅₀ values:10 µg/mL to > 100 µg/mL), suggesting solvent polarity significantly influences the bioactivity of phytoconstituents present in S. costus [37,45,78]. In contrast, other cancer types showed to be sensitive, such as ovarian, colorectal, skin, and soft tissue, regardless of polarity of the solvents or extraction method.

Skin cancer (SK-MEL-2) cells showed exceptional sensitivity to costunolide and dehydrocostus lacton, two well-characterized sesquiterpene lactones isolated from S. costus, with IC₅₀ ranging from 4.7 µM to 60 µM. These compounds demonstrated consistent tumor-suppressive activity across various studies. Advanced extraction techniques like supercritical CO₂ extraction yielded highly potent results, with IC₅₀ values of 0.44-0.74 μg/mL against HCT-116, MCF-7, and HepG2 cells [42]. Nanoparticle formulations also enhanced cytotoxicity: methanolic S. costus-derived palladium nanoparticles showed IC₅₀ values of 7.8-26.7 μg/mL, whereas magnesium oxide nanoparticles were moderately effective (IC₅₀ = 80 μg/mL) [14,43]. These findings highlight that supercritical extraction and specific nanoparticle formulations can optimize S. costus's therapeutic potential.

In vivo studies support the anticancer potential of S. costus: hexane extracts demonstrated a 55.71% inhibition rate on hepatocellular carcinoma (HCC) [52]. While ethanol extracts effectively normalized white blood cell counts in leukemia [50]. Costunolide (10 mg/kg/day) reduced breast and colon tumor volumes in mice, while dehydrocostuslactone (40 mg/kg/day) inhibited esophageal tumor growth [78]. These findings reinforce the therapeutic relevance of S. costus.

Mechanistically, S. costus exhibits multiple modes of action, including inhibition of the Epidermal Growth Factor Receptor (EGFR) and PI3K/Akt signaling pathways, as well as suppression of inflammation, invasion, and metastasis. EGFR dysregulation is linked to tumor progression. Thereover, targeting EGFR suppresses cancer cell proliferation [79]. Additionally, S. costus downregulates TNF-α and NF-κB, key mediators of tumor metastasis and chronic inflammation [80]. The ability to modulate multiple pathways makes S. costus a promising multi-targeted anticancer agent.

L. sativum has been evaluated in fourteen studies on different cancers, highlighting its potential versatility. The anticancer potency varied depending on extraction solvent and methodology. For instance, Nazir et al., (2021) observed differential activity across A-549 and HepG2 cell lines using various organic solvents [64]. Furthermore, the selectivity inhibition of the cancer cells has been tested in a study by Ibrahim et al. (2023), who utilized glucosinolates with L. sativum ethanol extracts [59]. The IC₅₀ values for these glucosinolate-treated extracts ranged from 38.5 to 92.6 µg/mL and were noted to have no adverse effects on normal cell lines. While some nanoparticle-based formulations improved bioactivity [57], others, like Ag-MgO nanoparticles, showed no enhancement [55], suggesting that nanoparticle composition critically influences therapeutic efficacy.

Although most L. sativum studies were in vitro, one in vivo study demonstrated a 37.14% increase in lifespan in mice with Ehrlich ascites carcinoma treated with L. sativum seed extracts [81]. L. sativum extracts induced apoptosis and cell cycle arrest—key processes in cancer treatment [59]. Apoptosis, a programmed cell death, is regulated at the genetic level, ensuring the orderly and efficient removal of damaged cells [82]. Thus, the ability of L. sativum extracts to induce the apoptosis underlying its potential as a therapeutic agent.

R. tripartite has demonstrated cytotoxic effects. Methanol extracts exhibited the lowest IC₅₀ values, particularly against the DLD-1 colon adenocarcinoma cell line (39.83 μg/mL) [68]. Aqueous extracts, on the other hand, showed less cytotoxicity, reaffirming the importance of solvent selection. The primary mechanism identified involves inhibition of the PI3K/AKT/mTOR pathway [70]. The PI3K/AKT/mTOR pathway plays a crucial role in survival, growth, and proliferation of the cells. Inhibition of this pathway results in suppression of the tumor progression [83].

The cytotoxic potential of P. communis was moderate and varied between studies, even though both used fruit extracts. IC₅₀ values ranged from 30.9 to 105 μg/mL in one study [72]; While the other reported lower cytotoxicity (IC₅₀: 0.4-3.2 mg/mL), possibly due to differences in extraction methods (hydroinstillation vs. UPLC-PDA-MS) [73]. While the findings indicate promising activity, the limited number of studies necessitates further investigation to validate their efficacy against cancer.

In contrast, C. murale demonstrated weak anticancer activity, with IC₅₀ values of 1504 μg/mL (MCF-7) and 1267 μg/mL (liver cancer) [74].These values indicate a relatively weak cytotoxic potential, which may limit its applicability in cancer therapy. However, further research using different extraction approaches or targeting other cancer types may yield better results.

E. hispanica showed moderate cytotoxic activity in one study, with IC₅₀ values ranging from 14.7 μg/mL to 21.4 μg/mL across different cancer cell lines[10]. Similarly, T. hamosa demonstrated promising cytotoxicity (IC₅₀ = 6.7-13.7 μg/mL), though only one study has investigated its potential [75]. The limited data highlights the necessity for further investigation into these plants to better understand their anticancer potential, considering the influence of plant parts, different solvents and mechanism of action.

This systematic review has several important limitations. First, the literature search was conducted exclusively using Google Scholar, which may not provide the same level of indexing rigor or coverage as more specialized scientific databases. This may have led to the omission of relevant studies. Second, the review only included studies published in English, introducing potential language bias. Another major limitation is the lack of formal risk of bias assessment of the included studies, which undermines the ability to critically evaluate the quality and reliability of the evidence. Furthermore, there was considerable heterogeneity in study designs, plant parts used, extraction methods, solvents, cancer types, and assay conditions, which makes it difficult to compare findings or draw definitive conclusions. Lastly, while some in vivo studies were included, the review is heavily weighted toward in vitro data, limiting the applicability of findings to clinical or physiological settings.

5. Conclusion

Cancer remains a complex, multifactorial disease that is difficult to treat. For decades, using plants as a source of potential therapeutic agents has been a key approach. This systematic review highlights promising anticancer properties of several plant extracts, particularly S. costus, L. sativum, and R. tripartite, due to their ability to induce apoptosis. Extensive in vitro and in vivo studies on S. costus have demonstrated its significant cytotoxic potential. For S. costus in vitro studies, the polarity of the extraction solvents played a significant role in cytotoxic potency. L. sativum and R. tripartita also demonstrated notable activity, other plants—such as P. communis, C. murale, E. hispanica, and T. hamosa—require further exploration. Importantly, A. ochroleuca and G. odoratum have not been studied at all in this context and represent important gaps in literature.

Overall, this review underscores the therapeutic promise of several medicinal plants in cancer treatment and emphasizes the need for standardized methodologies, in vivo studies, and deeper mechanistic investigations to fully harness their potential.

Abbreviations

ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; DHE: dehydrocostuslactone; EGF: epidermal growth factor; ER: endoplasmic reticulum; GL: glucosinolates of leaf cell suspension; GLM: glucosinolates of leaf cell suspension treated with L-methionine; GLT: glucosinolates of leaf cell suspension treated with L-tyrosine; GSH: glutathione; LAMP: lysosome-associated membrane protein; LC3II: microtubule-associated protein 1 light chain 3-II lipidation chain indicator; MDA: malondialdehyde; MEK: mitogen-activated protein kinase kinase MAPKK; MMP: matrix metalloproteinase; MS: mass spectrometry; NF-κB: nuclear factor-kappa B; OL: petroleum ether extract of leaf cell suspension; OR: petroleum ether extract of root cell suspension; PARP: poly ADP-ribose polymerase; PDA: photodiode array detector; PI3K/AKT/mTOR: phosphatidylinositol 3-kinase PI3K protein kinase B AKT mammalian target of rapamycin mTOR; RNS: reactive nitrogen species; ROS: reactive oxygen species; TIMP: tissue inhibitor of metalloproteinases; TNF-α: tumor necrosis factor-alpha; UPLC: ultra-performance liquid chromatography; VEGF: vascular endothelial growth factor.

Acknowledgements

The authors want to express their sincerest gratitude to King Abdullah International Medical Research Center (KAIMRC) for supporting this research project (grant number #SPR24/007/5).

Funding

This research project (grant number #SPR24/007/5) was financially supported by King Abdullah International Medical Research Center (KAIMRC).

Competing Interests

The authors have declared that no competing interest exists.

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