Summary of Recent Study on Urtica dioica (Stinging Nettle) and Cancer Prevention as published National Center for Biotechnology Information. An official website of the United States government.

Since the 20th century, advancements in microscopy, chemical engineering, and the rise of pharmaceutical companies have vastly expanded the pool of available drugs. Yet, even before the discovery of the microscopic world, ancestral medicines relied heavily on medicinal plants due to their therapeutic properties. Today, plants continue to play a critical role in both conventional and alternative medicine due to their chemical diversity, affordability, and cultural accessibility.

One notable plant is Urtica dioica (UD), commonly known as nettle or stinging nettle. Its name derives from the Latin “Urtica” meaning “to burn,” referencing the stinging hairs on its stems and leaves that release a burning fluid containing acetylcholine, serotonin, and histamine. Despite this initial irritation, the plant has remarkable therapeutic properties, particularly in the context of cancer prevention.

Key Findings on Cancer Prevention and Treatment:

1. Selective Anti-Cancer Properties:

   • UD exhibits potent chemo-preventive effects, particularly against prostate, breast, leukemia, colon, ovarian, and lung cancers.

   • It modulates cancer-related cell signaling pathways, helping to inhibit tumor growth and proliferation.

2. Mechanisms of Action:

   • Anti-proliferative activities: UD compounds can reduce the rapid multiplication of cancer cells.

   • Oxidative stress reduction: Its antioxidant properties protect cells from DNA damage caused by free radicals.

   • Apoptosis induction: UD encourages programmed cell death in malignant cells without harming healthy cells.

3. Clinical and Experimental Evidence:

   • In vitro studies demonstrate UD's ability to suppress cancer cell viability.

   • Animal studies have shown reduced tumor sizes and improved survival rates.

   • Preliminary clinical trials indicate potential benefits, though more large-scale studies are needed.

Prostate Cancer Research:

Prostate cancer is the second most common malignancy among males globally, with rising mortality rates highlighting the need for novel therapeutic strategies. Extensive research has investigated UD as a promising alternative treatment due to its proapoptotic activity in cancer cells.

• Types of Extracts: Different UD extracts, including dichloromethane, methanolic, and aqueous extracts, showed cytotoxic effects on prostate cancer cell lines (PC3 and LNCaP) in dose- and time-dependent manners.

• Hormonal Sensitivity: Studies revealed differential responses based on the androgen sensitivity of cancer cells. For instance, DTH (3,4-divanillyltetrahydrofuran) extract from UD roots was more cytotoxic to LNCaP cells compared to PC3 cells.

• Mechanisms of Action:

  • Induced G2/M cell cycle arrest, halting cell cycle progression.

  • Activation of apoptotic pathways through mitochondrial dysfunction, DNA damage, and caspase activation.

  • Reduction of mitochondrial membrane potential and inhibition of the antiapoptotic marker Bcl-2.

  • Promotion of reactive oxygen species (ROS) accumulation, leading to apoptosis.

• Ex Vivo Findings: An ex vivo study demonstrated UD’s ability to inhibit the adenosine deaminase (ADA) enzyme in prostate cancer tissues, potentially promoting cancer cell death by toxic metabolite accumulation.

Despite promising in vitro results, no in vivo studies have evaluated UD’s anticancer properties for prostate cancer. Further clinical trials and comprehensive research are needed to validate its efficacy.

Breast Cancer Research:

Several studies have revealed that UD exhibits antiproliferative and proapoptotic effects on many breast cancer cell lines, including MCF-7 and MDA-MB cells.

• Antiproliferative and Apoptotic Properties:

  • UD extracts showed dose-dependent antiproliferative activity on MCF-7 cells, attributed to its flavonoid content (kaempferol, quercetin, and rutin).

  • The apoptotic mechanism involves caspase-9 activation through calcium overload, leading to cytochrome c release and DNA fragmentation.

  • Increased Bax/Bcl2 ratios and inhibition of the PI3K/AKT pathway further demonstrated UD’s role in inducing apoptosis.

• Metastasis Inhibition:

  • UD was found to reduce migration and motility of MCF-7 and MDA-MB-231 cells by downregulating metastasis-related markers, including miR-21, MMPs, E-cadherin, and CXCR4.

• Combination with Chemotherapeutic Drugs:

  • UD enhanced the sensitivity of MDA-MB cells to paclitaxel and cisplatin treatments, promoting cell death and inhibiting migration.

• Nanoparticle Applications:

  • Silver nanoparticles synthesized from UD extracts exhibited stronger antiproliferative effects than the extract alone.

• In Vivo Studies:

  • Animal models showed substantial decreases in tumor development and volume upon treatment with UD extracts.

Translating these findings into clinical trials is essential to validate the anticancer properties of UD and improve treatment outcomes for breast cancer patients.

Leukemia (Blood Cancer) Research:

Leukemia is a blood cancer that arises in the bone marrow, often leading to abnormal leukocyte counts. Despite available treatments like chemotherapy and radiation, the demand for novel therapeutic strategies remains.

• Antiproliferative Effects:

  • UD leaf extracts inhibited the growth of leukemic cell lines HL-60, U937, and KG-1 in vitro.

  • Studies confirmed UD’s selective cytotoxicity, as it showed no significant harmful effects on normal human B lymphocytes and PBMC cells.

• Cell Cycle Targeting:

  • UD extract caused dose-dependent increases in pre-G0 content in U937 cells and increased sub-G1 phase content in HL-60, Jurkat, and Raji cells.

  • Downregulation of cell cycle pathway genes, including MDM2, was observed.

• Apoptotic Mechanisms:

  • Flow cytometry revealed significant Annexin V binding during apoptosis.

  • DNA fragmentation and mitochondrial membrane potential disruption were noted, leading to increased Bax/Bcl-2 ratios.

  • Downregulation of PARP2 promoted apoptosis, while PARP4 upregulation in certain cases inhibited cell growth.

  • Activation of caspases 3, 8, and 9 indicated involvement of both intrinsic and extrinsic apoptotic pathways.

• Targeted Cellular Mechanisms:

  • UD influenced the IGF1/IGF1R signaling pathway, essential for acute myeloid leukemia progression.

  • UD agglutinin promoted apoptosis in Jurkat cells but exhibited resistance in Raji cells due to a lack of caspase activity.

Further studies are required to investigate mechanisms behind resistance and validate these findings through animal models and clinical trials.

Colorectal Cancer Research:

Colorectal cancer is a common digestive malignancy with rising prevalence despite advancements in conventional treatments. This trend has prompted scientific exploration into alternative therapeutic options, including UD.

• Antiproliferative Effects:

  • UD extracts inhibited the proliferation of colorectal cancer cell lines HT29, HCT116, and Caco-2 in a dose- and time-dependent manner, with minimal cytotoxicity against healthy human colorectal cells (HFF).

• Oxidative Stress and Apoptosis:

  • UD treatment increased ROS content through lipid peroxidation, promoting oxidative stress.

  • Studies documented cell cycle arrest at the G2 phase and DNA fragmentation, signaling apoptosis induction.

  • Elevated Caspases 3 and 9 expression, decreased Bcl-2 expression, and increased Bax/Bcl-2 ratios were observed.

• Mechanistic Insights:

  • Although UD’s precise apoptotic signaling pathway remains elusive, compounds such as isolectins, phenols, and triterpenoic acids are believed to contribute to its anticancer effects.

• Chemo-Preventive Properties:

  • In animal models, UD supplementation reduced colon cancer incidence, restored antioxidant enzyme activity, and induced apoptosis through Caspase 3 upregulation.

• Nanotechnology Applications:

  • Nanoemulsion and nanoencapsulation of UD extracts significantly enhanced their antiproliferative effects against HCT-116 cells compared to conventional hydroethanolic extracts.

These findings underscore the potential for UD extracts to complement colorectal cancer treatment strategies, warranting further investigation in clinical trials.

Other Types of Cancer:

The anti-tumor effects of UD have also been reported for cervical, gastric, and lung cancers. Given the detrimental side effects of chemotherapy, combination therapies utilizing natural compounds have gained attention.

• Combination Therapies:

  • In bladder cancer, a combination of N-butanol UD extract and doxorubicin exceeded the apoptotic effect of each drug alone on T24 bladder cancer cells.

  • In non-small cell lung carcinoma (NSCLC), UD exhibited a selective antiproliferative effect without harming normal cells. Co-treatment with cisplatin promoted apoptosis through the extrinsic pathway and induced G2/M phase cell cycle arrest.

  • The combination of UD extracts with Wormwood (Artemisia absinthium) showed enhanced anticancer effects on HCT-116 cells compared to either extract alone.

These findings illustrate the potential for UD to enhance the efficacy of chemotherapeutic agents and provide a natural option for combination therapies. Further research is warranted to explore its applications across different cancer types.

Research Gaps and Future Directions:

The review underscores the need for further research to fully understand the bioactive compounds responsible for UD’s anti-cancer effects. Standardized dosage recommendations and long-term safety evaluations should be prioritized.

This study highlights the potential of stinging nettle as a complementary natural therapy in cancer prevention and treatment, emphasizing the importance of integrating traditional medicinal knowledge with modern oncological research.

Link to publication https://pmc.ncbi.nlm.nih.gov/articles/PMC11242153/