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Page 6 of 19 Davidson et al. J Cancer Metastasis Treat 2021;7:45 https://dx.doi.org/10.20517/2394-4722.2021.77

the ends of glycogen chains. Glycogen debranching enzyme assists in this process by removing G1P 1-6 α
[64]
glycosidic bonds formed by GBE .
There are several inhibitors designed to target the rate-limiting enzyme of glycogen breakdown, PYG. 1,4-
dideoxy-1,4-amino-D-arabinitol (DAB) is a potent PYG inhibitor and the only one that directly inhibits the
PYG active site [65,66] . DAB prevented hypoxia-induced cell survival in colorectal and breast cancer cells
[63]
following glucose deprivation . The remaining PYG inhibitors discussed here bind to the allosteric
“indole” pocket of PYG, named for the indole structure these inhibitors contain [58,60] . CP-91,149 was
designed to treat diabetes and was able to significantly decrease blood glucose levels in obese mice without
inducing hypoglycemia in lean mice . CP-91,149 is a pan PYG inhibitor that reduced cell viability in
[67]
models of hepatocellular, prostate, and lung carcinoma [68-70] . Excitingly, CP-91,149 was highly synergistic
[69]
with the BRAF inhibitor sorafenib in hepatocellular carcinoma, which is the standard therapy for ATC .
Additionally, CP-316819 enhanced melatonin cytotoxicity in Ewing sarcoma cells, and CP-320626 induced
apoptosis in pancreatic carcinoma cells [71,72] . Although PYG inhibitors have demonstrated robust success in
vitro, these promising results have yet to be validated for in vivo tumor models, let alone in any TC model.
Therefore, glycogen metabolism represents an exciting but unexplored avenue of therapeutic intervention
in TC.

THE PENTOSE PHOSPHATE PATHWAY
In addition to supplying energy and reducing equivalents in the form of ATP and NADH, glycolysis is used
to generate the building blocks for nucleotide synthesis and protecting against reactive oxygen species
(ROS) via the pentose phosphate pathway (PPP) [Figure 2] [73,74] . G6P can be diverted to the PPP via glucose
6 phosphate dehydrogenase (G6PDH). This enzyme forms 6-gluconophospholactone and regenerates
NADPH from NADP+. NADPH is used in fatty acid synthesis and reduces redox enzymes [15,35,73,74] . G6PDH
is the rate-limiting step in the PPP and represents an attractive target in cancer cell metabolism, particularly
in TC which has been shown to overexpress the enzyme in PTC, FTC, and ATC cells [31,75] . 6-
aminonicatinomide (6-AN) is a selective, competitive inhibitor of G6PDH that demonstrated success in
F
[75]
i n d u c i n g a p o p t o s i s i n P T C a n d A T C models . o l l o w i n g c o n v e r s i o n t o 6 P G v i a 6 -
phosphogluconolactonase, 6-phosphogluconate dehydrogenase (6PGDH) forms another equivalent of
[73]
NADPH as well as the intermediate ribulose-5-phosphate (RL5P) . 6PGDH was found to be significantly
expressed in PTC fine-needle aspirations as well as cell culture models of ATC following doxorubicin
treatment, possibly representing an evolutionary drug resistance mechanism [76,77] . This resistance was
[76]
overcome by inhibiting 6PGDH with physcion, which re-sensitized ATC cells to doxorubicin . RL5P is
converted to an epimer via ribulose-5-phosphate 3-epimerase (forming xylulose-5-phosphate, X5P) or
isomer using ribose-5-phosphate isomerase (forming ribose-5-phosphate, R5P) depending on the balance of
products and metabolic requirements in the cell [15,35,73,74] . R5P serves as the building block for forming
nucleotides. One equivalent of R5P and two equivalents of X5P are required to regenerate the glycolytic
intermediates GA3P and F6P. These interconversions are performed by transketolase and
transaldolase [35,73,74] . Transketolase is overexpressed in PTC and ATC cells, and inhibition by oxythiamine
[75]
suppressed PTC and ATC growth and exhibited drug additivity with 6-AN . The PPP is a crucial
metabolic pathway in cancer cells for forming nucleotides, a requirement for DNA synthesis and cell
division, and combating excessive levels of ROS. Inhibitors of this pathway have demonstrated impressive
success in ATC cell culture models, warranting further investigations in vivo.

FATE OF PYRUVATE IN THE MITOCHONDRIA
In a highly glycolytic cancer cell, pyruvate is most frequently converted to lactate [78-80] . However, pyruvate
can also generate acetyl-CoA for use in the TCA cycle. High pyruvate levels favor transport into the