Combination of ERK2 inhibitor VX-11e and voreloxin synergistically enhances anti-proliferative and pro-apoptotic effects in leukemia cells.

ERK1/2 inhibitors are new promising anticancer drugs. The aim of this study was to investigate the effect of the combination of ERK2 inhibitor VX-11e and voreloxin on MOLM-14, K562, REH and MOLT-4 leukemia cell lines. We found that VX-11e alone and in combination with voreloxin significantly decreased ERK activation in all cell lines tested. To evaluate the interactions of the drugs, cells were treated for 24 h with VX-11e or voreloxin alone and in combination at fixed ratios based on IC50 values. The combinatorial effects of both drugs were synergistic over a wide range of concentrations in MOLM-14, REH and MOLT-4 cell lines. In K562 cells, three effects were found to be additive, one antagonistic and only one synergistic. The results showed that incubation with both VX-11e and voreloxin inhibited the growth of leukemia cells, affected cell cycle and induced apoptosis. Furthermore, the molecular mechanism of these effects might be attributed to an increased expression of p21 and a decreased expression of survivin and NF-κB in all cell lines tested except from K562 cells. In conclusion, combination of VX-11e and voreloxin can exert a synergistic anticancer effect in leukemia cells.

1,8-Naphthyridine Derivatives: A Privileged Scaffold for Versatile Biological Activities.

1, 8- Naphthyridine nucleus belongs to significant nitrogen-containing heterocyclic compounds which has garnered the interest of researchers due to its versatile biological activities. It is known to be used as an antimicrobial, anti-psychotic, anti-depressant, anti-convulsant, anti- Alzheimer's, anti-cancer, analgesic, anti-inflammatory, antioxidant, anti-viral, anti-hypertensive, antimalarial, pesticides, anti-platelets, and CB2 receptor agonist, etc. The present review highlights the framework of biological properties of synthesized 1, 8-naphthyridine derivatives developed by various research groups across the globe.

TAK-733, a Selective MEK Inhibitor, Enhances Voreloxin-induced Apoptosis in Myeloid Leukemia Cells.

BACKGROUND/AIM: MEK inhibitors are new promising anticancer drugs. The aim of this study was to investigate the effect of the combination treatment of voreloxin with the MEK inhibitor TAK-733 on HL60 myeloid leukemia cells. MATERIALS AND METHODS: MAPK activity, cell viability, apoptosis, oxidative stress induction and AIF (apoptosis-inducing factor) distribution were assessed in HL60 cells cultured with each drug alone or with both drugs. RESULTS: TAK-733 alone at 5 µM significantly reduced MAPK activity and did not influence viability and apoptosis in HL60 cells. Voreloxin at concentration of 0.03-0.48 µM reduced cell viability and increased apoptosis rate. Incubation with both drugs caused further inhibition of cell viability and increased apoptosis associated with generation of reactive oxygen species (ROS) and nuclear translocation of AIF. CONCLUSION: Combination of TAK-733 and voreloxin can exert a synergistic anticancer effect in myeloid leukemia cells.

Vosaroxin is a novel topoisomerase-II inhibitor with efficacy in relapsed and refractory acute myeloid leukaemia.

INTRODUCTION: Vosaroxin is a first-in-class anti-cancer quinolone that inhibits topoisomerase-II leading to cell cycle arrest and apoptosis. It has shown efficacy in a range of solid organ and haematopoietic tumours in vitro, and several clinical trials are underway or completed in the field of Acute Myeloid Leukaemia (AML). The treatment of relapsed and refractory AML is a clinical challenge, where long-term survival is rare without allogeneic haematopoietic stem cell transplantation. AREAS COVERED: We review the data from the published clinical trials of vosaroxin, including the recently presented Phase III VALOR study. In combination with intermediate dose cytarabine, vosaroxin almost doubled complete response (CR) rates in relapsed and refractory AML compared with cytarabine alone, and prolonged median survival by 1.4 months. EXPERT OPINION: Vosaroxin is a promising new agent in the treatment of AML, with the potential to improve CR rates in a high-risk group of patients with relapsed and refractory AML. However, higher CR rates have been associated with higher rates of treatment-related morbidity and mortality, especially in elderly/unfit patients. Maximising the potential of vosaroxin will therefore require the identification of patients most likely to benefit from vosaroxin-containing combination regimens.