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the DLG domain, resulting in stabilization of Nrf2 and and loss of functional p53 are intrinsic factors known to
translocation of free Nrf2 to the nucleus. [101] Nrf2 is cause increased ROS production in cancer cells. [111] In
aberrantly accumulated in many types of cancer, and chemotherapy, 5-Fluorouracil (FU) generates mitochondrial
its expression is associated with a poor prognosis in ROS via a p53-dependent pathway. [120] Tumor cells which
patients. [102-106] In addition, Nrf2 expression is induced adapt to oxidative stress by increasing the production of
during the course of drug resistance in gastric cancer, [107] SOD2, Prx1 and Bcl-2 are resistant to 5-FU. [121] Products of
CRC [108] and esophageal SCC. [109] oxidative stress can slow cell-cycle progression of cancer
cells, cause cell-cycle checkpoint arrest and interfere with
ROS and Energy Metabolism in Cancer Cells the ability of anti-cancer drugs to kill cancer cells. [122] The

Oxygen free radicals are highly reactive with biological capacity of some chemotherapeutic agents to cause an
molecules, including DNA, proteins and lipids. The imbalance in ROS levels offers a therapeutic opportunity
free radical reaction could cause oxidative modifi cation for treating cancer.
of these biomolecules and alter their functions. Considering that cancer cells have increased ROS levels,
Mitochondria generate ROS that are thought to augment they may be selectively sensitive to the damaging effects
intra-cellular oxidative stress. In all cells, the majority of further increasing ROS. Cancer cells frequently
of ROS are by-products of mitochondrial respiration. have increased expression of anti-oxidants to maintain
Approximately, 2% of the molecular oxygen consumed homeostasis. Inhibiting anti-oxidants to expose cancer
during respiration is converted into the superoxide anion cells to endogenously produced ROS may be a
radical, the precursor of most ROS. Mitochondria possess therapeutic approach. [123] In support of this model, several
at least nine known sites that are capable of generating small molecule screens have identifi ed compounds that
superoxide anion, a progenitor ROS. [110] A mild increase specifi cally inhibit the growth of transformed cells.
in the level of ROS may result in transient cellular Piperlongumine increases ROS and apoptotic cell
alterations, whereas a severe increase of ROS in cells death in both cancer cells and normal cells engineered
could cause irreversible oxidative damage, leading to to have a cancer genotype, irrespective of p53 status,
cell death. [111] In normal cells, the ROS level is tightly with little effect on dividing primary normal cells. [124]
controlled by the endogenous anti-oxidant system. Beta-phenylethyl isothiocyanate (PEITC) is a natural
However, energy metabolism and ROS homeostasis in compound found in consumable cruciferous vegetables
cancer cells are different from those in normal cells. with chemopreventive activity. PEITC increases ROS and
During the transition phases from normal tissue to selectively kills cancer cells. [125] Malignant cells are often
invasive carcinoma, ROS levels increase because of resistant to conventional anti-cancer drugs. These cells
metabolic aberrations. [112] are under intrinsic ROS stress, so using small molecules
Severe accumulation of cellular ROS under various that induce ROS to kill such malignant cells may exert a
endogenous and exogenous stress stimuli may induce fatal therapeutic effect.
damage in cells that have inadequate stress responses or Cancer Treatment
adaptation. In cancer cells, ROS stress may induce adaptive
stress responses, including activation of redox-sensitive Novel small molecules targeting metabolic regulators
transcription factors, such as nuclear factor κB and Nrf2. and glycolytic enzymes have been reported to exert
These responses lead to an increase in the expression of anti-proliferative effects. [126] Phloretin, a natural product
ROS-scavenging enzymes, such as SOD and glutathione with GLUT inhibitory activity found in apples and
(GSH), elevation of survival factors such as Bcl-2 and pears, exerts anti-tumor effects in HCC and color
MCL1, and inhibition of cell death factors, such as cancer cell lines. [127,128] The WZB117 small molecule
caspases. [111,113,114] ROS-mediated DNA mutations or inhibitor of GLUT 1 was effective in inhibiting cancer
deletions promote genomic instability and thus induce an cell growth both in vitro and in vivo. [129] The widely
additional mechanism for stress adaptation. All these events used 3-bromopyruvate (3-BrPA) [130] depletes cellular
contribute to the survival of cells with high levels of ROS ATP. A previous study showed that 3-BrPA inhibits
and maintain cellular viability. [115] As these transcription HK2 expression and exhibits anti-proliferative effects
factors also have roles in regulating the expression of genes when combined with daunorubicin in CRC cell lines [131]
that are responsible for proliferation, senescence evasion, and when combined with protein disulfi de isomerase
angiogenesis and metastasis, and thus the redox adaptation in HCC cell lines. [132] DCA, a PDK-1 inhibitor, has
processes may promote cancer development. [116,117] reduced lactate production and increased responsiveness
[76]
The increase in GSH during the redox adaptation can to 5-FU in MKN45 cells and CRC cell lines. [133] DCA
enhance the export of certain anti-cancer drugs and their treatment exerts anti-proliferative effects and sorafenib
inactivation. This altered drug metabolism, together with resistance in HCC cell lines in vivo. [134] Oxmate, a LDH
enhanced cell survival, may render cancer cells more inhibitor, combined with phenformin, has exhibited
resistant to chemotherapeutic agents. [113,118,119] Activation of cytotoxic effects in diverse cancer cell lines, including
oncogenes, aberrant metabolism, mitochondrial dysfunction colon cancer. [135] Future studies should examine whether

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