cedrelone and Breast-Neoplasms

Cedrelone is a limonoid isolated from the plant Trichilia catigua (Meliaceae). Previous studies have demonstrated that cedrelone (1) has several damaging effects on triple negative breast tumor (TNBC) cell line MDA-MB-231. In this work we investigated two new derivatives of cedrelone, the acetate (1a) and the mesylate (1b), to examine whether their effects are improved in comparison to the lead molecule. Cedrelone acetate (1a) was the most cytotoxic compound on TNBC cells and was chosen for additional analyses in traditional two-dimensional (2D) monolayer cultures and three-dimensional (3D) assays. In 2D, 1a induced cell cycle arrest, apoptosis and inhibited essential steps of the metastasis process of the MDA-MB-231 cells, in vitro. Moreover, 1a was able to revert the malignant phenotype of the T4-2 cells in 3D. These effects were concomitant with the downregulation of EGFR, β1-integrin and phospho-Akt, which could have resulted in a decrease of NFκB levels and MMP9 activity. These results suggest that 1a could be used as an important model for the design of a new drug to be applied in cancer treatment and be further studied in vivo for its antitumor and antimetastatic effects.

Topics: Acetylation; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Culture Techniques; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Down-Regulation; ErbB Receptors; Female; Humans; Integrin beta1; Limonins; Meliaceae; Phenotype

Four 18 (13 → 14)-abeo limonoids, five cedrelone limonoids, and five walsurin limonoids were isolated from the fruits of Walsura robusta together with 21 known compounds. Their structures were determined by extensive studies of their one- and two-dimensional NMR spectra and mass spectroscopy results. Among all the isolated compounds, the absolute configurations of 11-oxo-dihydrocedrelone, walsuronoid B, dysoxylumosin G, and walsunoid H were confirmed by single crystal X-ray diffraction. Selected compounds were evaluated for their reversal of multidrug resistance (MDR) phenotype in human breast cancer cells in vitro. Walsurin A showed significant effect in sensitization of these resistant cancer cells at non-toxic concentration to doxorubicin with the modulation factor of 62.76.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Crystallography, X-Ray; Drug Resistance, Multiple; Female; Fruit; Humans; Limonins; Meliaceae; Molecular Conformation; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Triterpenes