Abstract
Glioblastoma multiforme (GBM) is the most malignant type of central nervous system tumor that is resistant to all currently used forms of therapy. Thus, more effective GBM treatment strategies are being investigated, including combined therapies with drugs that may cross the blood brain barrier (BBB). Another important issue considers the decrease of deleterious side effects of therapy. It has been shown that nanocarrier conjugates with biotin can penetrate BBB. In this study, biotinylated PAMAM G3 dendrimers substituted with the recognized anticancer agents cyclooxygenase-2 (COX-2) inhibitor celecoxib and peroxisome proliferator-activated receptor γ (PPARγ) agonist Fmoc-L-Leucine (G3-BCL) were tested in vitro on human cell lines with different p53 status: glioblastoma (U-118 MG), normal fibroblasts (BJ) and immortalized keratinocytes (HaCaT). G3-BCL penetrated efficiently into the lysosomal and mitochondrial compartments of U-118 MG cells and induced death of U-118 MG cells via apoptosis and inhibited proliferation and migration at low IC50 = 1.25 µM concentration, considerably lower than either drug applied alone. Comparison of the effects of G3-BCL on expression of COX-2 and PPARγ protein and PGE2 production of three different investigated cell line phenotypes revealed that the anti-glioma effect of the conjugate was realized by other mechanisms other than influencing PPAR-γ expression and regardless of p53 cell status, it was dependent on COX-2 protein level and high PGE2 production. Similar G3-BCL cytotoxicity was seen in normal fibroblasts (IC50 = 1.29 µM) and higher resistance in HaCaT cells (IC50 = 4.49 µM). Thus, G3-BCL might be a good candidate for the targeted, local glioma therapy with limited site effects.
Highlights
Glioblastoma multiforme (GBM), classified by WHO as grade IV, is the most lethal primary tumor of the central nervous system (CNS), with high prevalence in developed, industrialized countries [1,2]
The G3-BCL construct was toxic at a low concentration range for glioma cells (IC50 = 1.25 μM) and normal human fibroblasts (IC50 = 1.29 μM), whereas immortalized keratinocytes were more resistant (IC50 = 4.49 μM) (Figure 1)
It has been established that intracellular levels of ATP, supplied through glycolysis or oxidative phosphorylation, determines cell death by apoptosis, favored by a high level of intracellular ATP or necrosis, promoted by low energy level [79,80]
Summary
Glioblastoma multiforme (GBM), classified by WHO as grade IV, is the most lethal primary tumor of the central nervous system (CNS), with high prevalence in developed, industrialized countries [1,2]. Molecules 2019, 24, 3801 invasive nature of GBM is the main source of recurrence [3]. Among major signaling pathways affected in GBM, the mutation/inactivation of gene p53, a main switch coordinating cell fate between survival and death has been found in 54–87% of high-grade human gliomas [8,9,10]. The p53 mutations are associated with short survival time and resistance to chemo and radio therapy and the same mutants are known to gain oncogenic functions and promote tumorigenesis and cancer progression [11,12]. It is a matter of importance to recognize of the effectiveness of applied therapeutics against cancer cells with modified p53 status as compared with normal or non-cancerogenic immortalized cells with mutated p53
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