Sulforaphane and TRAIL induce a synergistic elimination of advanced prostate cancer stem-like cells

Abstract

Advanced androgen-independent prostate cancer (AIPC) is an aggressive malignancy with a poor prognosis. Apoptosis-resistant cancer stem cells (CSCs) have been identified in AIPC and are not eliminated by current therapeutics. Novel therapeutic options, which are currently being evaluated in patient studies, include TRAIL and the broccoli-derived isothiocyanate sulforaphane. Although neither agent targets normal cells, TRAIL induces apoptosis in most cancer cells, and sulforaphane eliminates CSCs. In this study, the established AIPC cell lines DU145 and PC3, with enriched CSC features, and primary patient-derived prostate CSCs were treated with sulforaphane and recombinant soluble TRAIL. We examined the effects of these drugs on NF-κB activity, self-renewal and differentiation potential, and stem cell signaling via spheroid- and colony-forming assays, FACS and western blot analyses, immunohistochemistry, and an antibody protein array in vitro and after xenotransplantation. We largely found a stronger effect of sulforaphane on CSC properties compared to TRAIL, though the agents acted synergistically when applied in combination. This was associated with the inhibition of TRAIL-induced NF-κB binding; CXCR4, Jagged1, Notch 1, SOX 2, and Nanog expression; ALDH1 activity inhibition; and the elimination of differentiation and self-renewal potential. In vivo, tumor engraftment and tumor growth were strongly inhibited, without the induction of liver necrosis or other obvious side effects. These findings suggest that sulforaphane shifts the balance from TRAIL-induced survival signals to apoptosis and thus explains the observed synergistic effect. A nutritional strategy for high sulforaphane intake may target the cancer-specific activity of TRAIL in CSCs.

Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy

“…Numerous natural compounds such as wogonin (derived from the popular Chinese herb Huang-Qin), sulforaphane (derived from enriched broccoli sprout extracts), and melittin (major component of bee venom) sensitize resistant malignant cells to TRAIL-induced apoptosis through the modulation of NF-iB signaling pathway. [102][103][104] Upregulation of TRAIL receptors through NF-kB is also mediated by other natural compounds such as the ethanolic extract of Brazilian green propolis (EEP) and curcumin (a substance found in turmeric). 105,106 However, kurarinone (a natural bioactive lavandulyl flavonoid), 107 resveratrol (a type of natural phenol), 108 artesunate (a derivative of the natural product artemisinin), 109 and combertastatin A-4 (isolated from the bark of combretum caffrum) 110 can also sensitize melanomas to TRAIL through abrogating TRAIL-induced NF-kB activation and modulation of expression of anti-apoptotic genes such as cFLIP, XIAP, and Bcl-xL.…”

Myrtucommulone-A treatment decreases pluripotency- and multipotency-associated marker expression in bladder cancer cell line HTB-9

“…The therapies focused on inhibiting self-renewal of cancer stem cells, inducing their differentiation or targeting their cell-surface molecular markers [15,47,48]. However, treatment strategies with existing anti-cancer agents like cisplatin, oxaliplatin and 5-fluorouracil were reported to enhance cell viability and promote the self-renewal and survival of cancer stem cells in different cancer models [49][50][51]. This constitutes the basis of tumor recurrence observed in many patients who undergo conventional chemotherapy.…”

Chemopreventive and Therapeutic Potential of Phytochemicals Targeting Cancer Stem Cells

“…In another study, combination of sulforaphane and recombinant soluble TRAIL was found to be superior to single treatment in reducing tumor growth and CSCs marker expression in the xenotransplantation model of androgen-independent prostate cancer (PC3) cells into chorioallantoic membrane of fertilized chicken eggs. This was associated with the inhibition of TRAIL-induced NF-κB DNA binding activity and expression of CXCR4, Jagged1, Notch1, Sox2, and Nanog [62]. Notably, pancreatic CSCs treated with sulforaphane (5 μM) downregulated Notch1 expression, whereas gemcitabine (25 nM) treatment led to induction of Notch1.…”

“…These include the induction of cytoprotective proteins and carcinogen-detoxifying enzymes [56], inhibition of inflammatory responses [57], induction of tumor cell apoptosis [58], and the blockade of angiogenesis and metastasis [59]. In recent studies, sulforaphane was found to be effective in targeting breast [60], prostate [61,62], pancreatic [61], and leukemia [63] CSCs. The plasma levels of sulforaphane in rats reached 46 ng/ml after administration of 0.5 mg/kg, and human studies consistently indicated similar levels of 12 and 18.2 ng/ml in plasma after broccoli consumption [64][65][66].…”