Useful Supportive Treatment for Chemotherapy in Pancreatic Cancer?
Vanessa Rausch¹², Wei Zhou¹², Sabrina Labsch¹², Georgios Kallifatidis¹², Li Liu¹², Bernd Baumann³, Jürgen Mattern¹², Jury Gladkich¹², Thomas Wirth³, Peter Schemmer², Markus W. Büchler², Alexei V. Salnikov¹, Ingrid Herr¹²
Pancreatic cancer is the fourth leading cause of cancer-related deaths in Germany. With a five-year survival rate of only 6%, it is one of the most aggressive malignancies in Europe. Despite advancements in standardizing and developing tumor treatments, surgical removal of the tumor for a potential cure is possible in only 20% of patients because the disease is often diagnosed at an advanced stage. In such cases, chemotherapy remains the only palliative treatment option, sometimes combined with radiation (radio/chemotherapy).
Pancreatic cancer is characterized by rapid growth, infiltration of surrounding structures, and early metastasis, especially via lymphatic and hematogenous routes. The molecular mechanism of this disease is still insufficiently understood, and the low success rate of current chemotherapy presents a therapeutic challenge. Recent scientific data suggest the existence of a subpopulation of tumor-initiating cells (TICs, or cancer stem cells, CSCs) that are inaccessible to conventional chemotherapy and therefore survive traditional treatments. In addition to their capacity for uncontrolled growth, treatment resistance, and aggressive metastasis, CSCs have the potential for regeneration and differentiation. This makes pancreatic cancer considered a “stem cell disease,” highlighting the urgent need for new therapeutic approaches targeting this chemotherapy-resistant tumor fraction.
Plants from the Brassicaceae family and their isolated mustard glucosides have been used since antiquity as natural antibiotics and key components of antiviral and antifungal therapy. Additionally, glucoraphanins (4-methylthiobutyl glucosinolates) and their product, the isothiocyanate sulforaphane, exhibit exceptionally potent anti-cancer effects. Sulforaphane was first isolated in 1959 from watercress. Subsequently, other sulforaphane-rich foods were identified, such as broccoli, cauliflower, radishes, and cabbage, with broccoli and its sprouts containing the highest concentrations. Unlike other antioxidants, sulforaphane indirectly eliminates free radicals by increasing phase II enzyme activity, leading to higher glutathione levels.
Sulforaphane also has long-term effects. Its connection to tumors was discovered in 1992, when mouse hepatoma models showed increased phase II enzyme activity, delaying tumor growth. Since then, the anti-cancer effects of sulforaphane have been experimentally and clinically confirmed for various cancer types. Moreover, sulforaphane has shown therapeutic potential against CSCs. It has been clearly demonstrated that sulforaphane mediates the inhibition of anti-apoptotic gene expression targeting NF-κB, a master molecular switch and inflammation mediator, which is overactive in pancreatic cancer but can be normalized by sulforaphane.
In preclinical pancreatic cancer research, sulforaphane enhances the response to chemotherapy agents such as sorafenib, 5-fluorouracil, doxorubicin, cisplatin, and gemcitabine in CSCs without negatively affecting non-malignant cells.
Background: Despite intensive efforts to develop therapies for pancreatic cancer, no drugs are currently available that fully cure this highly resistant and metastatic disease. Significant attention is directed at the broccoli compound sulforaphane, proposed as a combined therapy to target pancreatic cancer stem cells. However, concerns remain that antioxidants like sulforaphane may interfere with cytotoxic therapies, as suggested with certain vitamins.
Materials and Methods: The effects of sulforaphane combined with various standard chemotherapeutics, dietary compound quercetin, and multikinase inhibitor sorafenib were evaluated using in vitro and in vivo models of pancreatic cancer cells with stem-like phenotypes. Analyses included stem cell marker expression, ALDH1 activity, self-renewal potential, Notch signaling, migration activity, apoptosis induction, viability, proliferation, NF-κB signaling, and angiogenesis.
Since December 2013, a two-arm prospective pilot study, the POUDER Trial, has been conducted at the Clinic for General, Visceral, and Transplantation Surgery with the European Pancreas Center in Heidelberg. This study focuses on special supplements during palliative chemotherapy for pancreatic cancer patients.
The pilot phase aims to test the feasibility of administering highly concentrated sulforaphane in capsule form. Patients with advanced, inoperable pancreatic cancer receive 90 mg of sulforaphane daily alongside palliative chemotherapy. The sulforaphane is delivered via freeze-dried broccoli sprout powder (400 mg) encapsulated for ease of use. Placebo capsules contain methylcellulose. Forty patients with non-resectable pancreatic carcinoma treated in Heidelberg will be enrolled in this pilot phase.
The study evaluates tumor markers CEA and CA19-9, as well as patients’ quality of life. Imaging methods (CT, MRI) conducted every three months monitor tumor burden and assess potential progression or shrinkage. To ensure proper intake and metabolism of sulforaphane, its breakdown products are analyzed in the patients’ morning urine using a cyclocondensation method with 1,2-benzenedithiol. Quality of life is assessed every three months through standardized EORTC questionnaires, QLQ-PAN26 and QLQ-C30.
Common side effects of cruciferous vegetables, including broccoli and its sprouts, are bloating and a potential sulfurous odor. This arises during digestion due to the sulfur content in sulforaphane and its precursor, glucoraphanin. Sulforaphane acts as an indirect antioxidant, raising concerns that it might weaken the effects of radio- or chemotherapy, similar to discussions surrounding vitamins.
At our clinic, this hypothesis was tested on mice with transplanted human pancreatic cancer xenografts. Sulforaphane alone or combined with gemcitabine significantly inhibited tumor growth, with gemcitabine’s effect enhanced rather than diminished. These promising experimental findings now await confirmation in the patient study.
It’s worth noting that fresh sprouts can be susceptible to contamination by harmful bacteria, such as those causing the severe 2011 EHEC outbreak in Germany. However, contamination of broccoli sprouts used in this study is unlikely, as each batch is tested in an independent microbiological laboratory.
Broccoli contains other glucosinolates like glucobrassicin and progoitrin, which can potentially affect thyroid function. However, no changes in thyroid function have been observed in humans consuming typical amounts of broccoli and other cruciferous vegetables. Broccoli sprouts contain only minimal amounts of these compounds.
Supplementation with high doses of sulforaphane could represent a promising new approach in pancreatic cancer treatment. This prospective pilot study aims to test whether sulforaphane in a specialized supplement form can be administered without negative side effects and whether it can improve chemotherapy outcomes. Sulforaphane has already shown promise in other cancer types and could offer a significant advancement in treating tumors resistant to conventional chemotherapy.
Our data suggest that sulforaphane enhances the efficacy of various cytotoxic drugs, including sorafenib and quercetin, against cancer stem cells without causing additional toxicity in mice. This supports the concept that combining sulforaphane with conventional or novel therapeutics is a safe and promising strategy targeting pancreatic cancer stem cell phenotypes.
In simplified terms, the study explored how sulforaphane, found in broccoli, affects immune cells called dendritic cells, which play a crucial role in activating the immune system. Sulforaphane was found to enhance the ability of these cells to activate T-cells, which fight cancer. This effect was observed even in the presence of pancreatic cancer-associated antigens. Sulforaphane influences specific molecules and signaling pathways in cells, potentially leading 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)
