New curcumin analogues with enhanced growth suppressive activity in cancer cells

Abstract

1235

Curcumin, the active ingredient found in the rhizome of the tumeric plant (Curcuma longa), is one of the most widely studied and characterized of the phytochemicals. In addition to its well known antioxidant, anti-inflammatory, anti-proliferative, and anti-angiogenic effects; curcumin has been shown to prevent carcinogenesis and tumor formation as well as suppress metastasis in a variety of human and animal tumor models. Curcumin is not cytotoxic, however; as Phase I clinical trials have shown it to be safe in humans at dosages as high as 12 grams per day. Unfortunately, the bioavailability of curcumin is poor; apparently due to poor absorption, rapid metabolic conversion, and rapid systemic elimination. Additionally, the growth suppressive studies of curcumin show it to be not as effective, or potent, as many cytotoxic agents currently in use. To circumvent this problem, several novel analogues of curcumin were synthesized and tested in cancerous colon, breast, and pancreatic cell lines. Our preliminary results demonstrate that these new analogues are ten to thirty times more potent at inhibiting cellular viability of these cancerous cell lines than do curcumin. Additionally, these same concentrations of curcumin analogues have a much lower inhibitory effect on normal human mammary epithelial cells and human bladder cells as curcumin does. These new curcumin analogues also are capable of inducing apoptosis in cancer cells, as evidenced by the cleaved-PARP, at lower doses (2.5-5 µM) than curcumin (20 µM or higher). Curcumin’s ability to inhibit signal transducer and activation of transcription 3 (STAT3) and AKT/PKB, two important oncogenic pathways may contribute to its growth suppressive activities. For this reason, we further examined the potency of the new curcumin analogues of these two pathways. Our results indicate that these two pathways are inhibited at lower concentrations of the curcumin analogues (5 µM or lower) than that required of curcumin (20 µM or higher). These preliminary results indicate that the new curcumin analogues exhibit the potential to be used in the treatment of human cancers and, thus, warrant further research and development.