Determining the effectiveness of combined and alone inhibition of HO-1 and HIF-1 alpha genes with siRNA loaded nanoparticles in reducing resistance to chemotherapy drug cytarabine in AML cell lines

Abstract

Acute myeloid leukemia (AML), a malignancy Often resistant to common chemotherapy regimens (Cytarabine (Ara-c) + Daunorubicin (DNR)), is accompanied by frequent relapses. Many factors are involved in this chemoresistance. Heme Oxygenase-1 (HO-1) and Hypoxia-Inducible Factor 1-alpha (HIF-1α) are two of the most well-known genes, reported to be overexpressed in AML and promote resistance against chemotherapy according to several studies. A main chemotherapy agent used for AML treatment is Ara-c. We hypothesized that simultaneous targeting of HO-1 and HIF-1α could sensitize AML cells to Ara-c. Methods In this study, we used our recently developed, Trans-Activator of Transcription (TAT) - Chitosan-Carboxymethyl Dextran (CCMD) - Poly Ethylene Glycol (PEG) - Nanoparticles (NPs), to deliver Ara-c along with siRNA molecules against the HO-1 and HIF-1α genes to AML cell lines including THP-1, KG-1, and HL-60 (in vitro). Subsequently, the effect of the single or combinational treatment on growth inhibition as well as caspase-9 concentration was evaluated. Results The designed NPs had a high potential in transfecting cells with siRNAs and drug. Following the silencing of HO-1 and HIF-1α, caspase-9 and the rate of apoptosis in response to Ara-c increased significantly.