Triterpenoid pristimerin synergizes with taxol to induce cervical cancer cell death through reactive oxygen species-mediated mitochondrial dysfunction

Abstract

A combined treatment with conventional chemotherapies can enhance the effectiveness of chemotherapeutic agents against cancers. Here, we have shown that the naturally occurring triterpenoids synergistically enhance the response of cervical cancer cells to taxol. Of the triterpenoid compounds, pristimerin enhanced the anticancer effect of taxol with the highest efficiency by combination. Pristimerin synergizes with taxol to inhibit clonogenic survival and tumor growth in nude mice, and to enhance cell death in cervical cancer cells. A combined treatment with taxol and pristimerin induced cervical cancer cell death by increasing intracellular reactive oxygen species levels, upregulation of death receptor death receptor 5 (DR5), activation of Bax, and dissipation of mitochondrial membrane potential. Treatment with N-acetyl-L-cysteine, a thiol-containing antioxidant completely blocked combined treatment-induced Bax translocation as well as DR5 upregulation. Moreover, inhibition of Jun N-terminal kinase/c-Jun pathway attenuated cell death by blocking DR5 upregulation and Bax activation. These results indicate that the triterpenoid, pristimerin, synergistically enhances taxol response of cervical cancer cells through DR5 expression and Bax activation. Furthermore, the reactive oxygen species-dependent activation of the Jun N-terminal kinase/c-Jun pathway is required for the DR5 upregulation and Bax activation. The molecular mechanism revealed by this study may aid in the design of future combination cancer therapies against cells with intrinsically reduced sensitivity to taxol.

Pristimerin‐induced uveal melanoma cell death via inhibiting PI3K/Akt/FoxO3a signalling pathway

“…It has long been used as an anti‐malarial, anti‐inflammatory, anti‐oxidant and insecticide 2,3 . Recent studies have shown that Pristimerin potently induced anti‐proliferative and apoptosis activities in several human cancer cell lines, which originated from lung, breast, prostate, glioma, cervical, leukaemia and multiple myeloma tumours 2,4‐8 . Induction of apoptotic cell death by Pristimerin involved with different mechanisms, including caspase activation, proteasomes inhibition, mitochondrial dysfunction and different molecular mechanisms involved in the suppression of anti‐apoptotic NF‐κB, Akt and MAP kinases 9‐11 .…”

Novel activity of acriflavine against colorectal cancer tumor cells

“…gambogic acid, gambogic acid amide and tetragambogic acid). (16) Two other hit compounds, obutsaquinone (17) and pristimerin, (18) are also natural products. Only one of the hits, acriflavine, is a synthetic compound.…”

Pristimerin induces apoptosis of oral squamous cell carcinoma cells via G1 phase arrest and MAPK/Erk1/2 and Akt signaling inhibition

“…Apoptosis can be initiated either by the mitochondria (the intrinsic pathway) or through cell death receptors (the extrinsic pathway), leading to the activation of caspase cascades and resulting in apoptosis. Previous studies have reported that pristimerin may induce cell apoptosis via both the mitochondria and the death receptor-mediated extrinsic pathways in U87 glioma cells (29) and cervical cancer cells (30). Pristimerin likewise modulates the levels of B-cell lymphoma 2 (Bcl-2) family proteins, which are known to be involved in mitochondria-mediated apoptosis, in pancreatic cancer cells (31).…”