Prostate cancer cells frequently develop resistance toward
androgen-deprivation and
chemotherapy. To identify new approaches to treat
androgen-dependent
prostate cancer, we have performed a structure-activity analysis of
lignan polyphenols for
cancer cell specific sensitization to
tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL), a death
ligand that has ability to induce
tumor-specific cell death. In this study, we report that the
lignan nortrachelogenin (NTG) is the most efficient of the 27 tested
lignan compounds in sensitizing
prostate cancer cells to TRAIL-induced apoptosis. Importantly, pretreatment with NTG does not sensitize a non-malignant prostate cell line to TRAIL-induced cell death. The structural comparison of
lignans reveals that the dibenzylbutyrolactone skeleton is required for the apoptosis-sensitizing activity, while substitutions at the aromatic rings do not seem to play a critical role in this
lignan function. Our study also characterizes the cellular effects and molecular mechanisms involved in NTG anticancer activity. We previously reported that specific
lignans inhibit the Akt survival-signaling pathway in concert with TRAIL sensitization. While NTG is also shown to be a effective inhibitor of Akt signaling, in this study we further demonstrate that NTG potently inhibits
tyrosine kinase (RTK) activation in response to
growth factors, such as
insulin and
insulin-like growth factor I (
IGF-I). Our results identify NTG as a novel agent for
prostate cancer therapy with ability to inhibit Akt membrane localization and activity as well as the activation of
growth factor receptors (GFRs), thereby efficiently synergizing with TRAIL exposure.