口腔鳞状细胞癌模型中物质的抗癌活性及分子靶点

Anticancer Activity and Molecular Targets of Substances in Oral Squamous Cell Carcinoma Models.

作者信息

Machado Thaíssa Queiróz, Lima Maria Emanuelle Damazio, da Silva Rafael Carriello, Macedo Arthur Ladeira, de Queiroz Lucas Nicolau, Angrisani Bianca Roberta Peres, da Fonseca Anna Carolina Carvalho, Câmara Priscilla Rodrigues, Rabelo Vitor Von-Held, Carollo Carlos Alexandre, de Lima Moreira Davyson, de Almeida Elan Cardozo Paes, Vasconcelos Thatyana Rocha Alves, Abreu Paula Alvarez, Valverde Alessandra Leda, Robbs Bruno Kaufmann

机构信息

Postgraduate Program in Applied Science for Health Products, Faculty of Pharmacy, Fluminense Federal University, Niteroi 24241-000, RJ, Brazil.

Department of Organic Chemistry, Chemistry Institute, Fluminense Federal University, Niteroi 24020-141, RJ, Brazil.

出版信息

Biomedicines. 2023 Jul 6;11(7):1914. doi: 10.3390/biomedicines11071914.

Abstract

Oral squamous cell carcinoma (OSCC) is a worldwide public health problem, with high morbidity and mortality rates. The development of new drugs to treat OSCC is paramount. plant species have shown many biological activities. In the present study, we show that dichloromethane partition of (PCLd) is nontoxic in chronic treatment in mice, reduces the amount of atypia in tongues of chemically induced OSCC, and significantly increases animal survival. To identify the main active compounds, chromatographic purification of PCLd was performed, where fractions 09.07 and 14.05 were the most active and selective. These fractions promoted cell death by apoptosis characterized by phosphatidyl serine exposition, DNA fragmentation, and activation of effector caspase-3/7 and were nonhemolytic. LC-DAD-MS/MS analysis did not propose matching spectra for the 09.07 fraction, suggesting compounds not yet known. However, aporphine alkaloids were annotated in fraction 14.05, which are being described for the first time in and corroborate the observed cytotoxic activity. Putative molecular targets were determined for these alkaloids, in silico, where the androgen receptor (AR), CHK1, CK2, DYRK1A, EHMT2, LXRβ, and VEGFR2 were the most relevant. The results obtained from fractions point to promising compounds as new preclinical anticancer candidates.

摘要

口腔鳞状细胞癌(OSCC)是一个全球性的公共卫生问题,发病率和死亡率都很高。开发治疗OSCC的新药至关重要。植物物种已显示出许多生物活性。在本研究中,我们表明(PCLd)的二氯甲烷提取物在小鼠慢性治疗中无毒,可减少化学诱导的OSCC小鼠舌头中的异型细胞数量,并显著提高动物存活率。为了鉴定主要活性化合物,对PCLd进行了色谱纯化,其中馏分09.07和14.05活性和选择性最高。这些馏分通过以磷脂酰丝氨酸暴露、DNA片段化以及效应半胱天冬酶-3/7激活为特征的凋亡促进细胞死亡,并且不具有溶血作用。LC-DAD-MS/MS分析未为馏分09.07提出匹配的光谱,表明存在未知化合物。然而,在馏分14.05中注释了阿朴啡生物碱,这在首次被描述,并证实了观察到的细胞毒性活性。通过计算机模拟确定了这些生物碱的推定分子靶点,其中雄激素受体(AR)、CHK1、CK2、DYRK1A、EHMT2、LXRβ和VEGFR2最为相关。从馏分中获得的结果表明,有前景的化合物可作为新的临床前抗癌候选物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57f0/10377665/4ffbb4a6682d/biomedicines-11-01914-g001.jpg

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