Induction of apoptotic cell death specifically in rat and human cancer cells by pancratistatin

Abstract

The major challenge in the battle against cancer is the specific targeting of cancer cells. Most chemotherapeutics and radiotherapies induce cancer cell death by inducing DNA damage. These treatments also cause severe side effects by affecting normal cells causing toxicity and mutations that may predispose them to become cancerous. Some non-genotoxic drugs such as tamoxifen are useful but are of limited applicability. Natural compounds such as paclitaxel have been useful in cancer treatment, but due to its effect as a general microtubule stabilizer and genotoxic agent, it also induces death of normal cells. Pancratistatin is a natural compound isolated from Pancratium littorale that has been shown to have anti-viral and anti-neoplastic activity. The objective in the present study was to elucidate the mechanism of the anti-neoplastic action of pancratistatin and evaluate the specificity of this compound for cancer cells.

Methods: We used cancer cell lines and normal human endothelial and fibroblast cells to investigate the effect of pancratistatin treatment. Further, we compared the toxic effects of paclitaxel and VP-16 to that of pancratistatin on non-cancerous cells.

Results: Pancratistatin induced apoptosis in all the cancer cell lines used in this study at sub-micromolar concentrations. Interestingly, normal human fibroblasts and endothelial cells remained unaffected by pancratistatin treatment under identical conditions whereas paclitaxel and VP-16 were both toxic to these two normal cell lines.

Conclusion: The capability of pancratistatin to selectively induce apoptosis in cancer cells is an exciting finding and makes it a suitable anti-cancer agent. Since pancratistatin shows little structural similarity to any DNA intercalating drug or to paclitaxel derivatives, it appears to be non-genotoxic. Additionally, due to the unprecedented differential cytotoxicity observed in cancerous cells, we believe pancratistatin may act upon a novel target, allowing selective induction of apoptosis in cancer cells.