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oxidative damage caused by ROS in the body. If uncontrolled, ROS may lead to the development of various
chronic diseases and contribute to toxic side effects. It is because of these limitations that phytochemicals
are not having much success in clinical trials and hence are being investigated extensively to overcome
these obstacles.

FUTURE PERSPECTIVES AND CONCLUDING REMARKS
The relevance of autophagy in chronic diseases has been well established and shown to have a major role
in the development of these ailments, including cancer. Autophagic response in cancer development is
both tumor-suppressive and tumor promoting depending on such factors as cancer type, energy status
and metabolic processes within a cell. Moreover, the regulation of autophagy by phytochemicals in cancer
cells also depends on epigenetic mechanisms that modulate the expression of key proteins involved in its
[88]
[87]
induction . The overall chemopreventive effects of various phytochemicals , including those discussed
in the current review, were also attributed to their ability in regulating microRNA levels. Understanding
the molecular mechanisms by which autophagy playsa role in cancer stem cells is critical in developing
[89]
novel therapies . Cancer cells can stimulate the process of autophagy for accessing nutrients in their
microenvironment for their growth and proliferation, and hence, understanding the role of autophagy in
its microenvironment could result in radical approaches for a better therapeutic outcome. In this review,
we discussed four major phytochemicals that are abundantly present in various dietary sources and
consumed by different cultures across the world. These phytochemicals are shown to induce autophagic
response in different cancer models. The autophagic response evoked by phytochemicals not only can
mitigate resistance to conventional therapiesbut also serve as a type (type II) of cell death. The induction
of autophagy by different phytochemicals depends on various factors, including the type of cancer. For
example, genistein was shown to potentiate the antitumor effect of 5-FU by inducing apoptotic and
autophagic cell death. Similarly, CAP and cisplatin combination induced autophagy that served as a pro-
survival mechanism in OS cells, which when inhibited by bafilomycin resulted in upregulation of apoptotic
genes. WA-induced autophagy was shown to be cytoprotective in hepatocellular carcinoma, which was
abrogated in the presence of autophagy inhibitors, increasing the efficacy of combination therapy. The
autophagic response induced by PEITC increased overall cell death in prostate cancer cells, while the
response preserved the metastatic potential of lung cancer cells, which was abrogated in the presence
of chloroquine. In addition, PEITC’s ability to modulate the expression of miR-194, MMP2, and MMP9
proteins was vital in the induction of autophagy and prevention of metastatic potential in prostate cancer
cells.

A continued progress in understanding the pharmacology of these phytochemicals and advances
made to overcome the challenges associated with their pharmacokinetic profile have enabled their
commercialization. The market for various phytochemicals continues to grow as more and more people
are looking for alternate approaches in promoting their health and preventing disease development.
Several phytochemicals are marketed as dietary supplements and are widely available in various forms. In
conclusion, the utility of phytochemicals as therapeutic agents when used either alone or in combination
with other conventional therapies can only be achieved after addressing the pitfalls and understanding the
disease progression.

DECLARATIONS
Acknowledgments
The authors would like to acknowledge the faculty development funds awarded to Bommareddy A by
Wilkes University and to thank Dr. Paul S. Adams and the mentoring task force at Wilkes University for
providing summer research stipends to undergraduate students.