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inhibitors of glycolytic enzymes and metabolite cell lung cancer. [149] The small molecule 968 is identifi ed
transporters are effective in preclinical or clinical settings to block glutaminase activation and inhibit the growth
and evaluate adverse effects and feasibility for clinical of cancer cells, and this enzyme shows potential as a
practice. therapeutic strategy against cancer. [150]
The Nrf2 transcription factor is an important modifi er Conclusions and Perspective
of cellular responses to oxidative stress. Stable
RNAi-mediated knockdown of Nrf2 in human colon This review describes recent investigations in
cancer cells suppressed tumor growth in a xenograft model mitochondrial metabolism, anaerobic glycolysis and
with a reduction in blood vessel formation and VEGF the PPP in cancer. We also discussed the control of
expression. The Nrf2-inhibited cancer cells failed to ROS levels by the endogenous anti-oxidant system.
accumulate HIF-1A protein under hypoxic conditions. [136] Key regulators related to cell death in the mitochondria
HIF plays a crucial role in cellular adaptation to hypoxia are frequently altered in cancer cells, and mitochondria
and regulates the expression of genes responsible for in cancer differ functionally and structurally from
glucose metabolism, angiogenesis and cell survival. those of normal cells. Mitochondria dysfunction in
Conventional anti-cancer therapies typically target cancer is associated with the activation of oncogenes
actively dividing cells near the vasculature, though they and inactivation of tumor suppressors. Recent genetic
function poorly in hypoxic regions. [137] Cells in hypoxic and metabolic analyses have revealed the molecular
regions are relatively quiescent, and these cells also tend mechanisms of genes that are involved in cancer
to be refractory to agents targeting rapidly proliferating metabolism and tumorigenesis. The alterations of
cells. [138-140] gene expression in glycolysis are associated with poor
prognosis and may be associated with chemoradiotherapy
Novel therapeutic agents targeting the resistant hypoxic resistance. The PPP is positively regulated by oncogenes
zones may provide additional anti-tumor activity and and regulates cancer cell growth by supplying cells with
clinical benefi t when combined with conventional R5P and NADPH. Direct regulators that activate the PPP
treatments. Tirapazamine is a bioreductively activated, have been identifi ed. ROS levels are increased during
hypoxia-selective anti-tumor agent of the benzotriazine carcinogenesis from metabolic aberrations. Cancer cells
series; it is 35-450 times more cytotoxic to hypoxic frequently have increased expression of anti-oxidants
cells than to well-oxygenated cells. [141] Standard to maintain homeostasis. Anti-cancer agents targeting
cisplatin chemoradiotherapy plus tirapazamine has not ROS status may exert therapeutic effects. Novel small
been superior to cisplatin chemoradiotherapy in either molecules targeting metabolite transporters, glycolytic
progression-free survival or overall survival in locally enzymes and ROS status have been reported. However,
advanced cervix cancer. [142] TH-302 is a novel therapeutic further studies should examine whether these inhibitors
agent and a hypoxia-activated, cytotoxic prodrug with a are useful in cancer therapy and evaluate adverse effects
2-nitroimidazole component designed to release the DNA and feasibility for use in clinical practice.
cross-linker bromo-isophosphoramide mustard when
reduced by intra-cellular reductases in the setting of Financial support and sponsorship
severe hypoxia. [143] The phase II study by Borad et al. [144] Nil.
evaluated treatment of TH-302 in patients with either
locally advanced or metastatic pancreatic cancer and Confl icts of interest
found that the addition of TH-302 to gemcitabine There are no confl icts of interest.
resulted in a near doubling of progression-free survival
and objective response with acceptable toxicity. References

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Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦ 177