Farnesiferol C Induces Apoptosis in Chronic Myelogenous Leukemia Cells as an Imatinib Sensitizer via Caspase Activation and HDAC (Histone Deacetylase) Inactivation.

Ji Hoon Jung,Woon Yi Park,Eunji Im,Sung-Hoon Kim,Deok Yong Sim,Duckgue Lee,Bum-Sang Shim,Ji Eon Park

doi:10.3390/ijms20225535

Abstract

Herein the underlying apoptotic mechanism of Farnesiferol C (FC) derived from Ferula assafoetida was elucidated in chronic myelogenous leukemia (CML) K562 and KBM5 cells. FC showed significant cytotoxicity in K562 and KBM5 cells, more so than in U937 and UL-60 acute myeloid leukemia (AML) cells. Cleaved PARP and caspase 9/3 attenuated the expression of Bcl2 and induced G1 arrest in K562 and KBM5 cells. Also, FC effectively abrogated the expression of cell cycle related proteins, such as: Cyclin D1, Cyclin E, Cyclin B1 in K562, and KBM5 cells, but caspase 3 inhibitor Z-DEVD-FMK rescued the cleavages of caspase 3 and PARP induced by FC in K562 cells. Of note, FC decreased histone deacetylase 1 (HDAC1) and HDAC2, and enhanced histone H3 acetylation K18 (Ac-H3K18) in K562 and KBM5 cells. Furthermore, combination of FC and Imatinib enhanced the apoptotic effect of Imatinib as a potent Imatinib sensitizer in K562 cells. Overall, our findings provide scientific evidence that inactivation of HDAC and caspase activation mediate FC induced apoptosis in CML cells.

Highlights

Among bone marrow or blood cancers, leukemia with the abnormal proliferation feature of white blood cells is generally classified into myelogenous leukemia and lymphoblastic leukemia [1]
The underlying apoptotic mechanism of Farnesiferol C (FC) and its potential of Imanitib sensitizer for combinatorial therapy were explored in Chronic myeloid leukemia (CML) cells
FC exerted signCifiomcmaenntted [M35R34]: *, p value

Summary

Introduction

Among bone marrow or blood cancers, leukemia with the abnormal proliferation feature of white blood cells is generally classified into myelogenous leukemia and lymphoblastic leukemia [1]. FC induced the cleavages of PARP, caspase-9, and caspase-3, and decreased the expression of Bcl-2 in K562 and KBM5 cells (Figure 2A,B). FC induced the cleavages of PARP, caspase-9, and caspase-3, and decreased the expression of Bcl-2 in K562 and KBM5 cells It is well whether FC regulates cell cycle proteins, Western blotting was Aksnsohwownntihn aFitgFurCe 3i,nFdCuincheisbicteedllthceyecxlpereasrsrioenstofincycblirneDas1t, performed in K562 and KBM5 cells. FC Regulates HDAC (Histone Deacetylase) 1 and 2 through Acetylation H3 (K18) in CML Cells. Overexpression of HDAC1 weakly reduced the apoptotic ability of FC to attenuate pro-PARP expression compared to the FC alone control, which may be due to transfection efficiency in K562 suspension cells. Ent of FC and Imatinib attenuated the expression of HDAC1, upregulated Ac-H3K18, and cleaved PARP in K562 cells (Figure 6B). Uncro using HDAC1 and 2 antibodies. β-actin was used as an internal control

Discussion

Cell Culture

Cell Cycle Analysis

Western Blotting

Transfection Assay

Statistical Analysis