Abstract
Glioblastoma multiforme is one of the most aggressive brain tumors and current therapies with temozolomide or suberoylanilide hydroxamic acid (SAHA, vorinostat) show considerable limitations. SAHA is a histone deacetylase (HDAC) inhibitor that can cause undesirable side effects due to the lack of selectivity. We show here properties of a novel hybrid molecule, sahaquine, which selectively inhibits cytoplasmic HDAC6 at nanomolar concentrations without markedly suppressing class I HDACs. Inhibition of HDAC6 leads to significant α-tubulin acetylation, thereby impairing cytoskeletal organization in glioblastoma cells. The primaquine moiety of sahaquine reduced the activity of P-glycoprotein, which contributes to glioblastoma multiforme drug resistance. We propose the mechanism of action of sahaquine to implicate HDAC6 inhibition together with suppression of epidermal growth factor receptor and downstream kinase activity, which are prominent therapeutic targets in glioblastoma multiforme. Sahaquine significantly reduces the viability and invasiveness of glioblastoma tumoroids, as well as brain tumor stem cells, which are key to tumor survival and recurrence. These effects are augmented with the combination of sahaquine with temozolomide, the natural compound quercetin or buthionine sulfoximine, an inhibitor of glutathione biosynthesis. Thus, a combination of agents disrupting glioblastoma and brain tumor stem cell homeostasis provides an effective anti–cancer intervention.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive form of brain cancer, with limited treatment options and dismal survival rates
Sahaquine synthesis and physicochemical properties of the selected anticancer agents Sahaquine is a primaquine and hydroxamic acid derivative linked with glutaric acid
Results from this study show that sahaquine is more effective than TMZ in killing glioblastoma and brain tumor stem cells (BTSCs), as well as inhibiting glioblastoma invasiveness
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive form of brain cancer, with limited treatment options and dismal survival rates. Current treatment involves surgical resection followed by radiotherapy and chemotherapy with temozolomide (TMZ)[1]. More than half of GBM patients do not respond to TMZ due to the overexpression of DNA repair enzymes, notably O6-methylguanine transferase[2,3,4]. Suberoylanilide hydroxamic acid (SAHA, vorinostat) is a Food and Drug. Administration-approved drug for the treatment of cutaneous T cell lymphoma. It is currently in clinical trials for GBM as monotherapy and combined with radiotherapy[6,7,8,9]
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