Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo

Abstract

Glioblastoma is the deadliest brain tumor in humans. High systemic toxicity of conventional chemotherapies prompted the search for natural compounds for controlling glioblastoma. The natural flavonoids luteolin (LUT) and silibinin (SIL) have anti-tumor activities. LUT inhibits autophagy, cell proliferation, metastasis, and angiogenesis and induces apoptosis; while SIL activates caspase-8 cascades to induce apoptosis. However, synergistic anti-tumor effects of LUT and SIL in glioblastoma remain unknown. Overexpression of tumor suppressor microRNA (miR) could enhance the anti-tumor effects of LUT and SIL. Here, we showed that 20 µM LUT and 50 µM SIL worked synergistically for inhibiting growth of two different human glioblastoma U87MG (wild-type p53) and T98G (mutant p53) cell lines and natural combination therapy was more effective than conventional chemotherapy (10 µM BCNU or 100 µM TMZ). Combination of LUT and SIL caused inhibition of growth of glioblastoma cells due to induction of significant amounts of apoptosis and complete inhibition of invasion and migration. Further, combination of LUT and SIL inhibited rapamycin (RAPA)-induced autophagy, a survival mechanism, with suppression of PKCα and promotion of apoptosis through down regulation of iNOS and significant increase in expression of the tumor suppressor miR-7-1-3p in glioblastoma cells. Our in vivo studies confirmed that overexpression of miR-7-1-3p augmented anti-tumor activities of LUT and SIL in RAPA pre-treated both U87MG and T98G tumors. In conclusion, our results clearly demonstrated that overexpression of miR-7-1-3p augmented the anti-tumor activities of LUT and SIL to inhibit autophagy and induce apoptosis for controlling growth of different human glioblastomas in vivo.

The Influence of Lycopene, [6]-Gingerol, and Silymarin on the Apoptosis on U-118MG Glioblastoma Cells In Vitro Model

“…It was found that 20 µM and 50 µM concentrations almost completely blocked tumor cell invasion, inhibiting cell proliferation and migration of glioblastoma cells. On the other hand, silymarin stimulates the process of apoptosis by activating caspases [40]. It is also a confirmation of the results of our own study, where it was observed that self-acting silymarin induces the death of glioblastoma cells.…”

<p>Luteolin suppresses tumor proliferation through inducing apoptosis and autophagy via MAPK activation in glioma</p>

“…21 miRNAs are reported to be involved in luteolin's anticancer activity. 18,22 Chakrabarti and Ray discovered that luteolin induced apoptosis in glioblastoma by regulating miR-7-1-3p expression. 18 Yang et al found that miR-6809-5p mediated luteolin-induced anticancer effects by targeting flotillin 1 in hepatoma.…”

Apoptosis on the move

“…The effect was mediated through induction of apoptosis and full blockade of invasion and migration, through suppression of protein kinase C, downregulation of iNOS and induction of miR-7-1-3p. The flavonoid combination also inhibited rapamycin-induced autophagy, a pathway that can cause survival of cells [5]. A study by Chang et al showed that angiotensin II is able to induce apoptosis in endothelial cells, which could be suppressed by atorvastatin, the lipid-lowering drug Lipitor [6].…”