MARE-Marine and Environmental Sciences Centre, ARNET-Aquatic Research Network, Politécnico de Leiria, 2520-630 Peniche, Portugal.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
Mar Drugs. 2022 Oct 20;20(10):652. doi: 10.3390/md20100652.
Seaweeds are a great source of compounds with cytotoxic properties with the potential to be used as anticancer agents. This study evaluated the cytotoxic and proteasome inhibitory activities of 12-hydroxy-bromosphaerol, 12-hydroxy-bromosphaerol, and bromosphaerol isolated from . The cytotoxicity was evaluated on malignant cell lines (A549, CACO-2, HCT-15, MCF-7, NCI-H226, PC-3, SH-SY5Y, and SK-MEL-28) using the MTT and LDH assays. The ability of compounds to stimulate the production of hydrogen peroxide (HO) and to induce mitochondrial dysfunction, the externalization of phosphatidylserine, Caspase-9 activity, and changes in nuclear morphology was also studied on MCF-7 cells. The ability to induce DNA damage was also studied on L929 fibroblasts. The proteasome inhibitory activity was estimated through molecular docking studies. The compounds exhibited IC values between 15.35 and 53.34 µM. 12-hydroxy-bromosphaerol and 12-hydroxy-bromosphaerol increased the HO levels on MCF-7 cells, and bromosphaerol induced DNA damage on fibroblasts. All compounds promoted a depolarization of mitochondrial membrane potential, Caspase-9 activity, and nuclear condensation and fragmentation. The compounds have been shown to interact with the chymotrypsin-like catalytic site through molecular docking studies; however, only 12-hydroxy-bromosphaerol evidenced interaction with ALA20 and SER169, key residues of the proteasome catalytic mechanism. Further studies should be outlined to deeply characterize and understand the potential of those bromoditerpenes for anticancer therapeutics.
海藻是具有细胞毒性的化合物的重要来源,具有作为抗癌剂的潜力。本研究评估了从分离的 12-羟基-溴海兔醇、12-羟基-溴海兔醇和溴海兔醇的细胞毒性和蛋白酶体抑制活性。使用 MTT 和 LDH 测定法在恶性细胞系(A549、CACO-2、HCT-15、MCF-7、NCI-H226、PC-3、SH-SY5Y 和 SK-MEL-28)上评估了化合物的细胞毒性。还研究了化合物刺激过氧化氢 (HO) 产生和诱导线粒体功能障碍、磷脂酰丝氨酸外化、Caspase-9 活性和核形态变化的能力在 MCF-7 细胞上。还研究了在 L929 成纤维细胞上诱导 DNA 损伤的能力。通过分子对接研究估计了蛋白酶体抑制活性。这些化合物的 IC 值在 15.35 和 53.34 µM 之间。12-羟基-溴海兔醇和 12-羟基-溴海兔醇增加了 MCF-7 细胞上的 HO 水平,而溴海兔醇诱导了成纤维细胞上的 DNA 损伤。所有化合物均促进线粒体膜电位去极化、Caspase-9 活性以及核浓缩和碎裂。通过分子对接研究表明,这些化合物与糜蛋白酶样催化位点相互作用;然而,只有 12-羟基-溴海兔醇与 ALA20 和 SER169 相互作用,后者是蛋白酶体催化机制的关键残基。应该概述进一步的研究,以深入表征和理解这些溴二萜类化合物在抗癌治疗中的潜力。