Targeting apoptosis pathway with natural terpenoids: implications for treatment of breast and prostate cancer

Abstract

Terpenoids represent a large and diverse class of naturally occurring compounds found in a variety of fruits, vegetables and medicinal plants. Structurally some of the terpenoids are similar to human hormones. A diet rich in terpenoids is inversely related with the risk of chronic diseases including cancers. Breast and prostate cancers are hormone-related diseases and the second leading cause of female and male cancer mortality. Diterpenoid paclitaxel, and its semi-synthetic analogue docetaxel, have entered clinical use against established breast and prostate cancers. Here we reviewed potential molecular targets and biological properties of natural terpenoids, including monoterpenoids, diterpenoids, triterpenoids and tetraterpenoids, and their applications in treatment of human breast and prostate cancers. These terpenoids are able to inhibit tumor cell proliferation and induce tumor cell death by inhibiting multiple cancer-specific targets including the proteasome, NF-kappaB, and antiapoptotic protein Bcl-2. The efficacy of these terpenoids against breast or prostate cancer cells, as demonstrated in pre-clinical studies support clinical application of these naturally occurring terpenoids in treatment of hormone-related human cancers.

Fig. 1. Inhibition of the proteasome and NF-κB pathways by selected terpenoids

The proteasome contains a 20S multicatalytic core and one or two 19S regulatory caps. IκB–α, a proteasome substrate traps the active form of NF-κB (a dimer of RelA and p50, or of RelB and p52) in the cytosol. NFκB p50 or p52 are generated from the inactive precursor p105 or p100, respectively, through proteasome partial cleavage. After phosphorylation by IKK, a polyubiquitin chain (red square, ubiqutin) is attached to IκB-α with the help of β-TrCP E3 ligase. Then IκB-α is recognized and degraded by the proteasome, setting NF-κB free. The free, active NF-κB complex then enters into nucleus to transactivate target genes required for tumor proliferation. The selected terpenoids could target the ubiquitin-proteasome and NF-κB pathways at indicated specific steps, resulting in apoptosis induction and tumor growth inhibition.

Fig. 2. Chemical structure of selected terpenoids I

Structures of monoterpenoids and diterpenoids are shown.

Fig. 3. Chemical structure of selected terpenoids II

Structures of tritenpenoids and tetraterpenoids are shown.

Fig. 4. Molecilar docking of celastrol and pristimerin

A, High susceptibility towards nuceophilic attack of celastrol molecule was indicated by red center. B, Celastrol was docked the S₁ pocket of β5 subunit of the proteasome as shown by blue smesh. The distances from ketone carbons to OH group of Thr1 were 2.96 or 4.16 Å. C, Similarly, high electronic density was obtained at the ketone carbons surface of the pristimerin molecule. D, Pristimerin was shown in a confirmation that is suitable to interact with the OH group of Thr 1 of β5 subunit as shown by rainbow lines. The distances from ketone carbons to OH group of Thr1 were 3.15 or 4.05 Å. The celastrol and pristimerin molecules were shown in pink sticks.