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Sphingolipids
Cancer cells are sensitive to nutrient limitation because cancer cell’s ability to
generate ATP is compromised under these conditions. In addition, most cancer cells
have defects in autophagy, the catabolic process that provides nutrients from inter-
nal sources when external nutrients are unavailable. In contrast, normal cells can
adapt to the nutrient stress that kills cancer cells by becoming quiescent and cata-
bolic. A study has shown that FTY720, a water-soluble sphingolipid drug that is
effective in many animal models of cancer, selectively starves cancer cells to death
by down-regulating nutrient transporter proteins (Romero Rosales et al. 2011 ).
Consistent with a bioenergetic mechanism of action, FTY720 induced autophagy of
cancer cells but normal cells were protected. AAL-149, a FTY720 analog that lacks
FTY720’s dose-limiting toxicity, also triggered transporter loss and killed patient-
derived leukemia cells while sparing cells isolated from normal donors. Because
FTY720 analogs target the metabolic profi le of cancer cells rather than specifi c
oncogenic mutations, they should be effective against several tumor types, particu-
larly in combination with drugs that inhibit autophagy.
Hyperbaric Oxygen as Adjunct to Radiotherapy
Hyperbaric oxygen (HBO), i.e. oxygen under higher than atmospheric pressure, is
used for the treatment of several disorders. HBO has been investigated as an adjunct
to radiotherapy of cancer. It is well recognized that hypoxia infl uences the response
of cells and tissues to radiation and increases the resistance of cancer to radiother-
apy requiring higher radiation doses that can normal tissues. HBO is considered to
be the most effective method for counteracting tumor hypoxia for enhancing the
effect of radiotherapy on cancer, but this approach has been shown to be effective in
only some types of cancer, e.g. glioblastoma multiforme (Jain 2009 ). In spite of
several studies, the controversy has not been resolved. Combination of antineoplas-
tic agents and HBO induces dual injury to the mitochondrial respiration and cell
membranes. HBO can be added to regimes combining radiotherapy with chemo-
therapy. Concomitant HBO enhances the effects of 5-fl uorouracil on malignant
tumors but no clinical trials have been done to evaluate this combination.
Targeting Response to Transformation-Induced Oxidative Stress
Malignant transformation is often associated with enhanced cellular stress and DNA
damage. Cancer cells adapt to this stress to survive, and may become dependent
upon non-oncogenes that do not ordinarily perform such a vital function in normal
cells. Therefore, targeting this non-oncogene dependency may result in selective
death of cancer cells. A cell-based small-molecule screening and quantitative pro-
teomics approach led to the unbiased identifi cation of piperlongumine, a small mol-
ecule that selectively kills cancer cells but not normal cells (Raj et al. 2011 ).
Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic
10 Personalized Therapy of Cancer