Zolfaghari Behzad, Akbari Forough, Esmaeili Sajad, Aghaei Mahmoud, Mosaffa Fatemeh, Ghorbanhosseini Seyedeh Sara, Ghanadian Mustafa
Department of Pharmaceutics, Novel Drug Delivery Systems Research Centre, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran.
Isfahan Pharmaceutical Sciences Research center, Isfahan University of Medical Sciences, Isfahan, Iran.
Iran J Pharm Res. 2024 Nov 18;23(1):e147396. doi: 10.5812/ijpr-147396. eCollection 2024 Jan-Dec.
This study focused on macrocyclic diterpenes derived from Euphorbia, particularly myrsinanes, and their potential in cytotoxic and combination treatments for resistant cancer cells. We examine premyrsinanes isolated from and explore their cytotoxic properties.
was collected from Taragh-Roud, Natanz, Iran. The semi-polar chloroform/acetone extract was chromatographed and fractionated using a large silica column. Fractions containing diterpene resonances were selected based on H-NMR spectra and were further subjected to smaller silica or Sephadex columns, followed by a recycling HPLC system. The isolated compounds were identified through 1D and 2D-NMR experiments and mass spectrometry. The cytotoxicity of the isolated compounds was assessed using the MTT assay against A2780 wild and A2780 cisplatin-resistant (R-CIS) cells, both in mono and combination treatments with cisplatin.
Using a Waters 616 HPLC pump and a YMC prep silica column, we successfully isolated two new premyrsinane diterpenes (Malleatin A and Malleatin B) alongside two known compounds (beta-sitosterol and loliolide). Malleatin A exhibited cytotoxicity against A2780 wild and A2780 R-CIS cells, with an IC range of 50 - 65 μM in the MTT assay. While cisplatin demonstrated significant cytotoxic effects on the A2780 wild cell line, it was ineffective against the A2780 R-CIS cells due to their resistance. However, the combination therapy of Malleatin A and cisplatin exhibited a synergistic effect, significantly increasing the mortality rate of the resistant cells compared to monotherapy. The Combination Index (CI) of 0.58 indicates effective synergy, and the Dose Reduction Index (DRI) of 3.65 suggests a favorable reduction in the dosage of cisplatin needed, potentially reducing its associated side effects.
本研究聚焦于大戟属植物来源的大环二萜，特别是紫金牛烷类化合物，以及它们在耐药癌细胞的细胞毒性和联合治疗中的潜力。我们研究了从[具体植物]中分离出的前紫金牛烷类化合物，并探索它们的细胞毒性特性。
[植物样本]采自伊朗纳坦兹的塔拉格-鲁德。使用大型硅胶柱对半极性氯仿/丙酮提取物进行色谱分离和分级。根据氢核磁共振（H-NMR）光谱选择含有二萜共振峰的馏分，然后进一步通过较小的硅胶柱或葡聚糖凝胶柱，接着使用循环高效液相色谱系统。通过一维和二维核磁共振实验以及质谱对分离出的化合物进行鉴定。使用MTT法评估分离出的化合物对A2780野生型和A2780顺铂耐药（R-CIS）细胞的细胞毒性，包括单一治疗和顺铂联合治疗。
使用沃特世616高效液相色谱泵和YMC制备硅胶柱，我们成功分离出两种新的前紫金牛烷二萜（Malleatin A和Malleatin B）以及两种已知化合物（β-谷甾醇和洛里内酯）。Malleatin A对A2780野生型和A2780 R-CIS细胞具有细胞毒性，在MTT试验中IC50范围为50 - 65 μM。虽然顺铂对A2780野生型细胞系显示出显著的细胞毒性作用，但由于A2780 R-CIS细胞具有耐药性，顺铂对其无效。然而，Malleatin A和顺铂的联合治疗表现出协同效应，与单一治疗相比，显著提高了耐药细胞的死亡率。联合指数（CI）为0.58表明有有效的协同作用，剂量降低指数（DRI）为3.65表明所需顺铂剂量有良好的降低，这可能会减少其相关的副作用。
