INSTRUCTIVE MODIFICATION OF BETULINIC ACID TO CAUSE ER STRESS MEDIATED FERROPTOTIC DEATH:

INSTRUCTIVE MODIFICATION OF BETULINIC ACID TO CAUSE ER STRESS MEDIATED FERROPTOTIC DEATH:

ABSTRACT:

Ferroptosis is an iron dependent programmed cell death which can be brought about by regulating different pathway inside the cell. Herein, betulinic Acid, a natural product having moderate anticancer activity was instructively modified to form self-aggregating conjugates to cause ER stress. Endoplasmic reticulum (ER) stress plays an important role in ferroptosis , as the main component of ferroptosis - the lipid peroxides are transported via LPCAT3 which localises in the ER of the cell membrane. Lipidomics analysis indicate that the lipid peroxides generated due to the treatment of these betulinic acid conjugates contribute to the ferroptotic death of breast cancer(MCF-7) cells lines via upregulation of ACSL4 pathway. The synthesis, self-assembling characterisation, and other biological assays including western blot analysis suggest the ER mediated ferroptotic death pathway and this study provides very first example of a natural product modification to cause iron mediated cancer cell death.

INTRODUCTION:

Ferroptosis can be brought about in a cell through three different pathways: namely by disrupting the GSH-GPX4 antiporter pathway, ER mediated lipid peroxidation stress pathway and mitochondrial damage mediated pathway. In this study we have synthesised some instructive natural product to cause ER mediated stress leading to ferroptosis.