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Page 12 of 17 Wenner et al. J Cancer Metastasis Treat 2020;6:33 I http://dx.doi.org/10.20517/2394-4722.2020.73

Figure 1. Schematic diagram representing the mechanism by which phytochemicals inhibit PI3k/mTOR pathway to induce autophagy.
Induction of autophagy ensues upon negative regulation of mTOR that leads to formation of a phagophore and subsequent sequestration
of cellular constituents in the presence of important autophagy proteins (Atg proteins) and cleaved LC3-II. Fusion of the autophagosome
with lysosome results in lysis and generation of energy that is typically expended for cell survival or cell death (Type II). mTOR:
mammalian target of rapamycin

highest rate. Higher and rapid elimination of phytochemicals/metabolites indicates decreased biological
[86]
benefits at the tissue level in the individuals who are positive for the enzyme involved in its metabolism .
Similarly, studies identified that isothiocyanates (especially sulforaphane) are not effective as therapeutic
[86]
agents against chronic conditions that are known to be associated with oxidative stress . Pharmacokinetic
studies in preclinical models and human trials have shown that phytochemicals are avidly metabolized in
the body, which could limit theavailability of these compounds ortheir associated active metabolites at the
target organs distinct from the site of absorption. The therapeutic benefits of phytochemicals could only
be realized through repeated administration, which would eventually produce systemic concentrations at
the target sites. In addition, several studies including those discussed in the current review are exploring
the possibility of increasing the bioavailability of these compounds through pharmaceutical modifications.
Another important limitation of the administration of phytochemicals is their ability to cause the
generation of ROS, which plays a major role in their pharmacological effects. It is important to limit the