38 3 ART for Antitumor
inhibit CAT, but not other antioxidant enzymes. In the present study, we found that
ART can significantly inhibit CAT but not GSH-POX, leading to a steady-state
level of H 2 O 2 in mice. In contrast, when ASC was injected into mice, both CAT
and GSH-POX are significantly inhibited, suggesting that ASC kills tumor cells
more effectively due to a high level of H 2 O 2.
Regarding the possible cytotoxicity of each drug in ASC, it is known that MA
is equivalent to ART, while DM and AT are less toxic than ART. DM has low tox-
icity because it only inhibits GSH-POX by depleting GSH, but not affects other
POX. MA and AT are also low toxic because they do not interfere with the expres-
sion of any antioxidant enzymes.
Taken together, our study has confirmed that ASC confers a sensitizing effect
to ART by diminishing the antioxidative response of tumor cells, in which CAT
and GSH-POX can be potently inhibited. These results clearly reflected a fact
that ART killing tumor cells depends on oxidative stress that can be enhanced by
pro-oxidants.
3.3.4 Conclusions
To enhance the antitumor efficiency of ART, we designed the oxidation-enhanced
ASC by combining ART with three-type pro-oxidants, including a GSH exhauster,
a GSH-POX inhibitor, and a CAT inhibitor. The survival of tumor cells was eval-
uated in vitro and the size and weight of graft tumors were measured in vivo.
Consequently, cell proliferation is substantially inhibited by ASC with a higher
inhibition rate (67.26 %) than ART alone (46.76 %). As compared with the control,
graft tumors decrease to 30.42–35.58 % in weight and 25.50–37.35 % in volume by
ASC. Pro-oxidant treatment can dramatically decrease antioxidant enzyme activi-
ties. For example, CAT activity in the control is 50 units/mg of total proteins, while
that in ASC or ART treatment is only 5–10 units/mg of total proteins or 20 units/mg
of total proteins. Conclusively, pro-oxidants can sensitize ART for exerting more
effective antitumor roles through depriving antioxidants in tumor cells.
References
Beekman AC, Wierenga PK, Woerdenbag HJ, Van Uden W, Pras N, Konings AWT, El-Feraly
FS, Galal AM, Wikstrom HV (1998) Artemisinin-derived sesquiterpene lactones as potential
anti-tumour compounds: cytotoxic action against bone marrow and tumour cells. Plant Med
64:615–619
Chinje EC, Stratford IJ (1991) Role of nitric oxide in growth of solid tumours: a balancing
act. Essays Biochem 32:61–72
Clark EP, Epp ER, Biaglow JE, Biaglow JE (1984) Glutathione depletion, radiosensitization, and
misonidazole potentiation in hypoxic Chinese hamster ovary cells by buthionine sulfoximine.
Radio Res 98:370
Corrie PG, Pippa G (2008) Cytotoxic chemotherapy: clinical aspects. Medicine 36:24–28