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Page 2 of 17 Wenner et al. J Cancer Metastasis Treat 2020;6:33 I http://dx.doi.org/10.20517/2394-4722.2020.73

INTRODUCTION
Autophagy/macroautophagy is an evolutionarily conserved catabolic process that provides energy and
[1,2]
macromolecular precursors through lysosomal degradation of cellular material . Autophagy occurs at
an elementary level in all eukaryotic cells during their normal growth and development. Although the role
of autophagy in energy homeostasis is quintessential, its role in cellular processes such as degradation of
cytoplasmic organelles and proteins is also well established. The process of autophagy typically begins with
the formation of a phagophore, followed by recruitment and processing of light chain 3 I (LC3) to LC3-II
occurring in the presence of an autophagic stimulus with eventual sequestration into an autophagosome.
Subsequently, the newly developed autophagosome engulfs cellular proteins and organelles, fuses with
[2]
a lysosome, forming an autolysosome, where autophagy occurs . Intracellular components including
mitochondria and endoplasmic reticulum are engulfed by the newly formed phagophore before undergoing
degradation upon fusion with lysosomes. This process facilitates the recycling of bioactive ingredients for
[3-5]
cellular sustenance . The degradative products, which include simple carbohydrates and amino acids
are recycled back into the cytoplasm. The mammalian target of rapamycin (mTOR), a highly conserved
serine/threonine kinase senses signals from growth factors, energy status and stressful environment and
serves as a key regulator of cell growth and division. mTOR’s ability in mediating cellular responses is
known to depend on the availability of amino acids and growth factors. It is usually active in an amino
acid-rich environment and usually regulates protein translation but inhibits autophagy. When the levels
of extracellular amino acids are very low, the process of autophagy recycles intracellular components to
[6]
restore amino acid levels . Upregulation of mTOR results in excessive cell proliferation and eventually
leads to the development of cancerous growth. Inhibition of mTOR results in induction of autophagy. The
deregulation of autophagy has been clearly established in various chronic conditions including cancer. On
the basis of the stimuli and tumor type, autophagy has been reported to be tumor promoting, or tumor-
[4,5]
suppressive, indicative of the context-dependent role of autophagy in cancer . Studies also suggest that
pharmacological or genetic inhibition of the autophagic response increases the chemotherapeutic efficacy
of conventional agents, suggesting that autophagy inhibition in situations where it promotes cell survival
may be an appropriate strategy in the treatment of cancer.

A large body of evidence including several epidemiological studies shows an inverse association of a diet
[7-9]
rich in fruits and vegetables and the development of various cancers . In the last couple of decades,
scientists and especiallycancer biologists have started exploring the role of major dietary phytochemicals
consumed by people across the world. Studies have identified the ability of these phytochemicals
to modulate important signaling pathways and oncogenes associated with cancer development and
progression. To that end, various studies have also looked into the role of plant-derived phytochemicals
in the autophagic response and have reported important findings in their ability to modulate this cellular
process as a way to affect the development of chronic conditions including cancer [10-12] . However, further
research is essential to understand the mechanistic details associated with induction and/or inhibition of
autophagy by these bioactive compounds. The current review summarizes established findings related to
the autophagic response to four major phytochemicalswidely consumed by different cultures across the
world.

PHENETHYL ISOTHIOCYANATE
Phenethyl isothiocyanate (PEITC) is a naturally occurring isothiocyanate containing a phenethyl group
attached to its nitrogen. PEITC is found in various cruciferous vegetables in the form of gluconasturtiin.
Myrosinase, an important enzyme located in the cellular matrix, catalyzes the conversion of PEITC
from glucoasturtiin. When cruciferous vegetables, such as watercress, broccoli, radishes, or turnips are
[13]
chewed or crushed, myrosinase is activated . Myrosinase can also be activated in the digestive system,
which allows PEITC to be released after the vegetable has been ingested. Both myrosinase and PEITC