Bioprocessing of Plant In Vitro Systems for the Mass Production of Pharmaceutically Important Metabolites: Paclitaxel and its Derivatives

M.      Onrubia; R.M.      Cusido; K.      Ramirez; L.      Hernandez-Vazquez; E.      Moyano; M.      Bonfill; J.      Palazon

Abstract

Taxol (paclitaxel) and its derivatives are microtubule-stabilizing drugs widely used in the treatment of several types of cancer, including mammary, prostate, ovarian and non-small-cell lung carcinoma, as well as AIDS-associated Kaposi’s sarcoma and other types of tumor. Taxanes stabilize microtubules by enhancing their polymerization and inhibiting depolymerization. Microtubule dynamics are crucial to mitotic spindle formation and function; therefore, cells exposed to taxanes are unable to undergo chromosomal separation during mitosis, become arrested in the G2/M phases of the cell cycle, and are subsequently targeted for apoptosis. Plant cell cultures are used for industrial-scale biotechnological production of important bioactive plant secondary metabolites, including the anticancer agent paclitaxel. In the last two decades, there have been numerous empirical approaches to improve the biotechnological production of taxanes, leading to the conclusion that treatment of Taxus sp. cells with methyl jasmonate or other elicitors is the most effective strategy. However, little insight has been gained into how the elicitors increase taxane biosynthesis or how this process is regulated. In recent years, with the help of “omics” tools, a rational approach has provided new information about taxane metabolism and its control. Once pathway bottlenecks have been identified, it will be possible to engineer Taxus sp. cell lines with overexpression of genes that control the fluxlimiting steps, thus boosting taxane productivity. This review describes the chemical and biological characterization of paclitaxel and its derivatives and discusses future prospects for their biotechnological production.

Keywords: Anticancer agents, metabolic engineering, paclitaxel, plant cell cultures, taxane analogs, Taxus sp, microtubule-stabilizing drugs, non-small-cell lung, AIDS-associated, depolymerization