Aspirin Inhibits Natural Killer/T-Cell Lymphoma by Modulation of VEGF Expression and Mitochondrial Function

Abstract

Extranodal nasal-type natural killer/T-cell lymphoma (NKTCL) is an Epstein-Barr virus (EBV)-associated lymphoma with a strong tendency relapse or be refractory in response to chemotherapy. Development of a new strategy for NKTCL treatment is still quite necessary. In this study, we found that aspirin treatment suppresses VEGF expression in NKTCL SNK-6 cells. Further investigation showed that aspirin treatment increases histone methylation in the range of −100~0 that is proximal to the transcription start site on the VEGF promoter, subsequently decreasing the binding ability of Sp1 to the VEGF promoter with VEGF suppression. Furthermore, aspirin treatment modulates mitochondrial function with increased ROS formation and apoptosis in NKTCL cells. Aspirin treatment alone slightly inhibits NKTCL SNK-6 tumor growth and EBV replication; while in the presence of histone deacetylase inhibitor (HDACi) chidamide (CDM), aspirin significantly suppresses the VEGF signaling pathway with increased ROS overgeneration and EBV inhibition. We also showed that with the addition of chidamide, aspirin significantly suppresses NKTCL tumor growth in both in vitro cell culture and in vivo mouse model with prolonged mouse survival. This is the first time that the potential mechanism for aspirin-mediated VEGF suppression and anti-tumor effect has been discovered, and this study provides a new strategy for anti-tumor drug development for NKTCL treatment based on aspirin-mediated targeting of the VEGF signaling pathway and ROS formation.

HKDC1 C-terminal based peptides inhibit extranodal natural killer/T-cell lymphoma by modulation of mitochondrial function and EBV suppression

“…Tf-D-HKC8 peptide dissociates HKDC1 from VDAC1 and induces significant ROS overgeneration, subsequently resulting in EBV DNA damage and P-gp suppression. This is consistent with our previous finding that ROS overgeneration suppresses EBV-positive ENKTL cells [ 7 ]. P-gp is a membrane transporter coded by multiple drug resistance 1 gene that excretes drugs from the cytoplasm, resulting in high resistance to chemotherapy [ 9 ].…”

“…HKDC1 could be a novel potential therapeutic target for antitumor drug development [ 20 – 22 , 33 ]. ENKTL is highly resistant to current multidrug chemotherapies with a poor prognosis [ 6 , 7 ]. Many potential risk factors for ENKTL have been described [ 34 ], and EBV infection is considered to be the strongest one [ 31 ].…”

“…Advanced ENKTL progresses rapidly and relapses inevitably with multidrug chemoresistance, resulting in poor survival rates in just a few months. Currently, development of targeted therapy for ENKTL is still urgently needed [6,7].…”

Use of Oral Anticoagulation and Diabetes Do Not Inhibit the Angiogenic Potential of Hypoxia Preconditioned Blood-Derived Secretomes

“…ASA inhibits cyclooxygenase-1 (COX-1) in platelets, thereby blocking the production of prostaglandins [ 48 ] and the production of thromboxan-A 2 (TXA 2 ), leading to reduced platelet activation and aggregation [ 49 ]. Previous studies have demonstrated that ASA and its derivatives can alter the VEGF expression, leading to suppressed angiogenesis as a consequence, although how ASA decreases the VEGF expression remains unknown [ 50 , 51 , 52 , 53 ]. For example, in hypertensive patients who had significantly higher plasma levels of VEGF, there were significant reductions in VEGF plasma concentrations while following the treatment with ASA for three months, indicating that the use of ASA leads to a reduction in intraplatelet angiogenic growth factors and platelet activation [ 54 ].…”

Aspirin Induces Mitochondrial Ca2+ Remodeling in Tumor Cells via ROS‒Depolarization‒Voltage-Gated Ca2+ Entry

“…Aspirin and salicylate have been shown to evoke mitochondrial dysfunction. These two drugs induced loss of mitochondrial membrane potential (ΔΨ m ), decreased ATP production, and increased ROS generation in different cell types [ 23 , 24 , 25 ]. However, little is known about their effects on depolarization and role in mitochondrial dysfunction.…”