A useful supportive therapy to chemotherapy for pancreatic cancer?
Vanessa Rausch1,2, Wei Zhou1,2, Sabrina Labsch1,2, Georgios Kallifatidis1,2, Li Liu1,2, Bernd Baumann3, Jürgen Mattern1,2, Jury Gladkich1,2, Thomas Wirth3, Peter Schemmer2, Markus W. Büchler2, Alexei V. Salnikov1, Ingrid Herr1,2 – 1 Molecular Onco-Surgery, University of Heidelberg and German Cancer Research Center, 2 Department of General Surgery, University of Heidelberg, 3 Institute of Physiological Chemistry, University of Ulm, Ulm, Germany
Pancreatic cancer is the fourth most common cause of cancer death in Germany. With a five-year survival rate of only 6%, pancreatic cancer is one of the most aggressive malignancies in Europe. Despite advances in the standardisation and development of cancer treatment, surgical removal of the tumour with the aim of cure is only possible in 20 % of patients, as the disease is often only diagnosed at an advanced stage. In such cases, chemotherapy remains the only palliative treatment option. In some cases, it can be combined with radiation (radio/chemotherapy).
Pancreatic cancer is characterised by rapid growth and infiltration of surrounding structures and early metastasis, especially lymphogenous but also haematogenous. The molecular mechanism of this disease is still poorly understood and the low success rate of current chemotherapy poses a therapeutic challenge.Recent scientific data suggest the existence of a subpopulation of tumour-initiating cells (TICs, or tumourstem cells (TSZ)) that are not available for conventional chemotherapy and therefore survive traditional chemotherapy. In addition to their capacity for uncontrolled growth, resistance to treatment, and aggressive metastasis, TSZs have the potential for regeneration and differentiation. Because of this cellularity, pancreatic cancer is considered a “stem cell disease.” New therapeutic approaches are therefore urgently needed to treat this part of the tumour, which is completely resistant to chemotherapy.
Plants of the Brassicaceae family and the mustard glycosides isolated from them have been used since antiquity as natural antibiotics and the main components of antiviral and antifungal therapy. In addition, glucoraphanins (4-methylthio-butylglucosinolates) and their product, sulforaphane isothiocyanate, have particularly potent anticarcinogenic effects. Sulforaphane was first isolated in 1959 from brook trout. Subsequently, other sulforaphane-rich foods such as broccoli, cauliflower, radishes and cabbage have been identified, with broccoli and its sprouts containing the highest concentrations of sulforaphane. Unlike other antioxidants, sulforaphane eliminates free radicals indirectly by increasing the activity of phase II enzymes, leading to an increase in glutathione levels.
Sulforaphane also has a long-term effect. In 1992, its relationship to tumours was discovered when an increase in the activity of phase II enzymes was found in mouse hepatoma models, leading to a delay in tumour growth.
Since then, the anticarcinogenic effect of sulforaphane has been confirmed experimentally and clinically in various types of cancer. Moreover, it has been shown that sulforaphane could be used therapeutically against TSZ. It has been clearly demonstrated that sulforaphane mediates the inhibition of the expression of antiapoptotic genes targeting NF-κB. It is already known that NF-κB, which is a downstream molecular switch and mediator of inflammation, is upregulated in pancreatic cancer, but sulforaphane can normalize it.
In preclinical pancreatic cancer research, sulforaphane enhances response to chemotherapy with sorafenib, 5-fluorouracil, doxorubicin, cisplatin and gemcitabine at the TSZ without negatively affecting benign cells.
Background: Despite intensive efforts to develop treatments against pancreatic cancer, there are still no drugs available to completely cure this highly resistant and metastatic disease. Considerable attention has focused on a compound from broccoli, sulforaphane, which has been proposed as a combination therapy to target pancreatic cancer stem cells. However, there are concerns that antioxidant compounds such as sulforaphane may interfere with cytotoxic therapy – as has been suggested for vitamins, for example.
Material and Methods: The effects of sulforaphane in combination with various standard chemotherapeutic agents, the dietary substance quercetin, and inhibitingmultikinase inhibitor sorafenib were evaluated using in vitro and in vivo models of pancreatic cancer cells with a stem cell-like phenotype. Stem cell marker expression, ALDH1 activity, self-renewal potential, Notch signaling, migration activity, apoptosis induction, viability, proliferation, NF-κB signaling, and angiogenesis were analyzed.
Since December 2013, a two-arm prospective trial has been ongoing at the Department of General, Visceral and Transplant Surgery with the European Centre for Pancreas in Heidelbergvation pilot study (POUDER Trial) focusing on special supplements during palliative chemotherapy for pancreatic cancer patients.The aim of this trial is to test the feasibility of administering highly concentrated sulforaphane in capsules in a pilot phase.Patients with advanced, inoperable pancreatic cancer receive 90 mg sulforaphane daily in the form of freeze-dried broccoli sprouts (400 mg) packaged in capsules in addition to palliative chemotherapy. Methylcellulose capsules serve as placebo. Forty patients with unresectable pancreatic cancer treated at Heidelberg will be enrolled in the study during the pilot phase.
Tumor markers CEA and CA19-9 as well as the patients’ quality of life will be evaluated. Regular imaging (CT, MRI) every three months will be used to monitor the tumor burden and catch possible progression or shrinkage of the tumor. To monitor adequate intake and metabolism of sulforaphane, its breakdown products were analyzed in the patients’ morning urine. The analysis was performed by cyclocondensation with 1,2-benzenedithiol. Quality of life was assessed by standardized questionnaires EORTC, QLQ-PAN26 and QLQ-C30 every three months.
Typical side effects of cruciferous vegetables, including broccoli and its sprouts, are flatulence and possible sulphur smell. This occurs during digestion and is due to the sulphur content of sulforaphane and its precursor, glucoraphanin. Sulforaphane also acts as an indirect antioxidant and could theoretically weaken the effect of radio- or chemotherapy – similar to the effects of vitamins that have been discussed. In our clinic, this hypothesis was tested in mice with transplanted human pancreatic cancer xenografts. Sulforaphane alone or in combination with gemcitabine significantly inhibited tumor growth, and the effect of gemcitabine was not attenuated but rather enhanced. Confirmation of these promising experimental data in a patient study is now awaited. It is also worth noting that fresh sprouts may be susceptible to contamination by the dangerous intestinal bacteria that caused severe EHEC in Germany in 2011. However, contamination of the broccoli sprouts used in the study is not expected as each batch is tested in an independent microbiological laboratory. It is important to know that broccoli, in addition to the medicinal substances glucoraphanin and sulforaphane, also contains the goiter-causing glucosinolates, glucobrassicin and progoitrin. However, no changes in thyroid function have been found in humans after consuming normal amounts of broccoli and other cruciferous vegetables. Broccoli sprouts contain very small amounts ofstrum-causing substances.
Supplementation with high doses of sulforaphane could be a promising new approach in the treatment of pancreatic cancer. The aim of this prospective pilot study is to test whether sulforaphane in the form of a special supplement can be given to patients without negative side effects and whether it can improve the response to chemotherapy. This approach is already showing promise in other cancers and would be the next step in the treatment of tumours that are still untreatable with conventional chemotherapy.
Our data suggest that sulforaphane enhances the efficacy of various cytotoxic drugs, sorafenib and quercetin, against cancer stem cells without causing further toxicity in mice. Our results suggest that combining sulforaphane with conventional or novel therapeutics is a safe and promising new approach to target the pancreatic cancer stem cell phenotype.
Put simply, the study investigated how sulforaphane, a substance found in broccoli, affects immune cells called dendritic cells, which play an important role in activating the immune system. It was found that sulforaphane can improve the ability of these cells to activate T-cells, which are the cells that fight cancer. This effect has also been observed in the presence of antigens associated with pancreatic cancer. Sulforaphane affects certain molecules and signaling pathways in cells, which may lead to a more effective immune response against cancer.
Sulpharophane_enhances_ effects.pdf (uni-heidelberg.de)
Inhibition of miR30a-3p by sulforaphane enhances gap junction intercellular communication in pancreatic cancer – PubMed (nih.gov)