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Sulforaphane
Sulforaphane, an organic isothiocyanate compound derived from glucosinolates shows both cytoprotective
and cytotoxic activities. It activates nuclear factor E2-related factor 2 signaling that elevates the expression
of antioxidant response proteins in oxidative stress. A study in murine osteosarcoma cells reported that
sulforaphane induces apoptosis through cell cycle arrest and inhibits tumor cell growth [101] . It has also
been reported that the treatment of sulforaphane initiates various cellular processes in human prostate
cancer [102] . To investigate whether sulforaphane is reducing the cell growth or encourages cell death, a study
was conducted in human lens cell line and reported that sulforaphane reduced the cell viability in human
lens cell line and promotes cell death. The study also revealed that sulforaphane promotes ER stress and
autophagy induction via MAPK signaling [103] , and longer treatment with sulforaphane has shown significant
decrease in AMPK phosphorylation at thr-172 [104] in human prostate cancer cells.

FDA approved drugs with autophagy modulation activity
In addition to the above discussed autophagy modulators, few FDA approved drugs (for different indications)
are reported to have additional autophagy modulator activities [Table 2]. This section is intended to list
out these drugs and provide brief information and mode of autophagy modulation by these drugs. Some
of these drugs are already used as anticancer agents, while some are used for other indications. These data
suggests that some of the approved anticancer drug may be partly working through autophagy modulation.
Moreover, understanding the exact molecular mode of action of these drugs could help to repurpose these
drugs for cancer therapy in the future.

Temozolamide, an alkylating agent is a FDA approved drug for the treatment of glioblastoma multiforme in
combination with radiotherapy [105] . Recent studies have investigated the role of temozolamide in autophagy
modulation and reported that it induces autophagy in glioblastoma cancer cells through EGFR independent
manner [106] . Temozolamide also showed cytotoxicity in PI3K/AKT/mTOR pathway inhibited adenoma
cells [107] . Gefitinib which targets tyrosine kinase activity of EGFR and binds competitively to the ATP
[108]
binding site is a FDA approved drug for treating the patients with non-small cell lung cancer (NSCLC) .
Gefitinib induces autophagy in lung cancer cells through blocking of PI3K/AKT/mTOR pathway [109] and also
exhibited autophagy induction in combination with clarithromycine in NSCLC cells [110] .

Metformin, a biguanide antihyperglycemic agent is FDA approved for treating non-insulin-dependent
diabetes mellitus. It controls glucose level by means of decreasing hepatic glucose production and also by
increasing insulin-mediated glucose uptake. It is reported that metformin is involved in autophagy induction
by AMPK dependent manner. Several cancer models have shown significant growth inhibition upon
metformin treatment [111] . A study also reported that metformin promotes autophagy and selectively inhibits
esophageal squamous cell carcinoma cell growth by down regulating STAT3 signaling [112] . Studies on human
multiple myeloma cells show that metformin inhibits the cell proliferation by promoting autophagy and
cell cycle arrest and this study suggested metformin dual repression of mTORC1 and mTORC2 via AMPK
activation [113] .

Bortezomib is a proteosome inhibitor that specifically inhibits nuclear factor kappaB and is a FDA approved
drug to treat multiple myeloma [114] . Bortezomib has shown anticancer activities in several human cancers
including prostate cancer, colon cancer, ovarian cancer and breast cancer. Studies have explored the
possible role of Bortezomib in autophagy and found that it promotes cancer cell death through blockage
of autophagic flux in ERK phosphorylation dependent manner [115] . Sodium phenylbutyrate is a chemical
chaperon that inhibits histone deacetylase and is FDA approved drug to treat urea cycle disorders. Sodium
phenylbutyrate is also under clinical investigation in several human diseases including hemoglobinopathies,
motor neuron diseases, cancer and cystic fibrosis [115] . Sodium phenylbutyrate has been shown to reduce
dithiothreitol or tunicamycin induced autophagy [116] .