Plant-Derived Sulforaphane Suppresses Growth and Proliferation of Drug-Sensitive and Drug-Resistant Bladder Cancer Cell Lines In Vitro

Abstract

Combined cisplatin–gemcitabine (GC) application is standard for treating muscle-invasive bladder cancer. However, since rapid resistance to treatment often develops, many patients turn to supplements in the form of plant-based compounds. Sulforaphane (SFN), derived from cruciferous vegetables, is one such compound, and the present study was designed to investigate its influence on growth and proliferation in a panel of drug-sensitive bladder cancer cell lines, as well as their gemcitabine- and cisplatin-resistant counterparts. Chemo-sensitive and -resistant RT4, RT112, T24, and TCCSUP cell lines were exposed to SFN in different concentrations, and tumor growth, proliferation, and clone formation were evaluated, in addition to apoptosis and cell cycle progression. Means of action were investigated by assaying cell-cycle-regulating proteins and the mechanistic target of rapamycin (mTOR)/AKT signaling cascade. SFN significantly inhibited growth, proliferation, and clone formation in all four tumor cell lines. Cells were arrested in the G2/M and/or S phase, and alteration of the CDK–cyclin axis was closely associated with cell growth inhibition. The AKT/mTOR signaling pathway was deactivated in three of the cell lines. Acetylation of histone H3 was up-regulated. SFN, therefore, does exert tumor-suppressive properties in cisplatin- and gemcitabine-resistant bladder cancer cells and could be beneficial in optimizing bladder cancer therapy.

Sulforaphane Inhibits Adhesion and Migration of Cisplatin- and Gemcitabine-Resistant Bladder Cancer Cells In Vitro

“…The migration of all investigated cell lines, whether cisplatin- or gemcitabine-resistant or not, was significantly reduced after SFN exposure. The growth and proliferation of a panel of cisplatin- and gemcitabine-resistant bladder cancer cell lines have already been shown to be inhibited by SFN [ 7 ], indicating that it has inhibitory effects on other aspects contributing to tumor progression. Since acquired resistance and metastasis are major obstacles to successful cancer treatment, SFN could enhance the sensitivity to and therapeutic efficacy of cisplatin-based bladder cancer chemotherapy.…”

“…Cisplatin and gemcitabine resistance of RT4 (RT4 cis , RT4 gem ), TCCSUP (TCCSUP cis , TCCSUP gem ), T24 (T24 cis , T24 gem ), and RT112 (RT112 cis , RT112 gem ) were induced by exposing parental cells that were sensitive to cisplatin and gemcitabine (RT4 par , TCCSUP par , T24 par , RT112 par ) to increasing concentrations of cisplatin (Hexal, Holzkirchen, Germany) up to 1 µg/mL (TCCSUP, T24, RT112) or 2 µg/mL for RT4, or to increasing concentrations of gemcitabine (Hexal, Holzkirchen, Germany) up to 10 ng/mL (TCCSUP) or 20 ng/mL (RT4, T24, RT112). Resistance was verified by dose–response analysis [ 7 ].…”

Sulforaphane and bladder cancer: a potential novel antitumor compound

“…Therefore, targeting the cell cycle checkpoints and disrupting the cell cycle is an important direction for treating cancer. Increasing evidence suggests that SFN can significantly induce G2/M cell cycle arrest in BC cells, thereby inhibiting their proliferation ( Shan et al, 2006 ; Abbaoui et al, 2012 ; Jin et al, 2018 ; Xie et al, 2022 ). Part of the mechanism is due to the upregulation of CDK1, CDK2, cyclin A, and cyclin B by SFN, which alters the CDK-cyclin axis ( Xie et al, 2022 ).…”

“…Increasing evidence suggests that SFN can significantly induce G2/M cell cycle arrest in BC cells, thereby inhibiting their proliferation ( Shan et al, 2006 ; Abbaoui et al, 2012 ; Jin et al, 2018 ; Xie et al, 2022 ). Part of the mechanism is due to the upregulation of CDK1, CDK2, cyclin A, and cyclin B by SFN, which alters the CDK-cyclin axis ( Xie et al, 2022 ). Interestingly, histone H3 phosphorylation, a mid-phase marker of mitosis, regulates transcriptional activity in G1 phase and affects chromatin condensation in G2/M phase, and phosphorylation modification of histone H3 serine 10 [H3(Ser10)] is closely related to cell cycle and gene transcriptional regulation ( Nowak and Corces, 2004 ).…”

Glucosinolate Biosynthetic Genes of Cabbage: Genome-Wide Identification, Evolution, and Expression Analysis

“…Due to their effects on both plants and humans, GSLs are a current biology research focus [4][5][6][7][8][9]. Indeed, rapeseed breeders focus on harmful GSLs in rapeseed cakes, vegetable breeders are more interested in anticancer GSLs that are beneficial to humans, and medical scientists focus on GSLs that are inhibitory to tumor cells [10][11][12][13][14]. Sulforaphane, a secondary metabolite, relieves neuropathic pain caused by chemotherapy and inhibits prostate, colon, breast, pancreatic, and bladder cancers [15][16][17][18][19].…”