Induction of Apoptosis in Human Glioma Cells by Fucoxanthin via Triggering of ROS-Mediated Oxidative Damage and Regulation of MAPKs and PI3K–AKT Pathways

Abstract

Fucoxanthin, a natural carotenoid derived from algae, exhibits novel anticancer potential. However, fucoxanthin with high purity is hard to prepare, and the anticancer mechanism remains elusive. In the present study, fucoxanthin with high purity was prepared and purified from the marine microalgae Nitzschia sp. by silica-gel column chromatography (SGCC), and the underlying mechanism against human glioma cells was evaluated. The results showed that fucoxanthin time- and dose-dependently inhibited U251-human-glioma-cell growth by induction of apoptosis (64.4 ± 4.8, P < 0.01) accompanied by PARP cleavage and caspase activation (244 ± 14.2, P < 0.01). Mechanically, fucoxanthin time-dependently triggered reactive-oxygen-species (ROS)-mediated DNA damage (100 ± 7.38, P < 0.01), as evidenced by the phosphorylation activation of Ser1981-ATM, Ser428-ATR, Ser15-p53, and Ser139-histone. Moreover, fucoxanthin treatment also time-dependently caused dysfunction of MAPKs and PI3K–AKT pathways, as demonstrated by the phosphorylation activation of Thr183-JNK, Thr180-p38, and Thr202-ERK and the phosphorylation inactivation of Ser473-AKT. The addition of kinase inhibitors further confirmed the importance of MAPKs and PI3K–AKT pathways in fucoxanthin-induced cell-growth inhibition (32.5 ± 3.6, P < 0.01). However, ROS inhibition by the antioxidant glutathione (GSH) effectively inhibited fucoxanthin-induced DNA damage, attenuated the dysfunction of MAPKs and PI3K–AKT pathways, and eventually blocked fucoxanthin-induced cytotoxicity (54.3 ± 5.6, P < 0.05) and cell apoptosis (32.7 ± 2.5, P < 0.05), indicating that ROS production, an early apoptotic event, is involved in the fucoxanthin-mediated anticancer mechanism. Taken together, these results suggested that fucoxanthin induced U251-human-glioma-cell apoptosis by triggering ROS-mediated oxidative damage and dysfunction of MAPKs and PI3K–AKT pathways, which validated that fucoxanthin may be a candidate for potential applications in cancer chemotherapy and chemoprevention.

Pro-oxidant Actions of Carotenoids in Triggering Apoptosis of Cancer Cells: A Review of Emerging Evidence

“…Moreover, β-carotene can inhibit the growth of MCF-7 cells by increasing the ROS and Akt levels, inhibiting extracellular signal-regulated kinases (ERK)1/2, and activating p53 [ 61 ]. In another study, treatment with 20 μM fucoxanthin resulted in ROS-mediated oxidative DNA damage, time-dependent activation of mitogen-activated protein kinases (MAPKs), inhibition of phosphoinositide 3-kinases (PI3K)−AKT, and apoptosis of human glioblastoma cell line U251 [ 47 ]. ROS inhibition by antioxidant glutathione (GSH) can inhibit these effects, demonstrating that fucoxanthin-induced oxidation can result in apoptosis [ 47 ].…”

A steroidal saponin form <i>Paris vietnamensis</i> (Takht.) reverses temozolomide resistance in glioblastoma cells <i>via</i> inducing apoptosis through ROS/PI3K/Akt pathway

“…Previous studies have reported several bioactive compounds generated ROS to activate apoptosis signaling in cancer cells, while ROSdependent compounds suppressed the activity of the PI3K/Akt signaling pathway. Fucoxanthin induced apoptosis in human glioblastoma cells via triggering of ROS-mediated oxidative damage and regulation of MAPKs and PI3K-Akt pathways (30). Thioridazine enhanced TRAIL-mediated apoptosis via the ROSmediated inhibition of Akt signaling in renal carcinoma Caki cells (31).…”

Endoplasmic Reticulum Stress Contributes to Indomethacin-Induced Glioma Apoptosis

“…MAPKs and Akt are crucial regulators of glioma apoptosis under the control of multiple pathways, including ER stress [30][31][32][33][34]. We had already published that indomethacin caused proteolytic degradation of PARP-1 and a reduction of Akt phosphorylation in glioma cells [30].…”