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Page 18 of 25 Kondapuram et al. J Cancer Metastasis Treat 2019;5:32 I http://dx.doi.org/10.20517/2394-4722.2018.105

Figure 14. Autophagy inducers

Curcumin treatment of human lung adenocanrcinoma cell line A549 showed autophagy induction by means
[92]
of increased AMPK phosphorylation .
Quercetin
Quercetin, a well-known cancer therapeutic agent and autophagy modulator is abundantly present in
[93]
vegetables and fruits, and suppress tumor proliferation . It has been shown that quercetin suppresses Akt/
mTOR and Bcl-2 signaling pathways and activates LC3, ERK and caspase. Studies in human neuroglioma
cells U87 and in vivo studies revealed that quercetin nanoparticles significantly inhibit neuroglioma cell
proliferation by inducing autophagy and apoptosis. Cell proliferation assay of neuroglioma cells showed
that quercetin nanoparticles treatment with 10-50 µg/mL gradually reduced cell viability . A recent study
[94]
reports that quercetin modulate p-STAT3/Bcl2 pathway and there by induces protective autophagy in
ovarian cancer .
[95]
Obatoclax mesylate
Obatoclax, a small molecule indole bipyrrole compound is an inhibitor of Bcl2 family proteins and exhibited
[96]
anticancer activity in acute lymphoblastic leukemia . In addition to its involvement in apoptosis, obatoclax
[97]
has also been involved in triggering cell death via autophagy induction . Primarily, this compound plays
a key role in stimulation of necrosome assembly on autophagosome membrane to induce autophagy. Co-
immunoprecipitation studies indicated that obatoclax enhances the interaction between Atg5 and necrosome
components including FAD, RIP and RIP3. The same study investigated the role of obatoclax with 200 nmol/
L concentration in rhabdomyosarcoma cells to unravel whether cell death occurs via apoptosis or autophagy
and noticed little DNA fragmentation when the most of cell lost their viability.

Spermidine
Spermidine is a polyamine present in most of the mammalian cells and has important roles in several
cellular activities under physiological conditions. It is well known for its longevity-promoting activity in
association with autophagy enhancement. A study conducted in differentiated rat pheochromocytoma PC12
and human embryonic kidney 293 cells, revealed the possible role of spermidine in autophagy. After treating
the cells with spermidine, the cell death analysis and caspase activity assays indicated that spermidine
restricts neuronal injury via inhibiting caspase-3 dependent Beclin1 cleavage. Eventually, this mechanism
[98]
elevates dysregulated autophagy flux levels . Very recent immunoprecipitation and immunohistochemistry
studies in human chondrocytes and in vivo study conducted in mice reported that the cells treated
[98]
with spermidine (100 nmol/L) showed autophagy activation and promoted chondrogenesis . However,
spermidne role in cancer is still controversial as some studies reported that spermidine do not induce
[99]
tumorigenesis , whereas some studies established that spermidine synthase inhibitors show little cell
growth reduction in cancer cell lines [100] .