Attenuation of pro-tumorigenic senescent secretory phenotype by StN, a novel derivative of stevioside, potentiates its inhibitory activity on hepatocellular carcinoma.

Ent-13-Hydroxy-15-kaurene-19-acid N-Methylpiperazine Ethyl Ester (StN) is a novel derivative of the natural diterpene stevioside isolated from Stevia rebaudiana (Bertoni). In this study, we examined the effects of StN against hepatocellular carcinoma (HCC) in vitro and in vivo as well as its anticancer mechanisms by inhibiting proliferation and regulating the senescence-associated secretory phenotype (SASP). We showed that StN significantly inhibited HCC cell proliferation by inducing cellular senescence, as observed by increased senescence-associated β-galactosidase activity and cell cycle arrest. Mechanistically, StN impaired lysosomal stability and triggered the release of cathepsin B from the lysosomes into the nucleus where it promoted DNA damage. Cathepsin B-mediated DNA damage contributed to cellular senescence triggered by StN. Meanwhile, StN transcriptionally suppressed multiple pro-inflammatory SASP components, including IL-6, IL-1α, IL-1β, and IL-8, resulting in the reduction of pro-tumorigenic impact of SASP. Further study revealed that StN inactivated NF-κB and PI3K/Akt signaling, which significantly accounted for its inhibition on the SASP factors. In HCC xenograft mice, administration of StN significantly suppressed tumor growth, while no significant toxicity was detected. This study demonstrates a novel mechanism that suppressing the SASP by StN in senescent cells potentiates its anticancer efficacy, thus defining a potential compound for cancer treatment.