Podophyllotoxin–pterostilbene fused conjugates as potential multifunctional antineoplastic agents against human uveal melanoma cells

Uveal melanoma is the most common primary intraocular malignancy with a high tendency for early metastasis. There is an urgent need for novel anticancer agents for the therapy of uveal melanoma. In this paper, two novel conjugates of podophyllotoxin–pterostilbene were prepared and evaluated for their cytotoxicity against human uveal melanoma cells (MUM-2B and C918) by the CCK-8 assay. Conjugate B1 exhibited a significant IC50 value of 0.081 ± 0.004 μM against MUM-2B cells. Treatment of MUM-2B cells with B1 caused S cell cycle arrest through reductions in CyclinB1, CDK1 and CDK2 levels. In addition, B1 showed antimigratory activity by down-regulating the expression of VEGFR-2 and MMP-2, and up-regulating the level of E-cadherin. Furthermore, B1 treatment resulted in the induction of apoptosis as characterized by Hoechst 33342 staining, flow cytometry and cleavage of procaspases-3, -8, and -9. Finally, B1 significantly inhibited TOPOIIα and TOPOIIβ expression, simultaneously suppressing the ERK1/2 and AKT pathways in MUM-2B cells.