CXL146 - A NOVEL CHROMENE DERIVATIVE INDUCES APOPTOSIS THROUGH ER STRESS FOLLOWED BY THE INHIBITION OF NOTCH1 SIGNALING IN MULTIDRUG RESISTANT AML CELLS

Kavitha Chandagirikoppal Vijendra, Haifeng Sun, Sreekanth Narayana Pillai and Chengguo Xing

Department of Collegiate Education, Government College for Women Mandya, University of Mysore, Karnataka, India

Abstract

Acute Myeloid Leukemia (AML) is the most common type of acute leukemia diagnosed in adults and second most common in children. They acquire resistance to chemotherapeutic agents through multiple mechanisms. Thus, Multidrug resistance (MDR) has become a major hurdle in the treatment of cancer. High-level expression of GRP78/Bip, an Endoplasmic Reticulum (ER) chaperone confers resistance to drugs. Here, we noticed robust expression of GRP78/Bip and its associated proteins in drug resistant variant (HL60/MX2) compared to parental cells (HL60). Our compound 4H-Chromene derivative (CXL146), selectively kills HL60/MX2 cells and downregulate the expression of GRP78/Bip in HL60/MX2 cells at lower doses compared to HL60 cells. The reduction of GRP78/Bip induces the unfolded protein response as evidenced by the activation of IRE1-α and PERK. It is know that, Notch activation is crucial for the onset and progression of T cell leukemia. Here, we showed that our small molecule inhibits the activation of Notch1 in HL60/MX2 cells and alters the mRNA levels of Notch1 targets genes, HES1 and MYC. Given the significant downregulation of GRP78/Bip and inhibition of Notch1 signaling in HL60/MX2, our molecule, CXL146 holds great promises for future development as a novel anti-AML agent.