Effect of pentacyclic triterpenes found in Perilla frutescens alone or in combination with resveratrol on skin tumor promotion by 12-o-tetra-decanoylphorbol-13-acetate

Abstract

A series of pentacyclic triterpenes found in P. frutescens, including ursolic acid (UA), oleanolic acid (OA), augustic acid (AA), corosolic acid (CA), 3-epi-corosolic acid (3-epiCA), maslinic acid (MA), and 3-epi-maslinic acid (3-epiMA) were evaluated for their effects on skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). UA was also evaluated in a combination with resveratrol (Res) for possible combinatorial chemopreventive activity. All triterpene compounds significantly inhibited skin tumor promotion by TPA. MA and 3-epiCA, were significantly more effective than UA at inhibiting tumor development. Topical pretreatment with all of these compounds significantly inhibited epidermal proliferation induced by TPA, however, CA, 3-epiCA and MA were more effective than UA. All compounds reduced skin inflammation and inflammatory gene expression induced by TPA, however, 3-epiCA and MA were identified to be more effective than UA. Finally, the ability of these compounds to alter epidermal signaling pathways associated with skin tumor promotion by TPA was also evaluated. The greater ability of 3-epiCA and MA to inhibit skin tumor promotion was associated with greater reduction of Cox-2 and Twist1 proteins and inhibition of activation of IGF-1R, Stat3 and Src. The effect of combining UA + Res for combinatorial inhibitory effects on skin tumor promotion were also examined. The combination of UA + Res produced a greater inhibition of TPA-induced epidermal hyperproliferation, epidermal inflammatory signaling, and inflammatory gene expression when compared to UA or Res alone. Furthermore, NF-kB, Egr-1, and AP-1 DNA binding activities following TPA treatment were dramatically decreased by the combination of UA + Res. Treatment with UA + Res during skin tumor promotion by TPA produced greater inhibition of tumor multiplicity and tumor size than with either agent alone. Collectively, the current data demonstrate that UA and related triterpenes as well as the combination of UA + Res inhibited skin tumor promotion by TPA via effects on multiple cellular and biochemical/molecular mechanisms associated with this process similar to calorie restriction. Of the tritperpenes tested, 3-epiCA and MA were the most active. Furthermore, the favorable anti-tumor promoting effects of combining UA + Res suggest that phytochemical combination therapy may be a more efficacious strategy for cancer chemoprevention.