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Malleatin a and B: New Premyrsine-Type Diterpenes From Euphorbia Malleata With Cytotoxic Effects Against A2780 Wild and A2780 R-Cis Ovarian Cancer Cell Lines in Mono or Combination Treatment With Cisplatin Publisher



Zolfaghari B1 ; Akbari F2 ; Esmaeili S1 ; Aghaei M4 ; Mosaffa F4 ; Ghorbanhosseini SS3 ; Ghanadian M5, 6
Authors
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Authors Affiliations
  1. 1. Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Isfahan Pharmaceutical Sciences Research center, Isfahan University of Medical Sciences, Isfahan, Iran
  3. 3. Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
  4. 4. Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
  5. 5. Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  6. 6. Department of Phytochemistry, Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran

Source: Iranian Journal of Pharmaceutical Research Published:2024


Abstract

Background: 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 Euphorbia malleata and explore their cytotoxic properties. Methods:Euphorbia malleata 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 on1H-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. Results: 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 IC50range 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. © 2024, Zolfaghari et al.
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