The Occurrence, Uses, Biosynthetic Pathway, and Biotechnological Production of Plumbagin, a Potent Antitumor Naphthoquinone.

Plumbagin is an important naphthoquinone with potent anticancer properties besides multitudinous uses in healthcare. It is produced in a limited number of species and families but mostly in the roots of Plumbaginaceae family members. The biosynthetic pathway and the genes that regulate plumbagin synthesis are not completely known, but details of these are being revealed. Several species, including , , and others, are being uprooted for the extraction of plumbagin by pharmaceutical industries, leading to the destruction of natural habitats. The pharmaceutical industry is therefore facing an acute shortage of plant material. This necessitates enhancing the accumulation of plumbagin using suspensions and hairy roots to meet market demands. Many factors, such as the aggregate size of the inoculum, stability of the culture, and the sequential effects of elicitors, immobilization, and permeabilization, have been demonstrated to act synergistically and markedly augment plumbagin accumulation. Hairy root cultures can be used for the large-scale production, growth, and plumbagin accumulation, and the exploration of their efficacy is now imperative. The secretion of compounds into the spent medium and their in situ adsorption via resin has remarkable potential, but this has not been thoroughly exploited. Improvements in the quality of biomass, selection of cell lines, and production of plumbagin in bioreactors have thus far been sporadic, and these parameters need to be further exploited. In this review, we report the advances made relating to the importance of stable cell line selection for the accumulation of compounds in long-term cultures, hairy root cultures for the accumulation of plumbagin, and its semicontinuous production via total cell recycling in different types of bioreactors. Such advances might pave the way for industrial exploitation. The steps in the biosynthetic pathway that are currently understood might also aid us in isolating the relevant genes in order to examine the effects of their overexpression or heterologous downregulation or to edit the genome using CRISPR-Cas9 technology in order to enhance the accumulation of plumbagin. Its potential as an anticancer molecule and its mode of action have been amply demonstrated, but plumbagin has not been exploited in clinics due to its insolubility in water and its highly lipophilic nature. Plumbagin-loaded nanoemulsions, plumbagin-silver, or albumin nanoparticle formulations can overcome these problems relating to its solubility and are currently being tried to improve its bioavailability and antiproliferative activities, as discussed in the current paper.