Department of Pharmaceutical and Pharmacological Sciences, University of Padova, L.go Meneghetti 2, Italy.
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, L.go Meneghetti 2, Italy.
Fitoterapia. 2019 Jul;136:104173. doi: 10.1016/j.fitote.2019.104173. Epub 2019 May 11.
Propolis is a natural product obtained from bees, used since ancient times for its multiple pharmacological properties. Several evidences indicate that the antiproliferative effect of propolis against different cancer cell lines can be ascribed to its components. However, little is known about the possible use of this natural product in the treatment of chemo-resistant tumors. Combination experiments were carried out in order to study the ability of Cuban propolis extracts (CP) and its main component (nemorosone) to chemosensitize doxorubicin-resistant human colon carcinoma cells (LoVo Dox) compared to the sensitive cells (LoVo). Antiproliferative effect was determined by MTT assay after 24, 48 and 72 h exposure. Synergistic, additive or antagonistic effects of different combined treatments (CP-Dox and nemorosone-Dox), was evaluated by isobologram-combination index method. The interaction mechanisms between CP or nemorosone with doxorubicin were studied by flow cytometry to investigate cell death pathway and cell cycle arrest. Reactive oxygen species production (ROS) and mitochondrial membrane potential (ΔΨm) modification were also evaluated. Data showed that both CP and its main component nemorosone were able to reduce cell proliferation in a concentration- and time-dependent manner. Combined treatments induced a cell growth inhibition with a significantly synergistic antiproliferative and cytotoxic effect. Co-treatments induced also cell cycle arrest which results in apoptosis by a marked ROS production and drastic alteration of ΔΨm. In summary, our findings evidence the potential role of Cuban propolis extracts and their main component nemorosone as new chemosensitizing agents against drug-resistant human colon carcinoma cells.
蜂胶是一种从蜜蜂身上获得的天然产物，自古以来因其多种药理学特性而被广泛使用。有几项证据表明，蜂胶对不同癌细胞系的抗增殖作用可以归因于其成分。然而，对于这种天然产物在治疗化疗耐药肿瘤中的可能用途，人们知之甚少。为了研究古巴蜂胶提取物（CP）及其主要成分（nemorosone）与敏感细胞（LoVo）相比，对多柔比星耐药人结肠癌细胞（LoVo Dox）的化学增敏能力，进行了组合实验。在暴露 24、48 和 72 小时后，通过 MTT 测定法确定抗增殖作用。通过等对数图组合指数法评估不同联合治疗（CP-Dox 和 nemorosone-Dox）的协同、相加或拮抗作用。通过流式细胞术研究 CP 或 nemorosone 与多柔比星之间的相互作用机制，以研究细胞死亡途径和细胞周期停滞。还评估了活性氧物种（ROS）的产生和线粒体膜电位（ΔΨm）的改变。数据表明，CP 和其主要成分 nemorosone 均能以浓度和时间依赖性方式降低细胞增殖。联合治疗诱导细胞生长抑制，具有显著的协同抗增殖和细胞毒性作用。共同处理还诱导细胞周期停滞，通过明显的 ROS 产生和 ΔΨm 的急剧改变导致细胞凋亡。总之，我们的研究结果表明，古巴蜂胶提取物及其主要成分 nemorosone 作为新的化疗增敏剂，具有针对耐药人结肠癌细胞的潜力。
