Maciel-Silva Vera Lucia, da Rocha Claudia Quintino, Alencar Luciana Magalhães Rebelo, Castelo-Branco Patrícia Valéria, Sousa Israel Higino de, Azevedo-Santos Ana Paula, Vale André Alvares Marques, Monteiro Silvio Gomes, Soares Rossy-Eric Pereira, Guimarães Sulayne Janayna Araujo, Nascimento Jessyane Rodrigues do, Pereira Silma Regina Ferreira
Postgraduate Program in Biodiversity and Biotechnology-Bionorte, Federal University of Maranhão, São Luis, Brazil.
Laboratory of Genetics and Molecular Biology, Department of Biology, Federal University of Maranhão, São Luis, Brazil.
Drug Chem Toxicol. 2023 Nov;46(4):665-676. doi: 10.1080/01480545.2022.2080217. Epub 2022 May 29.
Notwithstanding the advances in molecular target-based drugs, chemotherapy remains the most common cancer treatment, despite its high toxicity. Consequently, effective anticancer therapies with fewer adverse effects are needed. Therefore, this study aimed to determine the anticancer activity of the dichloromethane fraction (DCMF) isolated from roots, whose components are three unusual dimeric flavonoids. The toxicity of DCMF was investigated in breast (MCF-7), prostate (DU145), and cervical (HeLa) tumor cells, as well as non-tumor cells (PNT2), using sulforhodamine B (cell viability), Comet (genotoxicity), clonogenicity (reproductive capacity) and wound healing (cell migration) assays, and atomic force microscopy (AFM) for ultrastructural cell membrane alterations. Molecular docking revealed affinity between albumin and each rare flavonoid, supporting the impact of fetal bovine serum in DCMF antitumor activity. The IC values for MCF7, HeLa, and DU145 were 2.77, 2.46, and 2.51 µg/mL, respectively, and 4.08 µg/mL for PNT2. DCFM was not genotoxic to tumor or normal cells when exposed to twice the IC for up to 24 h, but it inhibited tumor cell migration and reproduction compared to normal cells. Additionally, AFM revealed alterations in the ultrastructure of tumor nuclear membrane surfaces, with a positive correlation between DCMF concentration and tumor cell roughness. Finally, we found a negative correlation between roughness and the ability of DCMF-treated tumor cells to migrate and form colonies with more than 50 cells. These findings suggest that DCFM acts by causing ultrastructural changes in tumor cell membranes while having fewer toxicological effects on normal cells.
尽管基于分子靶点的药物取得了进展，但化疗仍然是最常见的癌症治疗方法，尽管其毒性很高。因此，需要具有更少副作用的有效抗癌疗法。因此，本研究旨在确定从根部分离得到的二氯甲烷馏分（DCMF）的抗癌活性，其成分是三种不寻常的二聚体黄酮类化合物。使用磺酰罗丹明B（细胞活力）、彗星试验（遗传毒性）、克隆形成试验（生殖能力）和伤口愈合试验（细胞迁移）以及原子力显微镜（AFM）检测肿瘤细胞膜超微结构变化，研究了DCMF对乳腺（MCF-7）、前列腺（DU145）和宫颈（HeLa）肿瘤细胞以及非肿瘤细胞（PNT2）的毒性。分子对接显示白蛋白与每种稀有黄酮类化合物之间具有亲和力，这支持了胎牛血清对DCMF抗肿瘤活性的影响。MCF7、HeLa和DU145的IC值分别为2.77、2.46和2.51μg/mL，PNT2的IC值为4.08μg/mL。当暴露于两倍IC值长达24小时时，DCFM对肿瘤细胞或正常细胞没有遗传毒性，但与正常细胞相比，它抑制了肿瘤细胞的迁移和繁殖。此外，AFM显示肿瘤核膜表面超微结构发生改变，DCMF浓度与肿瘤细胞粗糙度呈正相关。最后，我们发现粗糙度与DCMF处理的肿瘤细胞迁移和形成超过50个细胞的集落的能力之间呈负相关。这些发现表明，DCFM通过引起肿瘤细胞膜超微结构变化发挥作用，而对正常细胞的毒理学影响较小。
