9 - Metabolic engineering strategies to enhance the production of anticancer drug, paclitaxel

Abstract

Paclitaxel, an important diterpenoid with a taxane skeleton, is isolated from Taxus species (yew tree), and used as a component of anticancer drugs. The U.S Food and Drug Administration (FDA) has approved paclitaxel for treating many cancer types, such as breast, lung and ovarian cancers and Kaposi’s sarcoma. Furthermore, it is also known as a crucial agent for arterial stents to prevent the formation of scar tissues. Yew trees grow slowly, and yield low levels of paclitaxel (0.01%–0.03% of the dry weight), and hence extracting paclitaxel from the trees on a large scale is very challenging. Recently, a great number of yew trees have been destroyed by humans for the extraction of this important drug. Therefore, alternative ways, including metabolic engineering approach should be explored to enhance the production of paclitaxel. For instance, abiotic and biotic elicitors are generally employed to enhance the production of pharmaceutical terpenoids. Several research groups have successfully identified few effective elicitors, including coronatine, salicylic acid (SA), methyl jasmonate (MJ) and abscisic acid to induce paclitaxel accumulation in suspension cell lines. The biotic elicitor MJ, known for regulating plant defense was found as a very effective molecule to induce overproduction of paclitaxel in Taxus cell suspension cultures. In addition to elicitors, higher paclitaxel production was observed in bioreactors through co-culturing of Taxus cells with its endophytic fungi. In previous studies, many genes and enzymes involved in the biosynthetic pathways of taxanes have been partially identified in Taxus species tissues and cells. Overexpression of genes involved in paclitaxel synthesis is another remarkable tactic to enhance the production of this target drug. In this chapter, molecular engineering strategies such as elicitors, overexpression of genes involved in paclitaxel biosynthesis, and ectopic expression to produce higher amounts of paclitaxel are discussed.