29Abstract ART acts on tumor cells differentially by the threshold concentrations.
High-dose ART kills tumor cells upon the inhibition of NOS, whereas low-dose
ART benefits tumor propagation due to induce cytoprotective NO production. Pro-
oxidants that antagonize antioxidants can potentiate ART’s antitumor capacity.
The combination of ART with pro-oxidants should provide an effective solution to
the chemotherapy of multidrug resistant tumors.
Keywords ART · NOS · Pro-oxidants · Chemotherapy · Sensitization
3.1 An Overview on Tumor and Antitumor
The malignant tumor, or cancer, severely threatens human health, but the patho-
genesis of tumorigenesis/carcinogenesis is poorly understood. The solid tumor
might disappear after treatment by a single therapy or a combined regimen of
surgery with radiotherapy and/or chemotherapy. For chemotherapy, many options
are available for choosing antitumor drugs among alkylating agents, antimetabo-
lites, antimicrotubule agents, topoisomerase inhibitors, and cytotoxic antibiotics
(Corrie and Pippa 2008 ; Lind 2008 ). The antimalarial compound ART also exhib-
its antitumor activity although it has not been used for the clinical treatment of
cancer. ART’s antitumor activity, in an acceptable dose, is lower than commonly
used chemotherapeutics. This is perhaps why ART has not been practical for can-
cer treatment until now. In addition, the mechanism underlying ART killing tumor
cells remains unknown, and the specific machinery targeted by ART in tumor cells
has not been identified. Nevertheless, it is known that tumor cells resistant to the
present antitumor drugs are hypersensitive to ART, suggesting a different tumor-
killing mechanism (Efferth et al. 2003 ).
The cytotoxicity of ART to tumor cells was first evaluated by Woerdenbag
et al. ( 1993 ). Later, ART’s cytotoxicity was shown to be endoperoxide- dependent
(Beekman et al. 1998 ). An iron-dependent antitumor pattern of ART was also
Chapter 3
ART for Antitumor
© The Author(s) 2015
Q.-P. Zeng, Artemisinin and Nitric Oxide, SpringerBriefs in Molecular Science,
DOI 10.1007/978-3-662-47688-8_3