Novel Broccoli Sulforaphane-Based Analogues Inhibit the Progression of Pancreatic Cancer without Side Effects

Abstract

The naturally occurring isothiocyanate sulforaphane, found in Brassicaceae vegetables, is promising in cancer treatment, e.g., by the normalization of enhanced levels of NF-κB-signaling in tumor stem cells. We chemically synthesized seven sulforaphane analogues by substitution of the sulfinyl group (S(O)) to either sulfimidoyl (S(NR)) or sulfonimidoyl (S (O) (NR)) groups, and characterized them in the cell lines of pancreatic cancer and several other tumor entities, including the NCI-60 cell panel. MTT and colony forming assays, flow cytometry, immunohistochemistry, microRNA arrays, bioinformatics, tumor xenotransplantation, and Kaplan Meier survival curves were performed. Compared to sulforaphane, the analogue SF102 was most efficient in inhibition of viability, colony formation, tumor growth, and the induction of apoptosis, followed by SF134. Side effects were not observed, as concluded from the body weight and liver histology of chick embryos and survival of C. elegans nematodes. Among 6659 differentially regulated microRNAs, miR29b-1-5p, and miR-27b-5p were downregulated by sulforaphane compared to controls, but upregulated by SF102 and SF134 compared to sulforaphane, suggesting differential signaling. Each substance was involved in the regulation of several NF-κB-related target genes. In conclusion, sulforaphane analogues are promising for the development of highly active new drugs in cancer treatment.

Sulforaphane Inhibits the Expression of Long Noncoding RNA H19 and Its Target APOBEC3G and Thereby Pancreatic Cancer Progression

“…By mRNA microarray and subsequent bioinformatic analysis of the array data, we identified 2633 differentially expressed mRNAs, and the top 200 candidates with p < 0.01 are shown in a symbolic heatmap ( Figure 3 A; the detailed list of differentially regulated genes can be obtained via the gene array accession number #E-MTAB-7559). To limit the results to the most significant H19-target genes, we visualized overlapping genes between our actual gene array results and our recent gene array results [ 30 ], in which gene expression in BxPc-3 cells was examined before and 24 h after sulforaphane treatment, using a Venn diagram. By this way we identified 103 common candidate genes that are regulated by siH19 and sulforaphane ( Figure 3 B).…”

“…Based on these promising data many patients have hopes to sulforaphane-rich broccoli seeds or supplements thereof, which are offered by several companies [ 21 ]. Even the development of highly active sulforaphane analogues suited for medication is in progress and were able to inhibit the progression of PDAC without side effects in our former experimental studies [ 30 ]. Therefore, the elucidation of the exact mechanisms of action of sulforaphane has great importance.…”

Treatment of Human Glioblastoma U251 Cells with Sulforaphane and a Peptide Nucleic Acid (PNA) Targeting miR-15b-5p: Synergistic Effects on Induction of Apoptosis

“…SFN is an isothiocyanate generated by the hydrolysis of glucosinolate glucoraphanin by myrosinase (this enzyme is present in plants and gastrointestinal microflora) [42][43][44][45]. Several bioactive SFN analogues have been described [46]. In addition, an improvement of the stability of this compound was obtained after complexation with α-cyclodextrin (SFX-01) [47].…”

A high-efficiency PEG-Ca2+-mediated transient transformation system for broccoli protoplasts

“…Recent studies have found that broccoli is also rich in sulforaphane ( Li Z et al., 2021 ; Li et al., 2022 ), an active anticancer compound that significantly reduces the occurrence of various cancers, including liver, lung, stomach, breast, bladder, colorectal, and prostate cancers ( Keck et al., 2003 ; Chilakala et al., 2020 ; Mahn and Castillo, 2021 ; Li et al., 2022 ; Xie et al., 2022 ). It’s reported that sulforaphane could prevent and reduce the risks of cardiovascular and cerebrovascular diseases, hypertension, myopia, depression syndrome, and other conditions ( Georgikou et al., 2020 ). At present, according to the information center of the Ministry of Agriculture, the area in which broccoli is sown in China exceeds 120,000 hectares, accounting for more than 20% of the global output, and China is the main exporter of broccoli ( Li et al .,; Li et al., 2019 ; Huang et al., 2021 ).…”