Unlocking the Potential of Mistletoe Extracts in Bladder Cancer


Bladder cancer is a formidable adversary within the realm of oncology, standing as the most common malignancy of the urinary system with a staggering 550,000 cases reported worldwide each year.

This formidable disease poses a significant challenge to healthcare providers and researchers due to its diverse presentation and clinical course.

Alarmingly, while 75% of patients initially present with a localized, non-muscle invasive form, the disease takes a sinister turn, progressing to become muscle-invasive in 20–40% of cases [1]. Although advances in multimodal treatment strategies have been made in recent years, the prognosis remains bleak, primarily owing to high recurrence rates. Once bladder cancer metastasizes, the 5-year survival rate plummets to a grim 6% [2].

Current Treatment Modalities and Their Limitations

The primary therapeutic approach for managing advanced bladder cancer involves cisplatin-based chemotherapy. However, this standard of care therapy has yielded disappointing results, with a median overall survival of just 13.1 months [3]. It is essential to recognize that this survival rate reflects the average, implying that many patients face even grimmer prospects.

In recent years, immune checkpoint inhibitors (ICIs) have emerged as a promising avenue for bladder cancer therapy. These ICIs have been approved, particularly for cisplatin-ineligible patients, as both first and second-line therapies [4]. Despite the initial optimism surrounding ICIs, only select patients derive significant benefits from this treatment.

Moreover, substantial side effects and toxicity must be carefully considered, leading to a less-than-ideal balance between therapeutic gains and quality of life. Unfortunately, ICIs have not managed to substantially improve overall survival for bladder cancer patients [4].

The Rise of Complementary and Alternative Medicine (CAM)

In the face of these challenges, cancer patients and their loved ones often seek alternative approaches to combat the disease and improve their quality of life. This quest for hope and healing has fueled a growing interest in complementary and alternative medicine (CAM) options among cancer patients [5].

Among the multitude of CAM therapies available, extracts derived from European mistletoe (Viscum album) have garnered significant popularity. Approximately one-third of cancer patients, especially those grappling with bladder cancer, have reported using mistletoe, often administered as an injectable prescription drug [6].

Exploring Mistletoe as a Potential Solution

Preclinical studies have shed light on the potential impact of mistletoe extracts on various aspects of cancer, including tumor growth, apoptosis (programmed cell death), invasion, and immunomodulation. These effects are primarily attributed to the presence of bioactive compounds such as lectins and viscotoxins [7,8].

Excitingly, experiments conducted on non-small-cell lung cancer cells have provided compelling evidence suggesting that mistletoe use may not only enhance the effects of cisplatin chemotherapy but may also circumvent cisplatin resistance [9][10]. These findings hold promise for patients battling bladder carcinoma, where cisplatin-based therapy remains a cornerstone of treatment.

Mistletoe in Bladder Cancer: Mixed Results

However, when it comes to bladder cancer, the scientific landscape surrounding mistletoe extracts is far from uniform. In vitro studies examining the impact of mistletoe extracts on bladder carcinoma cell lines have indeed demonstrated the suppression of tumor proliferation, hinting at potential therapeutic benefits [11].

Furthermore, this effect has been confirmed in an orthotopic murine model, showcasing a growth blockade of urinary bladder carcinoma following intravesical application of an aqueous mistletoe extract. Regrettably, this approach failed to prevent the formation of multiple metastases [12].

The picture becomes even more complex when evaluating the results of studies involving animal models. For instance, in chemically induced urothelial carcinoma rat models, the subcutaneous injection of mistletoe extracts did not appear to reduce tumor development [13].

Turning our attention to clinical trials, the situation remains inconclusive. In some studies, the intravesical instillation of mistletoe in patients with non-muscle invasive bladder cancer was shown to be safe and well-tolerated, with promising efficacy [14]. Additionally, a retrospective analysis of patients with resectable bladder cancer undergoing high-dose mistletoe treatment suggested that mistletoe could potentially reduce the frequency of tumor recurrence [15].

Similarly, applying an aqueous mistletoe extract intravesically to patients with superficial urothelial bladder carcinomas yielded recurrence rates comparable to those treated with adjuvant Bacillus Calmette–Guerin, a standard therapy for non-muscle invasive bladder cancer [16].

Exploring Mistletoe’s Mechanisms of Action

To delve deeper into the clinical relevance of mistletoe extracts in bladder cancer treatment, an in vitro study has been initiated. This study seeks to explore the growth-blocking potential of mistletoe derived from different host trees on three distinct bladder cancer cell lines.

In addition to assessing growth and proliferation, researchers are examining cell cycle-regulating proteins, particularly those belonging to the CDK (cyclin-dependent kinases) and cyclin families. Furthermore, the study is investigating integrin α and β subtypes, as well as CD44 receptors, including standard (CD44s) and variant (CD44v) forms.

Integrins are heterodimeric transmembrane glycoprotein signaling receptors that play a pivotal role in a wide range of cellular functions, including cell migration, growth, proliferation, and apoptosis. In mammals, researchers have identified 18 α and 8 β subunits, each impacting cellular behavior and function.

CD44, another critical molecule under scrutiny, is a non-kinase cell surface transmembrane glycoprotein. While it is predominantly expressed in the CD44s form, encoded by constant exons, post-translational alternative splicing may result in the formation of different CD44v types (CD44v1-10). Integrin subtypes and CD44 members are known to play a significant role in determining the fate of tumor cells and have been linked to various aspects of bladder cancer, including tumor size, grade, and recurrence [18].

Discussion: Understanding Mistletoe’s Anti-Tumor Properties in Bladder Cancer

The discussion section of this research delves into the intricate details of the study’s findings, shedding light on the various aspects of mistletoe extracts’ impact on bladder cancer cells. It explores the differences between mistletoe extracts from various host trees, their effects on different bladder cancer cell lines, and the potential mechanisms underlying these effects. The section also considers the implications of these findings for future research and clinical applications.

Variability in Mistletoe Extracts

One of the key findings of this study is the variability in the anti-tumor properties of mistletoe extracts derived from different host trees. The Tiliae extract was identified as the most potent in suppressing the growth of UMUC3 and RT112 cells when applied at a high dilution. This suggests that the choice of mistletoe host tree can significantly impact its effectiveness against bladder cancer cells. Similar variations have been observed in other cancer models, including lung carcinoma cells, where extracts from Tiliae and Salicis host trees showed the strongest inhibition of proliferation [19]. This underscores the importance of understanding the specific properties of mistletoe extracts from different host trees in the context of bladder cancer treatment.

Cell Line Sensitivity and Tumor Differentiation

The study also highlights the variability in the sensitivity of different bladder cancer cell lines to mistletoe extracts. TCCSup cells were found to be less responsive to mistletoe extracts compared to UMUC3 and RT112 cells. Furthermore, the differentiation status of bladder tumors appeared to influence their response to mistletoe. Notably, low-grade bladder cancer cells might be more sensitive to mistletoe treatment. This raises the possibility that mistletoe therapy could be particularly beneficial for certain subtypes of bladder cancer, which warrants further investigation.

Integrin Receptor Expressions and Alterations

The study delves into the role of integrin receptors in mediating the effects of mistletoe extracts on bladder cancer cells. Integrin receptors, specifically α3 and α5 subtypes, were found to be differentially expressed on various bladder cancer cell lines. Importantly, mistletoe treatment induced distinct alterations in integrin expression, suggesting a potential mechanism by which mistletoe impacts bladder cancer growth.

CD44 Expression and Apoptosis

The study also observed differences in CD44 expression among bladder cancer cell lines in response to mistletoe treatment. CD44 has been implicated in bladder cancer progression, and its expression can vary widely across different tumor types. This study found that mistletoe extracts induced apoptosis in UMUC3 cells but did not significantly alter CD44s expression. This suggests that mistletoe’s impact on CD44 expression may require longer exposure, and further research is needed to understand the relationship between mistletoe and CD44 in bladder cancer cells.

Cell Cycle and Apoptosis

The study provides valuable insights into the effects of mistletoe extracts on the cell cycle and apoptosis in bladder cancer cells. It is intriguing to note that mistletoe extracts appeared to induce apoptosis at higher concentrations than those required for growth suppression. This underscores the complexity of mistletoe’s mechanisms of action and suggests that multiple pathways may be involved in its anti-tumor effects.

Implications for Bladder Cancer Treatment

The findings of this study have significant implications for the potential integration of mistletoe therapy into standard bladder cancer treatment regimens. While the study focused on understanding mistletoe’s effects at the cellular level, it raises the possibility that mistletoe could be a valuable adjunct to current treatment options. The potential to slow bladder cancer growth and reduce proliferation through mistletoe treatment, especially in low-grade bladder cancer, warrants further investigation.

Side Effects and Dosage

Finally, it is crucial to acknowledge the potential side effects of mistletoe therapy, which can include local skin reactions and systemic symptoms. Establishing appropriate dosage levels and regimens is a critical consideration to maximize mistletoe’s therapeutic benefits while minimizing adverse effects. The balance between efficacy and safety must be carefully evaluated in future research and clinical trials.

Conclusion and Future Directions

In conclusion, this study provides valuable insights into the complex interactions between mistletoe extracts and bladder cancer cells. It highlights the variability in mistletoe’s anti-tumor properties based on the host tree and the sensitivity of bladder cancer cell lines. Additionally, it underscores the importance of considering integrin receptors, CD44 expression, and cell cycle dynamics in mistletoe’s mechanisms of action.

Moving forward, further research is needed to elucidate the specific pathways and molecular mechanisms through which mistletoe exerts its anti-tumor effects in bladder cancer. This knowledge will be crucial in optimizing mistletoe therapy for bladder cancer patients, potentially improving their long-term outcomes and quality of life. Additionally, clinical trials assessing mistletoe’s safety and efficacy in combination with standard bladder cancer treatments are warranted to explore its full therapeutic potential.

reference link : https://www.mdpi.com/2072-6694/15/19/4849


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