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Betulinic acid (BA) is a pentacyclic triterpene natural product and is readily synthesized from betulin (lup-20(29)-ene-3β, 28-diol), a major chemical constituent of birch bark. BA is initially identified as a melanoma-specific cytotoxic agent which exhibits low toxicity in animal models. Subsequent studies show that BA induces apoptosis and antiangiogenic responses in tumors derived from multiple tissues; however, the underlying mechanism of action is unknown. Specificity proteins (Sps) such as Sp1, Sp3 and Sp4 are transcription factors overexpressed in many tumors, and these proteins are critical for cancer cell growth, survival (antiapoptosis), and angiogenesis. Using LNCaP prostate cancer cells as a model, we now show that BA decreases expression of vascular endothelial growth (VEGF) and the antiapoptotic protein survivin. The mechanism of these BA-induced antiangiogenic and proapoptotic responses in both LNCaP cells and in tumors is due to activation of selective proteasome-dependent degradation of the transcription factors Sp1, Sp3 and Sp4 which regulate VEGF and survivin expression. Thus, BA acts as a novel anticancer agent through targeted degradation of Sp proteins which are highly overexpressed in tumors.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA