Novel hybrid compounds of sclareol and doxorubicin as potential anticancer nanotherapy for glioblastoma

Abstract

Two novel hybrid compounds, CON1 and CON2, have been developed by combining sclareol (SC) and doxorubicin (DOX) into a single molecular entity. These hybrid compounds have a 1:1 molar ratio of covalently linked SC and DOX. They have demonstrated promising anticancer properties, especially in glioblastoma cells, and have also shown potential in treating multidrug-resistant (MDR) cancer cells that express the P-glycoprotein (P-gp) membrane transporter. CON1 and CON2 form nanoparticles, as confirmed by Zetasizer, transmission electron microscopy (TEM), and chemical modeling. TEM also showed that CON1 and CON2 can be found in glioblastoma cells, specifically in the cytoplasm, different organelles, nucleus, and nucleolus. To examine the anticancer properties, the U87 glioblastoma cell line, and its corresponding multidrug-resistant U87-TxR cell line, as well as patient-derived astrocytoma grade 3 cells (ASC), were used, while normal human lung fibroblasts were used to determine the selectivity. CON1 and CON2 exhibited better resistance and selectivity profiles than DOX, showing less cytotoxicity, as evidenced by real-time cell analysis, DNA damage determination, cell death induction, mitochondrial respiration, and mitochondrial membrane depolarization studies. Cell cycle analysis and the β-galactosidase activity assay suggested that glioblastoma cells die by senescence following CON1 treatment. Overall, CON1 and CON2 showed great potential as they have better anticancer features than DOX. They are promising candidates for additional preclinical and clinical studies on glioblastoma.