Radin Daniel P, Shifman Sophie, Outhwaite Ian R, Sharma Aryan, Bases Robert, Seeliger Markus A, Tsirka Stella E
Department of Pharmacological Sciences (D.P.R., S.S., I.R.O., A.S., M.A.S., S.E.T.) and Stony Brook Medical Scientist Training Program (D.P.R., S.S., I.R.O.), Renaissance School of Medicine at Stony Brook University, Stony Brook, New York.
Department of Pharmacological Sciences (D.P.R., S.S., I.R.O., A.S., M.A.S., S.E.T.) and Stony Brook Medical Scientist Training Program (D.P.R., S.S., I.R.O.), Renaissance School of Medicine at Stony Brook University, Stony Brook, New York
J Pharmacol Exp Ther. 2024 Mar 15;389(1):51-60. doi: 10.1124/jpet.123.002021.
Glioblastoma (GBM) is the most frequently diagnosed primary central nervous system tumor in adults. Despite the standard of care therapy, which includes surgical resection, temozolomide chemotherapy, radiation and the newly added tumor-treating fields, median survival remains only ∼20 months. Unfortunately, GBM has a ∼100% recurrence rate, but after recurrence there are no Food and Drug Administration-approved therapies to limit tumor growth and enhance patient survival, as these tumors are resistant to temozolomide (TMZ). Recently, our laboratory reported that lucanthone slows GBM by inhibiting autophagic flux through lysosome targeting and decreases the number of Olig2+ glioma stem-like cells (GSC) in vitro and in vivo. We now additionally report that lucanthone efficiently abates stemness in patient-derived GSC and reduces tumor microtube formation in GSC, an emerging hallmark of treatment resistance in GBM. In glioma tumors derived from cells with acquired resistance to TMZ, lucanthone retains the ability to perturb tumor growth, inhibits autophagy by targeting lysosomes, and reduces Olig2 positivity. We also find that lucanthone may act as an inhibitor of palmitoyl protein thioesterase 1. Our results suggest that lucanthone may function as a potential treatment option for GBM tumors that are not amenable to TMZ treatment. SIGNIFICANCE STATEMENT: We report that the antischistosome agent lucanthone impedes tumor growth in a preclinical model of temozolomide-resistant glioblastoma and reduces the numbers of stem-like glioma cells. In addition, it acts as an autophagy inhibitor, and its mechanism of action may be via inhibition of palmitoyl protein thioesterase 1. As there are no defined therapies approved for recurrent, TMZ-resistant tumor, lucanthone could emerge as a treatment for glioblastoma tumors that may not be amenable to TMZ both in the newly diagnosed and recurrent settings.
胶质母细胞瘤（GBM）是成人中最常被诊断出的原发性中枢神经系统肿瘤。尽管有包括手术切除、替莫唑胺化疗、放疗以及新增加的肿瘤治疗电场在内的标准治疗方案，但中位生存期仍仅约为20个月。不幸的是，GBM的复发率约为100%，但复发后没有美国食品药品监督管理局批准的疗法来限制肿瘤生长和提高患者生存率，因为这些肿瘤对替莫唑胺（TMZ）具有抗性。最近，我们实验室报告称，卢卡酮通过靶向溶酶体抑制自噬通量来减缓GBM的生长，并在体外和体内减少Olig2 +胶质瘤干细胞样细胞（GSC）的数量。我们现在还报告称，卢卡酮能有效消除患者来源的GSC中的干性，并减少GSC中肿瘤微管的形成，这是GBM中一种新出现的治疗抗性标志。在源自对TMZ获得性抗性细胞的胶质瘤肿瘤中，卢卡酮保留了干扰肿瘤生长的能力，通过靶向溶酶体抑制自噬，并降低Olig2阳性率。我们还发现卢卡酮可能作为棕榈酰蛋白硫酯酶1的抑制剂发挥作用。我们的结果表明，卢卡酮可能作为对TMZ治疗不敏感的GBM肿瘤的一种潜在治疗选择。意义声明：我们报告称，抗血吸虫药卢卡酮在替莫唑胺耐药性胶质母细胞瘤的临床前模型中阻碍肿瘤生长，并减少干细胞样胶质瘤细胞的数量。此外，它作为一种自噬抑制剂发挥作用，其作用机制可能是通过抑制棕榈酰蛋白硫酯酶1。由于目前尚无针对复发性、TMZ耐药性肿瘤的明确批准疗法，卢卡酮可能成为一种治疗方法，用于治疗新诊断和复发性情况下可能对TMZ不敏感的胶质母细胞瘤肿瘤。
