30 3 ART for Antitumor
proposed (Kwok and Richardson 2002 ). Tumor cells in exposure to ART
were found to exhibit a correlation of mitigated proliferation with repressed
angiogenesis (Krishna et al. 2008 ). Recent evidence suggests that ART may share
a common feature with the heme-interacting compound coralyne because both
exert the cytotoxicity in a heme-dependent manner (Zhang and Gerhard 2009 ).
An involvement of heme in anticancer activity was supported by the findings
that cobalt protoporphyrin, an inducer of heme oxygenase, abolishes the activity
of ART dimers, whereas tin protoporphyrin, an inhibitor of heme oxygenase,
enhances the activity of ART dimers (Wink et al. 1995 ). Nevertheless, the bona
fide targets to which ART binds remain under debate (O’Neill et al. 2010 ).
The endoperoxide bridge of ART can lead to the generation of carbon-centered
free radicals in vivo, causing oxidative stress implicated in the killing of malar-
ial parasites and tumor cells. However, the peroxidized structure is prone to be
destroyed by antioxidants abundant in cells. In regard to antimalarial activity, it
has been revealed that free radical generators (pro-oxidants) such as riboflavin
(vitamin B2) and menadione (vitamin K) are synergetic to ART, whereas free radi-
cal scavengers (antioxidants) including tocopherol (vitamin E), ascorbate (vitamin
C), glutathione (GSH), and dithiothreitol (DTT) are antagonistic to ART (Senok
et al. 1997 ). Furthermore, ART’s antimalarial efficacy would be potentiated when
antioxidant enzymes are inhibited (Meshnick et al. 1989 ). These results imply that
ART is more effective in an oxidative milieu.
3.2 ART Diminishes NO-Conferred Anticytotoxicity
of Tumor Cells to Chemotherapeutics
3.2.1 Purposes and Significance
The proposed mechanistic patterns or potential targets of ART for attacking the
malarial parasite include: (1) heme conjugation; (2) protein alkylation; (3) mem-
brane damage; (4) mitochondrial dysfunction; and (5) energy deficiency due to the
inhibition of malarial ATPase (PfATP6) (O’Neill et al. 2010 ). Although numerous
studies have indicated that ART can induce apoptosis and inhibit angiogenesis in
tumors, it remains unclear which definitive cellular targets are dependent by ART
and derivatives. Nevertheless, ART’s targets identified in tumor cells include at
least translationally controlled tumor protein (TCTP) (Efferth 2005 ) and sarco-
plasmic/endoplasmic reticulum Ca^2 +-ATPase (SERCA) (Uhlemann et al. 2005 ).
However, whether such targets are also in action for antitumor remains uncertain.
Recent evidence suggests that ART exhibits similarity with the heme-inter-
acting coralyne because coralyne and ART show a substantial increase in the
cytotoxicity when a synthetic heme exists. Detection of the altered absorbance
spectrum confirms the presence of a new ART-heme complex, which is consist-
ent with the decomposition of heme porphyrin rings (Zhang and Gerhard 2009 ).
These previous observations encouraged us to suggest that heme might be ART’s