Next generation antimitotic ß-carboline derivatives modulate microtubule dynamics and downregulate NF-κB, ERK 1/2 and phospho HSP 27.
Life Sci
; 351: 122836, 2024 Aug 15.
Article
in En
| MEDLINE
| ID: mdl-38879159
ABSTRACT
AIM:
Exploring the efficacy of ß-carboline-based molecular inhibitors in targeting microtubules for the development of novel anticancer therapeutics. MATERIALS ANDMETHODS:
We synthesized a series of 1-Aryl-N-substituted-ß-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. KEYFINDINGS:
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.SIGNIFICANCE:
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carbolines
/
NF-kappa B
/
Microtubules
Limits:
Humans
Language:
En
Journal:
Life Sci
Year:
2024
Document type:
Article
Affiliation country:
India
Country of publication:
Países Bajos