Malleatin A and B: New Premyrsine-Type Diterpenes from Euphorbia malleata with Cytotoxic Effects Against A2780 Wild and A2780 R-CISOvarian Cancer Cell Lines in Mono or Combination Treatment withCisplatin

Abstract

Background: This study focused on macrocyclic diterpenes derived from Euphorbia, particularly myrsinanes, and theirpotential in cytotoxic and combination treatments for resistant cancer cells. We examine premyrsinanes isolated fromEuphorbia malleata and explore their cytotoxic properties. Methods:Euphorbia malleata was collected from Taragh-Roud, Natanz, Iran. The semi-polar chloroform/acetone extract waschromatographed and fractionated using a large silica column. Fractions containing diterpene resonances were selected basedon 1H-NMR spectra and were further subjected to smaller silica or Sephadex columns, followed by a recycling HPLC system. Theisolated compounds were identified through 1D and 2D-NMR experiments and mass spectrometry. The cytotoxicity of theisolated compounds was assessed using the MTT assay against A2780 wild and A2780 cisplatin-resistant (R-CIS) cells, both inmono and combination treatments with cisplatin. Results and Conclusions: Using a Waters 616 HPLC pump and a YMC prep silica column, we successfully isolated two newpremyrsinane 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 IC50 range of 50 - 65 mu M in the MTT assay.While cisplatin demonstrated significant cytotoxic effects on the A2780 wild cell line, it was ineffective against the A2780 R-CIScells 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 0.58indicates effective synergy, and the Dose Reduction Index (DRI) of 3.65 suggests a favorable reduction in the dosage of cisplatinneeded, potentially reducing its associated side effects.