{Reference Type}: Journal Article
{Title}: Next generation antimitotic β-carboline derivatives modulate microtubule dynamics and downregulate NF-κB, ERK 1/2 and phospho HSP 27.
{Author}: Jash M;Ghosh S;Roy R;Mukherjee N;Sen S;Ghosh S;
{Journal}: Life Sci
{Volume}: 351
{Issue}: 0
{Year}: 2024 Aug 15
{Factor}: 6.78
{DOI}: 10.1016/j.lfs.2024.122836
{Abstract}: <B>OBJECTIVE: </B>Exploring the efficacy of β-carboline-based molecular inhibitors in targeting microtubules for the development of novel anticancer therapeutics.<BR><B>METHODS: </B>We synthesized a series of 1-Aryl-N-substituted-β-carboline-3-carboxamide compounds and evaluated their cytotoxicity against human lung carcinoma (A549) cells using the MTT assay. Normal lung fibroblast cells (WI-38) were used to assess compound selectivity. The mechanism of action of MJ-211 was elucidated through Western blot analysis of key pro-apoptotic and cell cycle regulatory proteins. Additionally, the inhibitory effect of MJ-211 on multicellular 3D spheroid growth of A549 cells was evaluated.<BR><B>RESULTS: </B>Lead compound MJ-211 exhibited remarkable cytotoxicity against A549 cells with an IC50 of 4.075 μM at 24 h treatment and IC50 of 1.7 nM after 72 h of treatment, while demonstrating selectivity towards normal WI-38 cells. MJ-211 activated pro-apoptotic factors Bim and p53, and suppressed Cyclin B1, Phospho HSP 27, BubR1, Mad 2, ERK1/2, and NF-κB, indicating its potent antimitotic and pro-apoptotic effects. MJ-211 significantly suppressed the migration of cells and inhibited the growth of A549 cell-derived multicellular 3D spheroids, highlighting its efficacy in a more physiologically relevant model.<BR><B>CONCLUSIONS: </B>Cytotoxic effect of MJ-211 against cancer cells, selectivity towards normal cells, and ability to modulate key regulatory proteins involved in apoptosis and cell cycle progression underscore its potential as a promising template for further anticancer lead optimization. Moreover, the inhibitory effect of MJ-211 on multicellular spheroid growth suggests its efficacy in combating tumor heterogeneity and resistance mechanisms, thereby offering a promising avenue for future anticancer drug development.