Piperlongumine promotes death of retinoblastoma cancer cells.

Nathalie Allaman-Pillet,Daniel F Schorderet

doi:10.18632/oncotarget.27947

Abstract

Retinoblastoma is the most common pediatric intraocular malignant tumor. While retinoblastoma initiation is triggered by the inactivation of both alleles of the retinoblastoma tumor suppressor gene (RB1) in the developing retina, tumor progression requires additional epigenetic changes, retinoblastoma genomes being quite stable. Although the management of RB has recently improved, new therapeutic agents are necessary to improve the treatment of advanced forms of retinoblastoma.In this report, we analyzed the pro-death effect of piperlongumine (PL), a natural compound isolated from Piper longum L., on two human retinoblastoma cell lines, WERI-Rb and Y79. The effects of PL on cell proliferation, cell death and cell cycle were investigated. PL effectively inhibited cell growth, impacted the cell cycle by decreasing the level of cyclins and CDK1 and increasing CDKN1A and triggered a caspase-3 independant cell death process in which reactive oxygen species (ROS) production is a major player. Indeed, PL toxicity in retinoblastoma cell lines was inhibited by a ROS scavenger N-acetyl-l-cysteine (NAC) treatment. These findings suggest that PL reduces tumor growth and induces cell death by regulating the cell cycle.

Highlights

Retinoblastoma is a malignant tumor derived from photoreceptor precursor cells
Other mechanisms than apoptosis should be involved in WERI-Rb killing as the broad-spectrum caspase inhibitor Z-VAD-FMK had no effect when added to WERI-Rb exposed to PL (Figure 1A)
It is well known that cancer cells have developed the capacity to reprogram their energy metabolism to survive in a rough environment [34, 35]

Summary

Introduction

Retinoblastoma is a malignant tumor derived from photoreceptor precursor cells. It affects retina at a very early stage of childhood with an incidence of one case per 15,000–20,000 live births and represents 4% of all pediatric malignancies [1]. The survival rate of patients with retinoblastoma is extremely high in developed countries, left untreated advanced tumors limit eye preservation and expose patients to risks of metastasis and death. A multi-step model for the progression of normal retina to retinoblastoma has been proposed [3], the first step being the inactivation of both alleles of the tumor suppressor gene RB1 in the developing retina. Even if the survival rate of children with RB is high (more than 85%), developing effective therapeutic strategies is the key to significantly improve the overall survival in patients

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