sildenafil-citrate and Lymphoma--T-Cell

Cyclic nucleotide phosphodiesterase 5 (PDE5) has been recently identified to play a crucial role in the progression of many cancers. PDE5 promotes tumorigenesis by dysregulating various cellular processes such as proliferation, apoptosis, angiogenesis, and invasion and migration. Interestingly, multiple studies have reported the promising chemosensitizing potential of PDE5 inhibitor sildenafil in breast, colon, prostate, glioma, and lung cancers. However, to date, the chemosensitizing action of sildenafil is not evaluated in T cell lymphoma, a rare and challenging neoplastic disorder. Hence, the present investigation was undertaken to examine the chemosensitizing potential of sildenafil against T cell lymphoma along with elucidation of possible involvement of altered apoptosis and glucose metabolism. The experimental findings of this study showed that sildenafil enhances the cytotoxic ability of cisplatin by apoptosis induction through altering the levels of apoptosis regulatory molecules: Bcl-2, Bax, cytochrome c (Cyt c), cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP). These molecular alterations were possibly driven by sildenafil through reactive oxygen species (ROS). Sildenafil deregulates glucose metabolism by markedly lowering the expression of glycolysis regulatory molecules, namely glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), hexokinase II (HKII), pyruvate kinase M2 (PKM2), and pyruvate dehydrogenase kinase 1 (PDK1) via suppressing hypoxia-inducible factor 1-alpha (HIF-1α) expression. Hence, sildenafil potentiates the tumor cell killing ability of cisplatin by augmenting ROS production through switching the glucose metabolism from glycolysis to oxidative phosphorylation (OXPHOS). Overall, our study demonstrates that sildenafil might be a promising adjunct therapeutic candidate in designing novel combinatorial chemotherapeutic regimens against T cell lymphoma.

Topics: Apoptosis; Cell Line, Tumor; Cisplatin; Glucose; Glycolysis; Humans; Lymphoma, T-Cell; Male; Phosphodiesterase 5 Inhibitors; Reactive Oxygen Species; Sildenafil Citrate

Romidepsin, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of relapsed and refractory peripheral T-cell lymphoma. However the use of romidepsin reportedly causes potent EBV (Epstein-Barr virus) reactivation leading to severe adverse events in patients with natural killer (NK)/T-cell lymphoma (NKTL). As inhibition of EBV lytic cycle reactivation may help prevent romidepsin-induced adverse events in NKTL, we herein set out to identify a safe and effective drug for inhibiting EBV reactivation and examine its mechanism of inhibition. EBV reactivation was evaluated by qRT-PCR of BZLF1 and BRLF1 mRNA expression, qPCR of EBV DNA, and immunoblotting of viral EA-D protein. High-throughput screening of FDA-approved drugs was performed to identify safe and effective molecules and test their effect on romidepsin-induced EBV reactivation in the EBV-positive NKTL cell lines, SNK6 and NK92MI. We found that phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra; Pfizer), appeared to be nontoxic and effective inhibitors of romidepsin-induced EBV reactivation. Clinical relevance was investigated by qPCR of EBV in two primary effusion samples of NKTL patients. We also investigated the molecular consequences downstream of sildenafil-induced PDE5 inhibition in NKTL cells. A negative correlation was established between the cGMP/PKG pathway and EBV reactivation in NKTL cells. On a molecular level, PDE5 inhibition downregulates BZLF1 and BRLF1 through cGMP/PKG signaling-induced ZNF overexpression. Co-treatment with romidepsin and sildenafil (inhibiting HDAC and PDE5, respectively) showed a synergistic inhibitory effect on NKTL cells, highlighting PDE5 as an attractive target for future therapy in NKTL.

Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Depsipeptides; DNA, Viral; Down-Regulation; Enzyme Inhibitors; Epstein-Barr Virus Infections; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Viral; Herpesvirus 4, Human; Histone Deacetylase Inhibitors; Humans; Immediate-Early Proteins; Lymphoma, T-Cell; Phosphodiesterase 5 Inhibitors; Signal Transduction; Sildenafil Citrate; Trans-Activators; Virus Activation; Zinc Fingers