Phenanthridone alkaloids of the Amaryllidaceae as activators of the apoptosis-related proteolytic enzymes, caspases

Abstract

Apoptosis-inducing anticancer drugs have garnered widespread interest in recent years. Targets which concomitantly also exhibit minimal adverse effects in normal, healthy cells have been particularly well-received. The phenanthridone alkaloids such as pancratistatin and narciclasine exemplify such a class of chemotherapeutics, with potent and selective cytotoxic effects in a wide variety of cancer cells which are manifested via the apoptotic mode of cell death. Caspases are central to the apoptotic process through their key function as effector molecules in apoptosis-related signaling pathways. Any attempt to mediate in such pathways, for example to probe the efficacy or mechanism of action of a drug, would inexorably serve to have a modulatory effect on these proteolytic enzymes. Apoptosis studies of phenanthridone alkaloids of the Amaryllidaceae have only gathered momentum over the past decade, following which caspases have understandably emerged as reliable biochemical markers of the process in an assortment of cancers. This review covers such studies of these alkaloids based on their structural-type, pointing out the various caspases which have been activated in different cancer cells and how structure modification can to a certain extent have a bearing on such activity. Also considered are clues to the apoptosis signaling pathways mediated following phenanthridone-induced activation of caspases.