Laschuk Herlinger Alice, Lovatto Michaelsen Gustavo, Sinigaglia Marialva, Fratini Lívia, Nogueira Debom Gabriela, Braganhol Elizandra, Brunetto de Farias Caroline, Lunardi Brunetto Algemir, Tesainer Brunetto André, da Cunha Jaeger Mariane, Roesler Rafael
Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, 90035-003, Brazil.
National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology - INCT BioOncoPed, Porto Alegre, RS, 90035-003, Brazil.
Neuromolecular Med. 2023 Dec;25(4):573-585. doi: 10.1007/s12017-023-08758-x. Epub 2023 Sep 23.
Medulloblastoma (MB) is a heterogeneous group of malignant pediatric brain tumors, divided into molecular groups with distinct biological features and prognoses. Currently available therapy often results in poor long-term quality of life for patients, which will be afflicted by neurological, neuropsychiatric, and emotional sequelae. Identifying novel therapeutic agents capable of targeting the tumors without jeopardizing patients' quality of life is imperative. Rosmarinic acid (RA) is a plant-derived compound whose action against a series of diseases including cancer has been investigated, with no side effects reported so far. Previous studies have not examined whether RA has effects in MB. Here, we show RA is cytotoxic against human Daoy (IC = 168 μM) and D283 (IC = 334 μM) MB cells. Exposure to RA for 48 h reduced histone deacetylase 1 (HDAC1) expression while increasing H3K9 hyperacetylation, reduced epidermal growth factor (EGFR) expression, and inhibited EGFR downstream targets extracellular-regulated kinase (ERK)1/2 and AKT in Daoy cells. These modifications were accompanied by increased expression of CDKN1A/p21, reduced expression of SOX2, and a decrease in proliferative rate. Treatment with RA also reduced cancer stem cell markers expression and neurosphere size. Taken together, our findings indicate that RA can reduce cell proliferation and stemness and induce cell cycle arrest in MB cells. Mechanisms mediating these effects may include targeting HDAC1, EGFR, and ERK signaling, and promoting p21 expression, possibly through an increase in H3K9ac and AKT deactivation. RA should be further investigated as a potential anticancer agent in experimental MB.
髓母细胞瘤（MB）是一组异质性的儿童恶性脑肿瘤，可分为具有不同生物学特征和预后的分子亚组。目前可用的治疗方法往往导致患者长期生活质量较差，患者会受到神经、神经精神和情感后遗症的折磨。确定能够靶向肿瘤而不损害患者生活质量的新型治疗药物势在必行。迷迭香酸（RA）是一种植物来源的化合物，其对包括癌症在内的一系列疾病的作用已得到研究，目前尚未报道有副作用。先前的研究尚未考察RA在MB中是否有作用。在此，我们表明RA对人Daoy（IC = 168 μM）和D283（IC = 334 μM）MB细胞具有细胞毒性。用RA处理48小时可降低组蛋白去乙酰化酶1（HDAC1）的表达，同时增加H3K9超乙酰化，降低表皮生长因子（EGFR）的表达，并抑制Daoy细胞中EGFR下游靶点细胞外调节激酶（ERK）1/2和AKT。这些改变伴随着CDKN1A/p21表达的增加、SOX2表达的降低以及增殖率的下降。用RA处理还可降低癌症干细胞标志物的表达和神经球大小。综上所述，我们的研究结果表明RA可降低MB细胞的增殖和干性并诱导细胞周期停滞。介导这些作用的机制可能包括靶向HDAC1、EGFR和ERK信号传导，以及促进p21表达，可能是通过增加H3K9ac和使AKT失活。RA应作为实验性MB中的潜在抗癌药物进一步研究。
