Abstract
Background and Objectives: Malignant glioblastoma (GBM) is caused by abnormal proliferation of glial cells, which are found in the brain. The therapeutic effects of surgical treatment, radiation therapy, and chemo-therapy against GBM are relatively poor compared with their effects against other tumors. Luteolin is abundant in peanut shells and is also found in herbs and other plants, such as thyme, green pepper, and celery. Luteolin is known to be effective against obesity and metabolic syndrome. The anti-inflammatory, and anti-cancer activities of luteolin have been investigated. Most studies have focused on the antioxidant and anti-inflammatory effects of luteolin, which is a natural flavonoid. However, the association between the induction of apoptosis by luteolin in GBM and autophagy has not yet been investigated. This study thus aimed to confirm the occurrence of luteolin-induced apoptosis and autophagy in GBM cells and to assess their relationship. Materials and Methods: A172 and U-373MG glioblastoma cell lines were used for this experiment. We confirmed the apoptosis effect of Luteolin on GBM cells using methods such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, immunofluorescence, Flow cytometry (FACS) western blot, and real-time quantitative PCR (qPCR). Results: In the luteolin-treated A172 and U-373MG cells, cell viability decreased in a concentration- and time-dependent manner. In addition, in A172 and U-373MG cells treated with luteolin at concentrations greater than 100 μM, nuclear fragmentation, which is a typical morphological change characterizing apoptosis, as well as fragmentation of caspase-3 and Poly (ADP-ribose) polymerase (PARP), which are apoptosis-related factors, were observed. Autophagy was induced after treatment with at least 50 μM luteolin. Inhibition of autophagy using 3MA allowed for a low concentration of luteolin to more effectively induce apoptosis in A172 and U-373MG cells. Conclusions: Results showed that luteolin induces apoptosis and autophagy and that the luteolin-induced autophagy promotes cell survival. Therefore, an appropriate combination therapy involving luteolin and an autophagy inhibitor is expected to improve the prognosis of GBM treatment.
Highlights
This article is an open access articleGlioma is the most common primary tumor in the central nervous system, along with astrocytoma, glioblastoma (GBM), and oligodendrocytoma, and it occurs primarily in glial or progenitor cells [1]
The average survival period of GBM patients undergoing aggressive treatment is as short as about one year; Due to the occurrence of new mutations, alteration of epigenetic regulators, increased UPR (Unfolded protein response) due to endoplasmic reticulum stress and mitochondrial damage, avoidance of apoptosis through direct or indirect mechanisms, and continuation of autophagy, it becomes resistant to chemotherapy rapidly, making it difficult to treat [4–6]
This study revealed that luteolin induces apoptosis and autophagy simultaneously and that luteolin-induced autophagy plays a role in cell survival
Summary
This article is an open access articleGlioma is the most common primary tumor in the central nervous system, along with astrocytoma, glioblastoma (GBM), and oligodendrocytoma, and it occurs primarily in glial or progenitor cells [1]. GBM is a considerably malignant tumor and has a poor prognosis despite the use of extreme therapeutic interventions, including surgery, radiation therapy, combination therapy, and adjuvant chemotherapy [2]. Temozolomide, doxorubicin, paclitaxel, and 5-fluorouracil are the drugs that are administered Since these drugs only prolong the survival period rather than bring a cure among brain tumor patients, questions regarding their effectiveness have been raised [3]. What is needed is a new therapeutic agent that inhibits the growth of brain tumors and avoids drug resistance, reducing the likelihood of recurrence and improving the prognosis of GBM patients. This study aimed to confirm the occurrence of luteolin-induced apoptosis and autophagy in GBM cells and to assess their relationship.
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