Investigation of the cytotoxic, anti-metastatic and apoptotic potential of multifloral honey and temozolomide-honey combined treatment on glioblastoma (Gbm) cell lines

Malignant glioma (glioblastoma or GBM) is the most common and aggressive primary brain tumor. Temozolomide (TMZ) is used as a first-line treatment for glioblastoma. Most glioblastoma patients die within 1-2 years of diagnosis, despite surgical, radiotherapy, and chemotherapy interventions. Honey has been used as food and a traditional medicine since ancient times. It has been reported that honey regulates many cellular mechanisms associated with cancer progression, such as tumor cell proliferation, apoptosis, and metastasis. The aim of this study was to investigate the cytotoxic effect and mechanisms of the combined use of honey with TMZ in GBM cell lines. For this purpose, the cytotoxic effects of the combined use of honey and honey + TMZ in human GBM (U-118 MG, T98G, U-87 MG) cell lines were evaluated using MTT analysis. The gene expression levels of the signaling pathways involved in the cytotoxicity of GBM cells in honey, TMZ and honey + TMZ groups were investigated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and changes in protein expression by Western blot method. In our research, we showed that honey reduces cell viability by various mechanisms. A dose-dependent cytotoxic effect was observed in the honey + TMZ applied groups in all three of the U-118 MG, U-87 MG, and T98G cell lines. In T98G and U-87 MG cell lines, a 5% honey-TMZ dose showed a more cytotoxic effect than 5% honey, indicating that there may be a synergistic effect between honey and TMZ. A statistically insignificant increase in pro-apoptotic Bax mRNA level and protein expression was observed as a result of Bal+TMZ application in U-118 MG cells. In addition, the ERK signaling pathway, which is associated with survival and plays an important role in drug resistance in GBM, was suppressed. As a result of honey application, an increase was observed in mRNA and protein expression of pro-apoptotic Bax as a result, while mRNA and protein expression of anti-apoptotic Bcl-2 protein were decreased. At the same time, the ERK signaling pathway was suppressed in the groups treated with Honey+TMZ and TMZ. The combination dose of Bal+TMZ applied to U-87 MG cells showed a synergistic effect, significantly increasing both mRNA and protein expression of pro-apoptotic Bax while synergistically decreasing the mRNA and protein expression of anti-apoptotic Bcl-2. Migration experiments showed that Honey+TMZ dose applications in all of the U-118 MG, T98G, and U-87 MG cells significantly inhibited cell migration. Understanding the molecular and biochemical mechanisms underlying the formation and progression of GBM tumors is anticipated to facilitate the creation of novel potential therapeutics. We conclude that natural bee honey is a promising source of natural compounds and dietary supplements for the treatment of brain tumors