Adriana A. Lopes1
Juliana da Silva Coppede1Pedro de Pádua G. Amatto1
Davi Casale Aragon2Suzelei de Castro França1
Fabio Carmona2
Ana Maria S. Pereira1,3*- 1Biotechnology Unit, University of Ribeirão Preto (UNAERP), Ribeirão Preto, São Paulo, Brazil
- 2Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
- 3Botanical Garden of Medicinal Plants Ordem e Progresso, Jardinopólis, São Paulo, Brazil
Background: Uncaria tomentosa (cat’s claw) is a medicinal plant with documented immunomodulatory and anti-inflammatory properties. Recent studies suggest potential anticancer effects, but evidence remains fragmented.
Objective: This systematic review aimed to assess the cytotoxic effects of different U. tomentosa extracts or fractions on normal and cancer cells, summarizing in vitro studies.
Methods: A systematic search was conducted in PubMed, Embase, and Scielo up to January 2025, following PRISMA guidelines. Inclusion criteria comprised in vitro studies evaluating U. tomentosa extracts or fractions on normal and cancer cells, reporting IC50 values or equivalent measures. Data on plant part, extraction method, and chemical composition were collected. Risk of bias was assessed using the modified CAMARADES checklist.
Results: Thirteen studies met the eligibility criteria. U. tomentosa extracts exhibited selective cytotoxicity in some cancer cell lines. The most promising findings were observed for crude aqueous bark extracts (72 h incubation) against squamous cell carcinoma and pentacyclic oxindole alkaloid (POA)-rich extracts against prostate cancer and leukemia. In contrast, tetracyclic oxindole alkaloid (TOA)- and proanthocyanidin (PAC)-rich fractions showed limited cytotoxicity. Most extracts were non-toxic to normal cells, except for the crude aqueous bark extract, which exhibited cytotoxicity in keratinocytes.
Conclusion: U. tomentosa has potential as a source of selective anticancer agents, particularly through crude aqueous bark and POA-rich extracts. The observed cytotoxic effects vary considerably depending on the extraction method and chemical composition, underscoring the need for standardization in future studies. Further standardized studies and mechanistic investigations are required to validate its therapeutic potential for cancer treatment.
Systematic Review Registration: https://osf.io/hfazq/.
Highlights
• Uncaria tomentosa extracts have selective cytotoxicity against a few cancer cell lines.
• Uncaria tomentosa extracts are non-toxic to normal cell lines.
• Pentacyclic oxindole alkaloid (POA)-rich extracts show the highest anticancer potential.
• Tetracyclic oxindole alkaloid and proanthocyanidin fractions exhibit limited cytotoxic effects.
• Most of U. tomentosa extracts are safe for normal cells, except for a crude aqueous and POA-rich extracts.
Introduction
Cancer remains a leading cause of morbidity and mortality worldwide, with an estimated 19.3 million new cases and approximately 10 million deaths reported in 2020 (Sung et al., 2021). Despite advancements in treatment, the global cancer burden continues to rise, highlighting an urgent need for novel, effective, and less toxic therapeutic options. Natural products have historically been a rich source of anticancer agents, and the exploration of medicinal plants offers promising avenues for drug discovery (Newman and Cragg, 2020).
Uncaria tomentosa (Willd. ex Schult.) DC. (Rubiaceae), commonly known as “cat’s claw,” is a vine native to the Amazon rainforest and has been traditionally used in South American medicine. This species has high medicinal properties and economic value in the world. In Brazil, this species is distributed in the states of Acre, Amapá, Amazonas, and Pará (Honório et al., 2016), and is disseminated by the Brazilian Ministry of Health to all municipalities through the National Health System (Sistema Único de Saúde, SUS) (BRASIL, 2022). The World Health Organization (WHO) described the traditional uses for cat’s claw as being applicable for diverse diseases and illnesses such as arthritis, rheumatism, gastric ulcers, abscesses, asthma, fevers, urinary tract infections, viral infections, wounds and as an emmenagogue (WHO, 2007). The plant is rich in bioactive compounds including pentacyclic (POA), tetracyclic (TOA) oxindole alkaloids, triterpenes, quinic acid esters, polyphenols (phenolic acids and proanthocyanidins), flavonoids, quinones, and glycosides, which have been attributed to its diverse pharmacological properties (Batiha et al., 2020). Notably, extracts from U. tomentosa exhibit immunomodulatory, anti-inflammatory, and potential anticancer activities (Araujo et al., 2018; Batiha et al., 2020; Blanck et al., 2022; Rojas-Duran et al., 2012; Urdanibia et al., 2013).
Tetracyclic oxindole alkaloids (TOA) act on the central nervous system. For instance, isorhynchophylline can improve memory problems by increasing the antioxidant levels, while D-galactose exerts an anti-inflammatory effect on brain tissues in mice (Xian et al., 2014). POA affect the immunocellular system (Reinhard, 1999), increasing the rate of phagocytosis by granulocytes (Wagner et al., 1985) and inducing lymphocyte specificity (Wurm et al., 1998).
Tetracyclic oxindole alkaloids (TOA) act mostly on the central nervous system, while POA affect the immunocellular system (Zhang et al., 2015). The POA mitraphylline and isopteropodine are the chemical markers used in the quality control of cat’s claw herbal medicine (USP-United States Pharmacopeia, 2022). Nevertheless, in recent years, the anticancer activity of this plant has been explored (Dreifuss et al., 2013; Kaiser et al., 2013).
A promising anticancer compound should exhibit minimal or no toxicity to normal cells and possess a clearly defined mechanism of action. The most common antitumor mechanism is the induction of apoptosis, a programmed cell death pathway that is often dysregulated in cancer cells. Several natural products are capable of reactivating apoptotic signaling in cancer cells. Oxindole alkaloids are particularly potent in their anticancer activities. They can induce apoptosis, inhibit cell proliferation, and exhibit cytotoxic effects against various cancer cell lines, making them valuable in the search for effective cancer therapies (Khetmalis et al., 2021; Kozielewicz et al., 2014).
Mitraphylline isolated from U. tomentosa bark showed cytotoxic effect on human Ewing’s sarcoma and breast cancer cell lines (García Giménez et al., 2010). Pteropodine, a POA from U. tomentosa, induced apoptosis in T lymphoblastic cells independently of the CD95/Fas death receptor pathway (Bacher et al., 2006). Moreover, both an n-butanol-soluble fraction and a hydroalcoholic extract of U. tomentosa activated caspase-3, a key executioner enzyme in the apoptotic cascade (De Martino et al., 2006; de Oliveira et al., 2014). Similarly, an ethyl acetate extract of U. tomentosa induced apoptosis through caspase activation in HL-60 leukemia cells, potentially engaging either mitochondrial (intrinsic) or receptor-mediated (extrinsic) pathways (Cheng et al., 2007).
Despite a growing body of evidence supporting the anticancer activity of various U. tomentosa extracts and isolated compounds, it remains unclear which specific extract types or chemical constituents are most effective against particular cancer cell lineages. Given the pharmacological relevance and chemical diversity of U. tomentosa, this systematic review aims to summarize in vitro studies investigating its anticancer properties, with a focus on the bioactivity of chemically distinct extracts and fractions derived from different parts of the plant.
Methods
This report was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines (Page et al., 2021). A protocol was deposited on the Open Science Framework (Carmona and Pereira, 2025).
Inclusion and exclusion criteria
This systematic review included only in vitro studies on the effects of U. tomentosa extracts (crude, fraction, or purified) on normal or cancer cells, and that reported half-maximal inhibitory concentrations (IC50) or other values that allow IC50 estimation. In vivo studies and those on mixtures of medicinal plants or isolated substances were not included. Only studies published in English, Portuguese, or Spanish were included.
Source of information and search strategy
Only articles published from inception to January 2025, were searched in the following databases: PubMed, Embase, and Scielo. The initial publication date was not limited. The query search used in Embase for this study is presented in Box 1. Similar queries were employed in the other databases. The reference lists of all selected studies were also searched to identify additional primary studies for inclusion.
Box 1 Search queries used in Embase for the systematic review.
(“cancer cell/exp OR “cancer cell” OR “cancer cell model” OR “cancer cells” OR “cancerous cell” OR “cancerous cells” OR “cell, cancer” OR “malignancy cell” OR “malignancy cells” OR “malignant cell” OR “malignant cells” OR “malignant tumor cell” OR “malignant tumour cell” OR “oncocyte” OR “oncocytes” OR “cancer cell line/exp OR “cancer cell line” OR “cancer cell lines” OR “cancer cell strain” OR “cancer derived cell line” OR “cancer line” OR “cancerous cell line” OR “malignancy cell line” OR “malignancy-derived cell line” OR “malignant cell line” OR “malignant line” OR “cells/exp OR “cell” OR “cells”) AND (“uncaria tomentosa/exp OR “uncaria tomentosa” OR “cat`s claw”) AND (“ic50/exp OR “cytotoxicity/exp OR “cell toxicity” OR “cytotoxic activity” OR “cytotoxic effect” OR “cytotoxic reaction” OR “cytotoxicity” OR “apoptosis/exp OR “ap-optosis” OR “apo-ptosis” OR “apoptosis” OR “apoptotic cell death” OR “apoptotic cellular death” OR “apoptotic death” OR “apoptotic suicide” OR “apoptotic-like cell death” OR “cell suicide” OR “cellular suicide” OR “programmed cell death” OR “programmed cell death type i OR “suicidal cell death)
Article selection
Two independent and initially blind reviewers (AAL, JSC, and PPGA) conducted the screening of articles by reading titles and abstracts. The entire process used the Rayyan software (Ouzzani et al., 2016). Disagreements were resolved by consensus among the reviewers (with a fourth reviewer, AMSP, when necessary). A PRISMA flowchart was built using the PRISMA Flow Diagram tool (Haddaway et al., 2022).
Data collection
Information on the plant parts used, methods of extraction, fractioning, or purification, extraction times, and the different types of cells studied were retrieved, whenever available. IC50 values were extracted from individual studies or calculated from MTT results [log (inhibitor) vs response, variable slope with four parameters] using GraphPad Prism 10 (LaJolla, CA, United States). When values were reported in charts, they were estimated by measuring bar heights using ImageJ (Schneider et al., 2012). The authors of the included studies were contacted when necessary (when some data or article was not available). The retrieved data were recorded in a Google Sheets spreadsheet (Alphabet Inc., Mountain View, CA, United States).
Quality assessment
For the risk of bias, two investigators (AMSP and FC) independently reviewed the selected studies according to a modified CAMARADES checklist (Macleod et al., 2004) and reported the risks of bias in a table.
Statistical analysis
Heatmaps for normal and cancer cells were plotted using the package pheatmap of R 4.3.2 (The R Foundation), and GraphPad Prism 10 (GraphPad, LaJolla, CA, United States), indicating the classes of major compounds of each extract or fraction and the embryonic origin of each cell tested. If more than one IC50 was obtained for the same extract and cell lineage, the average value was used.
To categorize the therapeutic potential based on IC50, the following arbitrary cutoff points were adopted, loosely inspired by previous studies (Badisa et al., 2009; Coussens and Werb, 2002; Shoemaker, 2006; Zhang et al., 2024):
• IC50 ≤ 10 μg/mL–Toxic (red color). Values in this range are typically considered highly potent, indicating strong cytotoxic activity, which is desirable against tumor cells, but not normal cells.
• IC50 10–50 μg/mL–Potentially toxic (orange color). This range is still considered promising for anticancer drugs, especially in resistant tumor cells, but for normal cells it is not considered safe.
• IC50 50–100 μg/mL–Potentially safe (yellow to green color). This range may be acceptable depending on the clinical context, especially if the drug shows high selectivity for tumor cells. However, potential toxicity to normal cells should be carefully monitored.
• IC50 ≥ 100 μg/mL–Safe (blue color). These values are considered indicative of low cytotoxicity, which is desirable for normal cells, but ineffective for cancer cells.
The National Cancer Institute (NCI) guidelines traditionally consider compounds with IC50 ≤ 10 µM (or µg/mL for crude extracts) as having high cytotoxic potential, especially in the NCI-60 human tumor cell line screen (Shoemaker, 2006). Classification ranges for natural products in breast cancer screening studies, with similar thresholds adapted to herbal extract data were also described (Zhang et al., 2024). In a cytotoxicity framework based on extract potency, IC50 values > 100 μg/mL are generally deemed non-toxic, while values < 10 μg/mL are considered highly cytotoxic (Badisa et al., 2009). These thresholds are not absolute and are primarily used in vitro as screening indicators for selectivity and potency. Additional in vivo studies would be necessary to establish clinical safety.
Results
Only 13 studies met the inclusion criteria (Figure 1) and are summarized in Table 1. Regarding toxicity to normal cells, a crude ethanolic stem bark extract, PAC-rich fractions or purified extracts, and a POA-trans-rich decoction were non-toxic (IC50 > 100 μg/mL) to Vero, NHDF, and LEC cells. The purified TOA-rich extract was potentially non-toxic (IC50 50–100 μg/mL), while crude POA-trans-rich extract bark and the purified POA-cis-rich extract bark were potentially toxic (IC50 10–50 μg/mL) to HL cells. The most worrisome case was the crude aqueous extract (72 h) of the bark, which was toxic (IC50 < 10 μg/mL) to HaCaT cells (Figure 2).
Figure 1. Flowchart of study selection.
Table 1. Summary characteristics of the included studies.
Figure 2. Half maximal inhibitory concentration (IC50, in µg/mL) of selected Uncaria tomentosa extracts to normal cells. Legend: Values in shades of yellow and green (IC50 50–100 μg/mL) or blue (IC50 ≥ 100 μg/mL) are the safest to normal cells. Values in orange are potentially toxic (IC50 10–50 μg/mL), while those in red (IC50 ≤ 10 μg/mL) are the most toxic to normal cells. POA, pentacyclic oxindole alkaloids; TOA, tetracyclic oxindole alkaloids; PAC, proanthocyanidins; QAPF, quinovic acid glycosides purified fraction.
Regarding toxicity to cancer cells, most extracts were non-toxic or only potentially toxic. Some preparations (extracts or fractions) showed clear toxicity in cancer cells, such as the crude aqueous bark extract (72 h) mostly for ectoderm-origin cancer cells (A431, SCC011, SCC013, and SCC022), the purified POA-trans-rich stem bark extract to MT-3 and MHH-ES-1cells, and the crude POA-trans-rich stem bark extract to T24 cells. Other promising potentially toxic extract were the crude hexane, butanolic, and ethylacetate extracts against HL-60 cells, the water + dicloromethane extract against A-549, KB, and MCF-7 cells, the crude POA-rich extract (72 h) against DU145 and LNCaP cells, the POA-cis-rich bark extract against HeLa and SW480 cells, and the POA-cis-rich crude 96% ethanolic extracts against KB and LL/2 cells. All PAC-rich fractions or purified extracts, from either leaf or bark, were nontoxic to cancer cells AGS and SW620 (Figure 3).
Figure 3. Half maximal inhibitory concentration (IC50, in µg/mL) of selected Uncaria tomentosa extracts to cancer cells. Legend: Values in shades of red (IC50 ≤ 10 μg/mL) are the most promising, while those in shades of orange (IC50 10–50 μg/mL) are potentially promising. Values in yellow to green (IC50 50–100 μg/mL) or blue (IC50 ≥ 100 μg/mL) are not promising to treat cancer. POA, pentacyclic oxindole alkaloids; TOA, tetracyclic oxindole alkaloids; PAC, proanthocyanidins; QAPF, quinovic acid glycosides purified fraction.
The risk of bias assessment (Table 2) revealed several methodological limitations across the included studies. Although all articles were published in peer-reviewed journals and most provided adequate control of temperature and reported outcome data, crucial elements such as blinding of outcome assessment and randomization were rarely addressed, being marked as “unclear” in over 90% of the studies. Additionally, nearly half of the studies did not include a non-cancer cell lineage control, which limits interpretation of selectivity.
Table 2. Risk of bias among the included studies.
Discussion
In this study, we demonstrated that POA-rich U. tomentosa extracts exhibit significant cytotoxic activity against various cancer cell lines, including epidermoid carcinoma, squamous cell carcinoma, breast cancer, Ewing’s sarcoma, and bladder transitional cell carcinoma (Batiha et al., 2020; Kaiser et al., 2016). Over 30% (10/32) of the tested extracts were toxic to cancer cells. In contrast, TOA- and PAC-rich extracts did not show promising cytotoxic effects. Importantly, most U. tomentosa extracts were non-toxic to normal cells, except some POA-rich extracts and the crude aqueous bark extract studied by Ciani et al. (2018). Nevertheless, the extracts’ overall low toxicity reinforces their potential as selective anticancer agents; however, further studies are necessary to confirm this finding across a broader range of cell types.
Our analysis also revealed that the cytotoxic effects of U. tomentosa extracts depend on multiple factors, including the plant part used, the extraction method (e.g., solvent, time, purification), and the specific chemotype (Kaiser et al., 2016). Chemotype I (POA cis-D/E ring junction) and chemotype III (TOA) displayed greater cytotoxicity to normal cells, whereas chemotype II (POA trans-D/E ring junction) was not toxic to normal cells. Notably, standardized POA-rich extracts (4.5% POA) demonstrated cytotoxic activity to prostate cancer cells (IC50 = 15.7 μg/mL) (Ribeiro et al., 2020), and ethyl acetate extracts showed dose- and time-dependent apoptotic effects (Cheng et al., 2007), emphasizing the role of extraction conditions in therapeutic efficacy. Conversely, PAC-rich fractions were nontoxic to normal or cancer cells (Navarro-Hoyos et al., 2017).
Alkaloids exhibit a wide range of biological activities relevant to cancer therapy, such as interfering with the cell cycle [vinblastine and vincristine, from Catharanthus roseus (L.) G.Don (Apocynaceae)], inducing apoptosis [berberine, from Berberis vulgaris L. (Berberidaceae)], and inhibiting angiogenesis [camptothecin, from Camptotheca acuminata Decne. (Nyssaceae)] (Newman and Cragg, 2020). Additionally, oxindole alkaloids can generate reactive oxygen species (ROS), which can lead to oxidative stress and subsequent cell death (Cheng et al., 2007). This property is particularly beneficial as it selectively targets malignant cells while sparing normal cells, reducing side effects commonly associated with chemotherapy. This multifactorial action enhances their anticancer efficacy and helps overcome drug resistance (Batiha et al., 2020). The oxindole nucleus is a fundamental component of numerous anticancer pharmaceutical agents, both those that are currently available and those that are currently under investigation. The majority of oxindole nucleus-containing compounds exhibited anticancer activity upon substituting at the carbon-3 position with the formation of a spiro ring. Moreover, the methoxy group at the 5th position was found to be partially critical for upregulation of tumor suppressor proteins (Khetmalis et al., 2021).
Compounds such as mitraphylline and other POAs have demonstrated significant cytotoxicity against a range of cancer cell lines, including breast cancer, Ewing’s sarcoma, and glioblastoma, with IC50 values lower than those of standard chemotherapeutic agents (García Giménez et al., 2010). The anticancer properties of POAs compounds have been demonstrated through a variety of methods. These include inhibition of cell growth, blocking of the cell cycle, and induction of cell apoptosis, among others (Wang et al., 2025). Further exploration into their pharmacological profiles and mechanisms of action is warranted to fully understand their potential in cancer therapy. PACs may exert their anticancer effects via two pathways: the caspase-dependent and the caspase-independent pathways.
Proanthocyanidins (PACs), a class of polyphenolic compounds found abundantly in various plants, have emerged as promising candidates for cancer therapy due to their antioxidant, anti-inflammatory, and antiproliferative properties (Navarro et al., 2017). They can exert anticancer effects through multiple mechanisms, including inducing apoptosis by modulating caspases, Bax, and Bcl-2, inhibiting angiogenesis via VEGF downregulation, and interfering with cell proliferation by modulating cyclins and CDKs (Navarro-Hoyos et al., 2017). PACs have previously demonstrated efficacy against breast, prostate, colorectal, and lung cancers. One of the most promising aspects of PACs is their ability to enhance existing cancer treatments. PACs have the potential to treat resistant and malignant tumors, so researchers investigated PAC activity at the molecular level. These studies found that PACs produce reactive oxygen species to stimulate apoptosis pathways (Albogami, 2020). PACs can sensitize cancer cells to chemotherapy and radiation therapy, inhibit DNA repair pathways, and mitigate chemotherapy-induced oxidative stress and inflammation (Navarro et al., 2017). This dual action makes PACs attractive for combination therapy. Furthermore, PACs are generally well-tolerated and exhibit low toxicity, even at high doses (Navarro-Hoyos et al., 2017). Our findings align with previous studies showing that different U. tomentosa extracts selectively target malignant cells while sparing normal cells (Batiha et al., 2020; Kaiser et al., 2016). Standardized hydroethanolic and aqueous extracts enriched in POAs have consistently exhibited cytotoxicity across various cancer types, including hepatoma, adenocarcinoma, and leukemia. However, some studies reported an absence of activity against specific cancer lines, such as MDA-MB-231 breast cancer cells and CHO hamster ovary cells (Kośmider et al., 2017), indicating that the efficacy of U. tomentosa may not be universally applicable across all malignancies. Interestingly, while oxindole alkaloids have traditionally been considered the main bioactive compounds, some non-alkaloid fractions also exhibited anticancer activity. Glycosylated quinovic acids contributed to cytotoxicity in bladder cancer cells (Dietrich et al., 2014), and alkaloid-poor fractions inhibited medullary thyroid and breast cancer cell proliferation, though without pro-apoptotic effects (Rinner et al., 2009).
Despite the promising anticancer properties of alkaloids and PACs, several challenges must be addressed in drug development (Urdanibia et al., 2013). Firstly, the cytotoxicity of alkaloids varies significantly depending on their chemical structure and functional groups, influencing their interaction with cellular targets (Kaiser et al., 2016). Secondly, alkaloids and polyphenols, including PACs, often exhibit low water solubility, limiting their formulation for intravenous administration (Newman and Cragg, 2020). Thirdly, cancer cells may develop resistance via efflux pumps (e.g., P-glycoprotein), reducing drug intracellular concentration and effectiveness (Gurrola-Díaz et al., 2011). Fourthly, the biological activity of PACs is influenced by polymerization degree and monomer types, leading to efficacy and safety differences. Developing standardized extracts with consistent composition and potency is crucial for clinical applications (Navarro-Hoyos et al., 2017). Lastly, the high risk of different types of bias identified in the studies may affect the internal validity and reduce the confidence in the pooled conclusions. While the general trend indicates that U. tomentosa extracts show selective cytotoxicity with low toxicity to normal cells, the lack of methodological transparency in many studies calls for cautious interpretation and highlights the need for more rigorously designed experiments in future research.
Future research should focus on optimizing formulations and conducting well-designed clinical trials to confirm safety, efficacy, and dosing. The transition from preclinical research to clinical trials requires well-structured studies assessing PACs and alkaloids in cancer patients. Collaborations between researchers, clinicians, and industry stakeholders will be crucial in advancing U. tomentosa-derived compounds as viable anticancer agents.
Conclusion
In conclusion, U. tomentosa extracts are promising to treat some types of cancer cells, including epidermoid carcinoma, squamous cell carcinoma, breast cancer, Ewing’s sarcoma, and bladder transitional cell carcinoma. The observed toxicity can be attributed to the presence of POAs and PACs, which promote apoptosis and enhance efficacy against tumors. Moreover, these extracts from U. tomentosa are generally safe to normal cells, except POA-rich extracts, which are potentially toxic to these cells.
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Author contributions
AL: Data curation, Investigation, Methodology, Validation, Writing – original draft, Writing – review and editing. JC: Investigation, Methodology, Validation, Writing – original draft, Writing – review and editing. PA: Data curation, Investigation, Methodology, Validation, Writing – original draft, Writing – review and editing. DA: Data curation, Investigation, Writing – original draft, Writing – review and editing. SF: Investigation, Methodology, Writing – original draft, Writing – review and editing. FC: Investigation, Methodology, Writing – original draft, Writing – review and editing. AP: Conceptualization, Investigation, Validation, Writing – original draft, Writing – review and editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This research was funded by the Biotechnology Unit, University of Ribeirão Preto (UNAERP).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that Generative AI was used in the creation of this manuscript. ChatGPT was used in manucript revision and translation to English.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Albogami, S. (2020). Proanthocyanidins reduce cellular function in the most globally diagnosed cancers in vitro. PeerJ 8, e9910. doi:10.7717/peerj.9910
Araujo, L. C. C., Feitosa, K. B., Murata, G. M., Furigo, I. C., Teixeira, S. A., Lucena, C. F., et al. (2018). Uncaria tomentosa improves insulin sensitivity and inflammation in experimental NAFLD. Sci. Rep. 8, 11013. doi:10.1038/S41598-018-29044-Y
Bacher, N., Tiefenthaler, M., Sturm, S., Stuppner, H., Ausserlechner, M. J., Kofler, R., et al. (2006). Oxindole alkaloids from Uncaria tomentosa induce apoptosis in proliferating, G0/G1-arrested and bcl-2-expressing acute lymphoblastic leukaemia cells. Br. J. Haematol. 132, 615–622. doi:10.1111/j.1365-2141.2005.05907.x
Badisa, R. B., Darling-Reed, S. F., Joseph, P., Cooperwood, J. S., Latinwo, L. M., and Goodman, C. B. (2009). Selective cytotoxic activities of two novel synthetic drugs on human breast carcinoma MCF-7 cells. Anticancer Res. 29, 2993–2996.
Batiha, G.E.-S., Magdy Beshbishy, A., Wasef, L., Elewa, Y. H. A., Abd El-Hack, M. E., Taha, A. E., et al. (2020). Uncaria tomentosa (willd. Ex Schult.) DC.: a review on chemical constituents and biological activities. Appl. Sci. 10, 2668. doi:10.3390/app10082668
Blanck, J. J., Huebner, T. M., Rolls, A. M., Cornell, J. S., and Hwang, C. S. (2022). Comprehensive review of the components in cat’s claw (uncaria tomentosa) and their antibacterial activity. AppliedChem 2, 1–29. doi:10.3390/appliedchem2010001
BRASIL (2022). Relação Nacional de Medicamentos Essenciais: Rename 2022. Ministério da Saúde, Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde, Departamento de Assistência Farmacêutica e Insumos Estratégicos, Brasília.
Carmona, F., and Pereira, A. M. S. (2025). Cytotoxic effect of different uncaria tomentosa (Cat’s Claw) Extracts or Fractions on Normal and Cancer Cells: a Systematic Review. Open Sci. Framew. doi:10.17605/OSF.IO/HFAZQ
Cheng, A.-C., Jian, C.-B., Huang, Y.-T., Lai, C.-S., Hsu, P.-C., and Pan, M.-H. (2007). Induction of apoptosis by Uncaria tomentosa through reactive oxygen species production, cytochrome c release, and caspases activation in human leukemia cells. Food Chem. Toxicol. 45, 2206–2218. doi:10.1016/j.fct.2007.05.016
Ciani, F., Tafuri, S., Troiano, A., Cimmino, A., Fioretto, B. S., Guarino, A. M., et al. (2018). Anti-proliferative and pro-apoptotic effects of Uncaria tomentosa aqueous extract in squamous carcinoma cells. J. Ethnopharmacol. 211, 285–294. doi:10.1016/j.jep.2017.09.031
Coussens, L. M., and Werb, Z. (2002). Inflammation and cancer. Nature 420, 860–867. doi:10.1038/nature01322
De Martino, L., Martinot, J. L. S., Franceschelli, S., Leone, A., Pizza, C., and De Feo, V. (2006). Proapoptotic effect of Uncaria tomentosa extracts. J. Ethnopharmacol. 107, 91–94. doi:10.1016/j.jep.2006.02.013
de Oliveira, L. Z., Farias, I. L. G., Rigo, M. L., Glanzner, W. G., Gonçalves, P. B. D., Cadoná, F. C., et al. (2014). Effect of Uncaria tomentosa Extract on Apoptosis Triggered by Oxaliplatin Exposure on HT29 Cells. Evidence-Based Complementary Altern. Med. 2014, 274786. doi:10.1155/2014/274786
Dietrich, F., Kaiser, S., Rockenbach, L., Figueiró, F., Bergamin, L. S., Cunha, F.M. da, et al. (2014). Quinovic acid glycosides purified fraction from Uncaria tomentosa induces cell death by apoptosis in the T24 human bladder cancer cell line. Food Chem. Toxicol. 67, 222–229. doi:10.1016/j.fct.2014.02.037
Dreifuss, A. A., Bastos-Pereira, A. L., Fabossi, I. A., Lívero, F. A., dos, R., Stolf, A. M., et al. (2013). Uncaria tomentosa Exerts Extensive Anti-Neoplastic Effects against the Walker-256 Tumour by Modulating Oxidative Stress and Not by Alkaloid Activity. PLoS One 8, e54618. doi:10.1371/journal.pone.0054618
Fazio, A. L., Ballén, D., Cesari, Í. M., Abad, M. J., Arsenak, M., and Taylor, P. (2008). An ethanolic extract of Uncaria tomentosa reduces inflammation and B16- BL6 melanoma growth in C57BL/6 mice. Bol. Latinoam. Caribe Plantas Med. Aromat. 7, 217–224.
García Giménez, D., García Prado, E., Sáenz Rodríguez, T., Fernández Arche, A., and De la Puerta, R. (2010). Cytotoxic Effect of the Pentacyclic Oxindole Alkaloid Mitraphylline Isolated from Uncaria tomentosa Bark on Human Ewing’s Sarcoma and Breast Cancer Cell Lines. Planta Med. 76, 133–136. doi:10.1055/s-0029-1186048
Gurrola-Díaz, C. M., García-López, P. M., Gulewicz, K., Pilarski, R., and Dihlmann, S. (2011). Inhibitory mechanisms of two Uncaria tomentosa extracts affecting the Wnt-signaling pathway. Phytomedicine 18, 683–690. doi:10.1016/j.phymed.2010.11.002
Haddaway, N. R., Page, M. J., Pritchard, C. C., and McGuinness, L. A. (2022). PRISMA2020: An R package and Shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and Open Synthesis. Campbell Syst. Rev. 18, e1230. doi:10.1002/cl2.1230
Honório, I. C. G., Bertoni, B. W., and Pereira, A. M. S. (2016). Uncaria tomentosa and Uncaria guianensis an agronomic history to be written. Ciência Rural. 46, 1401–1410. doi:10.1590/0103-8478cr20150138
Kaiser, S., Carvalho, Â. R., Pittol, V., Dietrich, F., Manica, F., Machado, M. M., et al. (2016). Genotoxicity and cytotoxicity of oxindole alkaloids from Uncaria tomentosa (cat’s claw): Chemotype relevance. J. Ethnopharmacol. 189, 90–98. doi:10.1016/j.jep.2016.05.026
Kaiser, S., Dietrich, F., Resende, P., Verza, S., Moraes, R., Morrone, F., et al. (2013). Catʼs Claw Oxindole Alkaloid Isomerization Induced by Cell Incubation and Cytotoxic Activity against T24 and RT4 Human Bladder Cancer Cell Lines. Planta Med. 79, 1413–1420. doi:10.1055/s-0033-1350742
Khetmalis, Y. M., Shivani, M., Murugesan, S., and Chandra Sekhar, K. V. G. (2021). Oxindole and its derivatives: A review on recent progress in biological activities. Biomed. and Pharmacother. 141, 111842. doi:10.1016/j.biopha.2021.111842
Kośmider, A., Czepielewska, E., Kuraś, M., Gulewicz, K., Pietrzak, W., Nowak, R., et al. (2017). Uncaria tomentosa Leaves Decoction Modulates Differently ROS Production in Cancer and Normal Cells, and Effects Cisplatin Cytotoxicity. Molecules 22, 620. doi:10.3390/molecules22040620
Kozielewicz, P., Paradowska, K., Erić, S., Wawer, I., and Zloh, M. (2014). Insights into mechanism of anticancer activity of pentacyclic oxindole alkaloids of Uncaria tomentosa by means of a computational reverse virtual screening and molecular docking approach. Monatsh. für Chem. - Chem. Mon. 145, 1201–1211. doi:10.1007/s00706-014-1212-y
Macleod, M. R., O’Collins, T., Howells, D. W., and Donnan, G. A. (2004). Pooling of Animal Experimental Data Reveals Influence of Study Design and Publication Bias. Stroke 35, 1203–1208. doi:10.1161/01.STR.0000125719.25853.20
Navarro, M., Zamora, W., Quesada, S., Azofeifa, G., Alvarado, D., and Monagas, M. (2017). Fractioning of Proanthocyanidins of Uncaria tomentosa. Composition and Structure-Bioactivity Relationship. Antioxidants 6, 60. doi:10.3390/antiox6030060
Navarro-Hoyos, M., Lebrón-Aguilar, R., Quintanilla-López, J., Cueva, C., Hevia, D., Quesada, S., et al. (2017). Proanthocyanidin Characterization and Bioactivity of Extracts from Different Parts of Uncaria tomentosa L. (Cat’s Claw). Antioxidants 6, 12. doi:10.3390/antiox6010012
Newman, D. J., and Cragg, G. M. (2020). Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. J. Nat. Prod. 83, 770–803. doi:10.1021/acs.jnatprod.9b01285
Ouzzani, M., Hammady, H., Fedorowicz, Z., and Elmagarmid, A. (2016). Rayyan-a web and mobile app for systematic reviews. Syst. Rev. 5, 210–10. doi:10.1186/s13643-016-0384-4
Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., et al. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372, n71. doi:10.1136/BMJ.N71
Pilarski, R., Filip, B., Wietrzyk, J., Kuraś, M., and Gulewicz, K. (2010). Anticancer activity of the Uncaria tomentosa (Willd.) DC. preparations with different oxindole alkaloid composition. Phytomedicine 17, 1133–1139. doi:10.1016/j.phymed.2010.04.013
Pilarski, R., Gurrola-Díaz, C. M., García-López, P. M., Soldevila, G., Olejnik, A., Grajek, W., et al. (2013). Enhanced proapoptotic response of the promyelocytic leukemia HL-60 cells treated with an Uncaria tomentosa alkaloid preparation. J. Herb. Med. 3, 149–156. doi:10.1016/j.hermed.2013.04.002
Reinhard, K.-H. (1999). Uncaria tomentosa (Willd.) D.C.: Cat’s Claw, Uña de Gato, or Savéntaro. J. Altern. Complementary Med. 5, 143–151. doi:10.1089/acm.1999.5.143
Ribeiro, A. F., Santos, J. F., Mattos, R. R., Barros, E. G. O., Nasciutti, L. E., Cabral, L. M., et al. (2020). Characterization and in vitro antitumor activity of polymeric nanoparticles loaded with Uncaria tomentosa extract. An Acad Bras Cienc 92, e20190336. doi:10.1590/0001-3765202020190336
Rinner, B., Li, Z. X., Haas, H., Siegl, V., Sturm, S., Stuppner, H., et al. (2009). Antiproliferative and pro-apoptotic effects of Uncaria tomentosa in human medullary thyroid carcinoma cells. Anticancer Res. 29, 4519–4528.
Rojas-Duran, R., González-Aspajo, G., Ruiz-Martel, C., Bourdy, G., Doroteo-Ortega, V. H., Alban-Castillo, J., et al. (2012). Anti-inflammatory activity of Mitraphylline isolated from Uncaria tomentosa bark. J. Ethnopharmacol. 143, 801–804. doi:10.1016/j.jep.2012.07.015
Schneider, C. A., Rasband, W. S., and Eliceiri, K. W. (2012). NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671–675. doi:10.1038/nmeth.2089
Shoemaker, R. H. (2006). The NCI60 human tumour cell line anticancer drug screen. Nat. Rev. Cancer 6, 813–823. doi:10.1038/nrc1951
Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., et al. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 71, 209–249. doi:10.3322/caac.21660
Urdanibia, I., Michelangeli, F., Ruiz, M.-C., Milano, B., and Taylor, P. (2013). Anti-inflammatory and antitumoural effects of Uncaria guianensis bark. J. Ethnopharmacol. 150, 1154–1162. doi:10.1016/j.jep.2013.10.055
USP-United States Pharmacopeia (2022). “Cat’s Claw Capsules,” in Dietary supplement monographs: USP-United States Pharmacopeia (Rockville: USP-United States Pharmacopeia).
Wagner, H., Kreutzkamp, B., and Jurcic, K. (1985). Die Alkaloide von Uncaria tomentosa und ihre Phagozytose-steigernde Wirkung. Planta Med. 51, 419–423. doi:10.1055/s-2007-969537
Wang, Z., Xiang, S., Zhang, W., Chen, H., and Yang, C. (2025). Uncaria-derived compounds for cancer treatment: mechanistic insights and therapeutic potential. Med. Chem. Res. 34, 517–534. doi:10.1007/s00044-025-03370-z
WHO (2007). WHO Monographs on selected medicinal plants. 1st ed., Vol. 3. Geneva: World Health Organization.
Wurm, M., Kacani, L., Laus, G., Keplinger, K., and Dierich, M. (1998). Pentacyclic Oxindole Alkaloids from Uncaria tomentosa Induce Human Endothelial Cells to Release a Lymphocyte-Proliferation-Regulating Factor. Planta Med. 64, 701–704. doi:10.1055/s-2006-957561
Xian, Y.-F., Mao, Q.-Q., Wu, J. C., Su, Z.-R., Chen, J.-N., Lai, X.-P., et al. (2014). Isorhynchophylline Treatment Improves the Amyloid-β-Induced Cognitive Impairment in Rats via Inhibition of Neuronal Apoptosis and Tau Protein Hyperphosphorylation. J. Alzheimer’s Dis. 39, 331–346. doi:10.3233/JAD-131457
Zhang, J., Wu, Y., Li, Y., Li, S., Liu, J., Yang, X., et al. (2024). Natural products and derivatives for breast cancer treatment: From drug discovery to molecular mechanism. Phytomedicine 129, 155600. doi:10.1016/j.phymed.2024.155600
Keywords: half-maximal inhibitory concentration (IC50), keratinocytes, oxindole alkaloids, proanthocyanidins, Rubiaceae
Citation: Lopes AA, Coppede JdS, Amatto PdPG, Aragon DC, França SdC, Carmona F and Pereira AMS (2025) Cytotoxic effect of different Uncaria tomentosa (cat’s claw) extracts, fractions on normal and cancer cells: a systematic review. Front. Pharmacol. 16:1584840. doi: 10.3389/fphar.2025.1584840
Received: 27 February 2025; Accepted: 29 April 2025;
Published: 14 May 2025.
Edited by:
Cheorl-Ho Kim, Sungkyunkwan University, Republic of KoreaReviewed by:
Tshepo Mashela, University of Limpopo, South AfricaSaikat Sena, Lovely Professional University, India
Copyright © 2025 Lopes, Coppede, Amatto, Aragon, França, Carmona and Pereira. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ana Maria S. Pereira, YXBlcmVpcmFAdW5hZXJwLmJy