Ursolic acid derivative induces apoptosis in glioma cells through down-regulation of cAMP

The present study was designed to synthesize and evaluate ursolic acid hybrid compounds against glioma cells. Initial screening revealed that most of the synthesized compounds displayed better inhibitory effect on glioma cell proliferation compared to parent ursolic acid. The mechanism of inhibitory effect of the most potent compound 6d on glioma cells was investigated in detail. Treatment with compound 6d significantly (p < 0.001) reduced U251 and C6 cell proliferation at 48 h. The growth of U251 and C6 glioma cells was reduced to minimum level (17 and 21%) on treatment with 10 mu M concentration of compound 6d. Treatment of the U251 cells with 10 mu M concentration of compound 6d caused a significant (p < 0.05) inhibition of CAMP level. In U251 cell cultures treatment with compound 6d at 10 AM concentration enhanced proportion of apoptotic cells to 69.32% compared to 2.34% in the control cultures. The compound 6d treatment of U251 cells for 48 h caused arrest of cell cycle in the G0/G1 phase with consequent decrease of cell population in G2/M and S phases. The results from TEM showed that compound 6d treatment of U251 cells for 48 h caused blebbing of the cell membranes, chromatin condensation, appearance of foamy cytoplasmic material and autophagic vacuoles. The results from SEM revealed that compound 6d treatment of U251 cells caused a marked inhibition of microvilli and extensions on the cell surfaces. Thus present study demonstrates that compound 6d inhibits glioma cell growth, induces apoptosis and arrest cell cycle through metabolic pathway down-regulation. Therefore, compound 6d can be evaluated further for the treatment of glioma. (C) 2019 Elsevier Masson SAS. All rights reserved.