Luteolin enhances erlotinib’s cell proliferation inhibitory and apoptotic effects in glioblastoma cell lines

Abstract

The epidermal growth factor (EGFR) receptor is frequently overexpressed in glioblastoma multiforme IV (GBM). Increased expression of EGFR leads to increased proliferation, decreased apoptosis, and increased resistance to chemotherapeutic agents. A small molecule called erlotinib inhibits EGFR receptors by binding to their adenosine triphosphate (ATP) binding sites. It is FDA approved to treat a variety of EGFR-mediated cancers. Several clinical trials have explored a combination of erlotinib with other agents to treat glioblastoma since it is believed that erlotinib would benefit patients with GBM with EGFR mutations or expression. Luteolin, a natural flavonoid, inhibits cell growth and induces apoptosis in cancer cells. We investigated the combined effects of erlotinib and luteolin on proliferation and apoptosis on glioblastoma cell lines overexpressing EGFR or glioma cells expressing truncated EGFR (ΔEGFR). In a concentration-dependent fashion, the combination of luteolin and erlotinib reduced cell proliferation (p < 0.05) and induced apoptosis by cleaving PARP and increasing caspase expression. In addition, the combination of luteolin and erlotinib reduced the phosphorylation of downstream EGFR cell signaling molecules such as Akt, NF kappa B, and STAT3 in a concentration-dependent manner. These findings suggest that combining luteolin with erlotinib offers a potential treatment strategy for glioblastoma multiforme IV.

Comparison of 3D and 2D cultures for evaluating the effect of combination therapy with Erlotinib and Imatinib on Glioblastoma multiforme

“…These concentrations were chosen for evaluating next steps and preparing combined dilutions of drugs. Ratio of 1:1 was used to prepare corresponding dilutions [20,22]. CIs of Erlotinib and Imatinib were acquired (Fig.…”

“…Study demonstrated that a concentration ratio of 1:1 for each drug in a therapeutic combination reduces excess concentrations and side effects [20,22]. Combination of 8.55 µM drugs in 12h (P > 0.05), 24h ( ** P < 0.01), 36h ( *** P < 0.001), and 48h ( *** P < 0.001) after treatment increased scratch area in treatment groups compared to 0h.…”

Therapeutic Potential of Luteolin on Cancer

“…The molecular effects of Luteolin were also investigated in relation to the epidermal growth factor (EGF)-induced proliferation of glioblastoma cells and the ability of Luteolin to induce apoptosis in these cells, as EGFR was found to be overexpressed in glioblastomas [ 99 , 100 ]. In their study, Anson et al, 2018 showed that Luteolin significantly decreased the proliferation of glioblastoma cells in vitro in the presence or absence of EGF, wherein Luteolin caused a decrement in the expression levels of phosphorylated Akt, mTOR, p70S6K, and MAPK in the presence of EGF.…”

“…Similarly, Powe et al, 2022 showed that Luteolin combined with Erlotinib, an EGFR inhibitor, decreased proliferation and induced apoptosis in glioblastoma cell lines overexpressing EGFR or glioma cells expressing truncated EGFR. Mechanistically, the combination of Luteolin with Erlotinib was found to reduce the phosphorylation of downstream signaling molecules of EGFR, including Akt, NF kappa B, and STAT3 [ 100 ]. Furthermore, it was suggested that the effectiveness of Erlotinib might be enhanced by combining it with Luteolin, which can hold a new therapeutic strategy for glioblastoma [ 100 ].…”

“…Mechanistically, the combination of Luteolin with Erlotinib was found to reduce the phosphorylation of downstream signaling molecules of EGFR, including Akt, NF kappa B, and STAT3 [ 100 ]. Furthermore, it was suggested that the effectiveness of Erlotinib might be enhanced by combining it with Luteolin, which can hold a new therapeutic strategy for glioblastoma [ 100 ].…”