Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell–like spheroids, and tumor xenografts through multiple cell signaling pathways

Abstract

Objective Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)—a constituent of cruciferous vegetables with a multitargeted effect—as a therapeutic agent for GBM. Methods The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. Results SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of γ-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell–induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10. Conclusions These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy.

Sulforaphane Suppresses the Growth of Triple-negative Breast Cancer Stem-like Cells In vitro and In vivo

“…These sulfur-rich compounds are hydrolyzed by the plant endogenous enzyme, myrosinase, to release an active compound, sulforaphane (11). Recently, sulforaphane has been shown to target the self-renewal properties of CSCs in a variety of cancer types including skin, breast, pancreatic, and glioblastoma (12)(13)(14)(15). Despite the increasing evidence and interest shown in modulating effects of sulforaphane on CSCs and their involvement with the early development of tumor formation, limited data is available for the utility of sulforaphane to prevent the CSC-mediated processes of tumor development and maintenance.…”

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

“…To explain why the AZ + SFN combination would be most effective as a therapeutic regimen we offer the following. Recent studies support SFN as a potent antitumor agent against multiple signaling pathways in diverse cancers and targeting of mitochondrial functions where normal cells are protected [45][46][47][48][49][50]. Expression of carbonic anhydrase IX (CAIX) is highly relevant to rapidly growing and aggressive tumor cells adapting to the acidic microenvironment in rapidly growing tumors in order to maintain a more intracellular physiological pH, and thus inhibitors of CAIX can potently inhibit tumor cell viability [51,52].…”

Sulforaphane-N-Acetyl-Cysteine Induces Autophagy Through Activation of ERK1/2 in U87MG and U373MG Cells

“…It is believed that ITC compounds play key roles in inhibiting cancer, motivating their potential clinical use, including in combination therapies. Recently, Bijangi et al made an encouraging discovery that sulforaphane reduces the survival of GBM cells, glioblastoma stem-cell-like spheroids, and tumor xenografts through multiple cell signaling pathways and that this treatment does not affect the survival of normal human brain cells or normal human MSCs in both the cellular and animal experiments [43]. This study helps us better understand the mechanism of action of SFN and its analogs in tumor cells and can guides future clinical applications that utilize the degradation of tubulin by SFN analogs.…”