A natural remedy for brain metastasis

Milk thistle extract might be a promising complementary treatment for cancer patients, reports Andrea Zangara, Scientific Marketing Manager, Euromed

Milk thistle (Silybum marianum) has been used as a medicinal plant for centuries. Extracts from its seeds have validated benefits for liver health. They have also been used both preventively and curatively to protect the liver from toxins such as alcohol, aspirin, acetaminophen, heavy metals and the death cap mushroom. And now, more recent studies suggest that a specific milk thistle extract may have further benefits that go beyond liver support.

The active constituent of milk thistle is a flavonoid called silymarin, which is obtained from the seeds of the plant. As an antioxidant, silymarin is known to scavenge harmful free radicals in addition to having several other biological properties. Its key component is silibinin. A silibinin standardised extract has been shown to be beneficial in the field of oncology to patients with brain metastases.1,2

Difficulty in treating brain metastasis

Brain metastases are a major challenge in the field of oncology. Lung cancers are the primary source of these tumours … and patients who develop brain metastases usually experience severe neurological symptoms and report a low quality of life. Despite multimodal therapy approaches, their prognosis remains poor.

Dr Joaquim Bosch-Barrera, Head of the Lung Cancer Unit at the Catalan Institute of Oncology in Girona, Spain, explains: “It depends on the type of cancer a patient has, but it is estimated that around 10% of people develop brain metastases, which worsens their prognosis significantly. These are also very difficult to treat, so we need to find a new therapeutic option.”

Once brain metastases occur, current treatment options are limited and the use of chemotherapy is challenging because the blood-brain barrier restricts the delivery of therapeutic drugs inside the brain. However, silibinin has been shown to cross the blood-brain barrier and to inhibit the activation of the signal transducer and activator of transcription 3 (STAT3).3

STAT3 is a protein that is activated in many different types of cancer and it plays a pivotal role in tumour growth, driving metastasis and mediating resistance to conventional chemo-/radiotherapies as well as modern targeted drugs.4

Milk thistle shows promising results

Preclinical studies show that silibinin is highly effective in targeting the migratory and invasive characteristics of cancer cells, demonstrating anticancer effects in vitro and in vivo.4,5 In 2016, Dr Bosch-Barrera and his team reported positive brain responses to an oral supplement containing silibinin in two patients with non-small cell lung cancer with no other treatment options.

Silibinin use resulted in the significant clinical and radiological improvement of brain metastases with poor performance status that progressed after whole brain radiotherapy and chemotherapy.1 The patients experienced a 70–85% reduction in the volume of their brain metastases. The treatment procedure for one of these patients is outlined here by way of example.

Case study example: A 62-year-old female who had never smoked presented with an episode of myoclonic seizure of the upper right extremity and decreased levels of consciousness. Magnetic resonance imaging (MRI) of the brain in June 2014 revealed five metastases, the largest measuring 24 × 25 × 28 mm. The patient’s work-up included a computed tomography (CT) scan, which showed multiple bilateral lung nodules of different sizes that were solid and with well-defined margins, and some with a tendency to coalesce — all suggestive of malignancy.

Several milk thistle preparations are available on the market, but their quality can differ because of different standards in agricultural and production methods — which may also result in variations in their silymarin and silibinin content.

After initial neurological improvement with dexamethasone, the patient underwent whole brain radiotherapy treatment. Chemotherapy treatment was started one week later. On the sixteenth day post third cycle, the patient consulted her oncologist with worsening neurological symptoms.

A brain MRI in September 2014 revealed persistence of the lesions with a minor decrease in their volume but an increase in the surrounding oedema. Neurological deterioration persisted, despite high doses of dexamethasone, and the patient presented an Eastern Co-operative Oncology Group (ECOG) score of 3. Oncologic treatments were stopped at this point and the patient was transferred to a palliative care unit.

When the patient asked about additional treatment options to improve her symptoms, the compassionate use of a nutraceutical product containing silibinin was offered. One-week dosing titration was performed to achieve the desired total dose, with no undesirable side-effects.

The patient was discharged from the palliative care unit two weeks later owing to clinical improvement. Four weeks after starting silibinin supplementation, pemetrexed monotherapy (400 mg/m2) was started in combination with the silibinin supplement (five capsules/day).

A brain MRI performed in December 2014 revealed a marked reduction in lesion volume and a decrease in brain oedema. The patient received an additional cycle of pemetrexed and then continued with the silibinin supplement alone.

Another brain MRI in March 2015 showed a mild reduction in the size of the left frontal lesion and in the extent of the surrounding oedema, and a CT scan proved stable pulmonary disease. Lung progression was evident in June 2015 and a brain MRI revealed the persistence of partial response to silibinin therapy in four of the five brain metastases.

New data published in 2018

After previous promising results, the authors investigated further — with 18 patients with lung cancer and brain metastasis for whom compassionate use of silibinin was granted in combination with standard treatment. Twenty per cent of them showed a complete response (brain metastases disappeared) and 55% a partial response (reduction of metastases higher than 30%): a very positive and clinically relevant outcome. The study describes the first targeted therapy for brain metastasis that acts by attacking its tumour microenvironment and was published in Nature Medicine last year.2

Hope for cancer patients

Because patients with brain metastases have an impaired survival prognosis and need immediate tumour control, the combination of brain radiotherapy with silibinin-based nutraceuticals might not only alleviate brain oedema but also give time for either classical chemotherapeutics or new immunotherapeutic agents to have an effect. Dr Bosch-Barrera’s research offers hope that this may be possible in the future. Further studies must now be conducted before silibinin can be used in clinical practice.

Several milk thistle preparations are available on the market, but their quality can differ because of different standards in agricultural and production methods — which may also result in variations in their silymarin and silibinin content. Thus, not all extracts are equal, warns Dr Bosch-Barrera: “Euromed’s pharmaceutical-grade milk thistle fruit extract has an optimal release rate and excellent absorbability. This can help to overcome the limitations of oral administration of silibinin to cancer patients.”

A recently published study by Dr Bosch-Barrera and colleagues, compared three milk thistle extracts with the Caco-2 cell monolayer model and concluded that Euromed’s silibinin formulation exhibits the highest intestinal permeability rate. Moreover, it was the sole formulation reaching a similar value to that observed when using a pure standard of silibinin, thereby suggesting a higher potential to permeate the blood-brain barrier compared with a silibinin-phosphatidylcholine complex.6

Euromed only uses botanicals that are verified, grown and harvested in a sustainable manner and in a way that preserves plant integrity and bioactive profiles.

Each production batch, from the herb to the final extract, undergoes several laboratory tests for identity, potency and potential impurities to guarantee the highest quality and safety standards.

With the company’s PhytoProof seal, brand owners can highlight the reliable sourcing and quality of the botanicals in their end-products. The seal confirms that Euromed’s ingredients are unadulterated and do not contain any undesirable contaminants.

References

  1. J. Bosch-Barrera, et al., “Response of Brain Metastasis from Lung Cancer Patients to an Oral Nutraceutical Product Containing Silibinin,” Oncotarget 7(22), 32006–32014 (2016).
  2. N. Priego, et al., “STAT3 Labels a Subpopulation of Reactive Astrocytes Required for Brain Metastasis,” Nat. Med. 24(7), 1024–1035 (2018).
  3. Y. Lee, et al., “Silibinin Prevents Dopaminergic Neuronal Loss in a Mouse Model of Parkinson’s Disease via Mitochondrial Stabilization,” J. Neurosci. Res. 93, 755–765 (2015).
  4. S. Verdura, et al., “Silibinin is a Direct Inhibitor of STAT3,” Food Chem. Toxicol. 116(PtB), 161–172 (2018).
  5. A.B. Siegel and J. Stebbing, “Milk Thistle: Early Seeds of Potential,” Lancet Oncol. 14, 929–930 (2013).
  6. A. Pérez-Sánchez, et al., “Intestinal Permeability Study of Clinically Relevant Formulations of Silibinin in Caco-2 Cell Monolayers,” Int. J. Mol. Sci. 20(7), 1606 (2019).

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