The pterocarpanquinone LQB‑118 compound induces apoptosis of cytarabine‑resistant acute myeloid leukemia cells

Abstract

Acute myeloid leukemia (AML) is a complex hematological disorder characterized by blockage of differentiation and high proliferation rates of myeloid progenitors. Anthracycline and cytarabine-based therapy has remained the standard treatment for AML over the last four decades. Although this treatment strategy has increased survival rates, patients often develop resistance to these drugs. Despite efforts to understand the mechanisms underlying cytarabine resistance, there have been few advances in the field. The present study developed an in vitro AML cell line model resistant to cytarabine (HL-60R), and identified chromosomal aberrations by karyotype evaluation and potential molecular mechanisms underlying chemoresistance. Cytarabine decreased cell viability, as determined by MTT assay, and induced cell death and cell cycle arrest in the parental HL-60 cell line, as revealed by Annexin V/propidium iodide (PI) staining and PI DNA incorporation, respectively, whereas no change was observed in the HL-60R cell line. In addition, the HL-60R cell line exhibited a higher tumorigenic capacity in vivo compared with the parental cell line. Notably, no reduction in tumor volume was detected in mice treated with cytarabine and inoculated with HL-60R cells. In addition, western blotting revealed that the protein expression levels of Bcl-2, X-linked inhibitor of apoptosis protein (XIAP) and c-Myc were upregulated in HL-60R cells compared with those in HL-60 cells, along with predominant nuclear localization of the p50 and p65 subunits of NF-κB in HL-60R cells. Furthermore, the antitumor effect of LQB-118 pterocarpanquinone was investigated; this compound induced apoptosis, a reduction in cell viability and a decrease in XIAP expression in cytarabine-resistant cells. Taken together, these data indicated that acquired cytarabine resistance in AML was a multifactorial process, involving chromosomal aberrations, and differential expression of apoptosis and cell proliferation signaling pathways. Furthermore, LQB-118 could be a potential alternative therapeutic approach to treat cytarabine-resistant leukemia cells.

Eltrombopag and its iron chelating properties in pediatric acute myeloid leukemia

“…Hence, we studied the effect of treatments on cell viability, apoptosis, cell cycle progression and proliferation. First of all, we showed that cytarabine reduced cell viability and also increases apoptosis levels in THP-1 cells, as already demonstrated in other leukemia cell lines [38]. DFX and ELT instead did not affect cell viability when alone but exacerbated the effect of cytarabine, especially ELT, thus letting hypothesize…”

“…ELT is able also to increase the pro-apoptotic effects of cytarabine, as demonstrated by cytofluorimetry and by the significant increase in BAX/Bcl-2 protein expression levels ratio. Bcl-2 protein is normally responsible for inhibiting apoptosis and in case of resistance to cytarabine it is often up-regulated [ 38 ]. An increase in BAX/Bcl-2 ratio indicates a prevalence of the pro-apoptotic processes and interestingly in THP-1 cell line this beneficial anticancer effect is evident only when cytarabine is combined with ELT.…”

“…Therefore, it could be interesting to investigate on the hypothesis formulated by Shi et al ., which observed an arrest in G0/G1 phase after treating leukemia cells with ELT and decitabine [ 37 ] and attributed this anticancer effect to the alteration in intracellular ROS levels caused by ELT [ 40 ]. We also evaluated the effect of treatments on cell proliferation by analyzing the expression levels of nuclear transcription factor-kappa beta (NFkB), one of the principal mediators of inflammation, carcinogenesis [ 45 , 46 ] and chemotherapy resistance [ 38 ]. NFkB pathway is also involved in iron metabolism and in particular its inhibition reduces iron overload [ 47 ].…”

“…ELT is able also to increase the pro-apoptotic effects of cytarabine, as demonstrated by cytofluorimetry and by the significant increase in BAX/ Bcl-2 protein expression levels ratio. Bcl-2 protein is normally responsible for inhibiting apoptosis and in case of resistance to cytarabine it is often up-regulated [38].…”

Targeting Apoptosis to Overcome Chemotherapy Resistance

“…PR-619, a deubiquitinating enzyme (DUB) inhibitor, enhanced the antitumor effects of cisplatin in cisplatin-naïve and -resistant metastatic urothelial carcinoma both in vitro and in vivo through suppressing anti-apoptotic BCL-2 protein (132). The pterocarpanquinone LQB-118 compound induced apoptosis and reversed cytarabine-resistance in AML cells (133). Calmodulin can directly biund to DR5 in a Ca 2+ dependent manner.…”