PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells

Abstract

We determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with clinically relevant chemotherapies to kill medulloblastoma cells. In medulloblastoma cells PDE5 inhibitors interacted in a greater than additive fashion with vincristine/etoposide/cisplatin to cause cell death. Knockdown of PDE5 expression recapitulated the combination effects of PDE5 inhibitor drugs with chemotherapy drugs. Expression of dominant negative caspase 9 did not significantly inhibit chemotherapy lethality but did significantly reduce enhanced killing in combination with the PDE5 inhibitor sildenafil. Overexpression of BCL-XL and c-FLIP-s suppressed individual and combination drug toxicities. Knockdown of CD95 or FADD suppressed drug combination toxicity. Treatment with PDE5 inhibitors and chemotherapy drugs promoted autophagy which was maximal at ~12 h post-treatment, and in a cell type-dependent manner knockdown of Beclin1 or ATG5 either suppressed or enhanced drug combination lethality. PDE5 inhibitors enhanced the induction of chemotherapy-induced DNA damage in a nitric oxide synthase-dependent fashion. In conclusion, our data demonstrate that the combination of PDE5 inhibitors with standard of care chemotherapy agents for medulloblastoma represents a possible novel modality for future treatment of this disease.

PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer

“…PDE5 inhibitors enhanced and prolonged the induction of DNA damage as judged by Comet assays along with histone H2AX and checkpoint kinase-2 (CHK2) phosphorylation. Sildenafil was also found to interact with multiple standard of care chemotherapeutic agents (vincristine, etoposide, and cisplatin) in an additive fashion to kill medulloblastoma cells by induction of DNA damage in a NO synthase-dependent pathway (Roberts et al, 2014). These results suggested that sildenafil enhances chemotherapeutic efficacy through both death receptor and mitochondrial signaling as part of the combinatorial killing process.…”

“…In recent years, there has been tremendous interest in identifying new clinical uses of PDE5 inhibitors in various ailments including cardiovascular disease (Kukreja et al, 2004; Kukreja et al, 2005; Kukreja et al, 2011), diabetes (Giannetta et al, 2012; Koka et al, 2012; Koka et al, 2013; Koka et al, 2014; Varma et al, 2012) and cancer (Black et al, 2008; Booth et al, 2014a; Booth et al, 2014c; Booth et al, 2014b; Das et al, 2010; Hamilton et al, 2013; Resnick et al, 2009; Roberts et al, 2014). Today, close to 100 clinical trials (http://www.clinicaltrials.gov) with PDE5 inhibitors focusing on the potential cardiovascular benefits have been completed or are ongoing.…”

Autophagy is not uniformly cytoprotective: a personalized medicine approach for autophagy inhibition as a therapeutic strategy in non-small cell lung cancer

“…In small cell lung cancer, autophagy appeared to protect against both cisplatin and etoposide cytotoxicity 42 while in leukemic cells, the opposite outcome was observed in that activation of autophagy increased sensitivity to both etoposide and adriamycin 43 . In several medulloblastoma cell lines, the combination of etoposide and sildenafil (utilized as a potential sensitizer to chemotherapy) resulted in different functions of autophagy in a cell line-dependent manner 44 . siRNA-mediated silencing of ATG5 and Beclin-1 resulted in increased sensitization (by trypan blue exclusion) of HOSS1 cells to the etoposide/sildenafil combination while it decreased sensitivity to the same combination in DAOY and D283 cell lines.…”

Role of Nitric Oxide Synthase in Normal Brain Function and Pathophysiology of Neural Diseases

“…Then, they co-treated cells with L-NAME and found out that NOS inhibition accompanying PDE5 inhibitors suppressed cell killing. Most probably NO/NOS has a role in killing of medulloblastoma cells [81]. A study done in knockout mice exhibited that iNOS has an important role in medulloblastoma formation.…”