Zhang Issan, Beus Maja, Stochaj Ursula, Le Phuong Uyen, Zorc Branka, Rajić Zrinka, Petrecca Kevin, Maysinger Dusica
1Department of Pharmacology and Therapeutics, McGill University, Montreal, QC Canada.
2Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia.
Cell Death Discov. 2018 Sep 26;4:41. doi: 10.1038/s41420-018-0103-0. eCollection 2018.
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.
多形性胶质母细胞瘤是最具侵袭性的脑肿瘤之一，目前使用替莫唑胺或辛二酰苯胺异羟肟酸（SAHA，伏立诺他）的治疗方法存在相当大的局限性。SAHA是一种组蛋白脱乙酰酶（HDAC）抑制剂，由于缺乏选择性，会导致不良副作用。我们在此展示了一种新型杂合分子sahaquine的特性，它在纳摩尔浓度下选择性抑制细胞质HDAC6，而不会显著抑制I类HDAC。抑制HDAC6会导致显著的α-微管蛋白乙酰化，从而损害胶质母细胞瘤细胞中的细胞骨架组织。sahaquine的伯氨喹部分降低了P-糖蛋白的活性，而P-糖蛋白与多形性胶质母细胞瘤的耐药性有关。我们提出sahaquine的作用机制涉及HDAC6抑制以及对表皮生长因子受体和下游激酶活性的抑制，这些是多形性胶质母细胞瘤中的主要治疗靶点。sahaquine显著降低了胶质母细胞瘤类肿瘤以及脑肿瘤干细胞的活力和侵袭性，而脑肿瘤干细胞是肿瘤存活和复发的关键。sahaquine与替莫唑胺、天然化合物槲皮素或谷胱甘肽生物合成抑制剂丁硫氨酸亚砜胺联合使用时，这些作用会增强。因此，联合使用破坏胶质母细胞瘤和脑肿瘤干细胞内环境稳定的药物可提供有效的抗癌干预措施。
