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Kondapuram et al. J Cancer Metastasis Treat 2019;5:32 I http://dx.doi.org/10.20517/2394-4722.2018.105 Page 17 of 25

Figure 13. Lysomotrophic inhibitors

HCQ, a derivative of CQ is a 4-aminoquinoline that has antimalarial and anti-inflammatory activities; it is
currently being investigated as the inhibitor for autophagy. Several clinical trials of HCQ in combination
with other anti-cancer drugs (e.g., temozolomide, bortezomib, temsirolimus, vorinostat, doxorubicin, etc.)
showed partial response and stable disease outcome for various cancers (melanoma, colorectal cancer,
[86]
myeloma and renal cell carcinoma) . As a drug, this basic compound alkalinizes acidic environment
of lysosomes and thereby prevents autophagosome-lysosome fusion. HCQ is proved to be threefold less
toxic than CQ and can augment the cytotoxicity of a number of chemotherapies and targeted therapies. A
recent meta-analysis of clinical trials of CQ and HCQ concluded that their use in cancer patients has better
[87]
treatment response, when used in combination with existing anti-cancer therapy .

Based on the 4-aminoquinoline core structure of CQ and HCQ, Lys05 was designed; it was more potent in
in vitro and in vivo as a single agent. The increased activity of Lys05 was due to the bivalent aminoquinoline
rings, C7-chlorine and a short triamine linker. Lys05 trihydrochloride is water soluble and shows potent
anti-tumor activity in several human cancer cell lines as a single agent. Intermittent high dose or chronic
daily dosing of Lys05 at lower doses have shown early blockage of autophagy in melanoma and colon cancer
[88]
xenograft models . Comparative study in cancer cells also revealed that HCQ at 100 µmol/L cannot show
complete deacidification of endovascular compartment; whereas 50 µmol/L of Lys05 has shown complete
deacidification. Further, in mice models Lys05 at high dose (80 mg/kg, i.p.) causes Paneth cell dysfunction
with loss of lysozyme biosynthesis and bowel pseudo-obstruction [88,89] . Studies evidenced that high dose of
Lys05 is associated with intestinal toxicity and it has been also observed that high dose of HCQ also causes
low grade nausea and constipation in patients. Lys05 is a new lysosomal inhibitor that has a potential to be
further developed as a drug for cancer treatment.

Autophagy inducers
In addition to the above agents/compounds that were designed to modulate the autophagy process by
specifically interacting with targets in autophagy pathways, there are other agents that induce autophagy.
Particularly, naturally occurring compounds have multiple modes of action and targets different pathways.
Some of them induce autophagy by targeting autophagy pathway signaling molecules and are discussed in
this section [Figure 14].

Curcumin
Curcumin, a natural compound of golden spice turmeric shows numerous activities including anti-
inflammatory, antimicrobial, antioxidant, hypoglycemic and wound healing activities. Considering these
activities, curcumin has been investigated in many clinical conditions such as multiple myeloma, breast
cancer and non small cell lung cancer. Although, it has proven efficacy in several clinical aspects, curcumin
has therapeutic limitations due to rapid systemic elimination, rapid metabolism and poor absorption.
[90]
Curcumin showed anticancer effects by sensitizing chemotherapy and radiation therapy . In gastric
cancer cell lines SGC-7901 and BGC-823, curcumin significantly inhibited cell proliferation by exhibiting
autophagy induction. The studies have reported that curcumin induces autophagy by its dual functionality
[91]
in up-regulation of p53 and p21, and down-regulation of PI3K/Akt/mTOR signaling pathways . Another
[91]
recent investigation also reported that curcumin induces autophagy in human pancreatic cancer cell lines .