Oral artemisinin prevents and delays the development of 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer in the rat
Lai H, Singh NP. Cancer Letters. Volume 231, Issue 1, 8 January 2006, Pages 43–48
Artemisinin, a compound isolated from the sweet wormwood Artemisia annua L., has previously been shown to have selective toxicity towards cancer cells in vitro. In the present experiment, we studied the potential of artemisinin to prevent breast cancer development in rats treated with a single oral dose (50 mg/kg) of 7,12-dimethylbenz[a]anthracene (DMBA), known to induce multiple breast tumors. Starting from the day immediately after DMBA treatment, one group of rats was provided with a powdered rat-chow containing 0.02% artemisinin, whereas a control group was provided with plain powdered food.
For 40 weeks, both groups of rats were monitored for breast tumors. Oral artemisinin significantly delayed (P<.002) and in some animals prevented (57% of artemisinin-fed versus 96% of the controls developed tumors, P<.01) breast cancer development in the monitoring period. In addition, breast tumors in artemisinin-fed rats were significantly fewer (P<.002) and smaller in size (P<.05) when compared with controls. Since artemisinin is a relatively safe compound that causes no known side effects even at high oral doses, the present data indicate that artemisinin may be a potent cancer-chemoprevention agent.
Artemisinin and its derivatives (ARTs)
Artemisinin is an active terpene of the Chinese medicinal herb Artemisia annua (huang hua hao) used in China to treat malaria and fever. ARTs, such as dihydroartemisinin (DHA) and artesunate exhibit anti-cancer activities in vitro and in vivo (1-4). DHA is one of the main metabolites of ARTs and artesunate is a semi-synthesized derivative of ARTs; both compounds exhibit anti-cancer potentials. The anti-cancer potential of ARTs has been demonstrated in various cancer cells including those of leukemia and other cancer cells of breast, ovary, liver, lung, pancreas and colon (2,3). The selective anti-cancer potential of ARTs was related with the expression of different molecules such as c-MYC, cdc25A, EGFR, γ-glutamycysteine synthetase (GLCLR) (3,4). ARTs also exert anti-cancer effects in vivo in multiple cancer types (1,5,6). For example, either DHA or artesunate has anti cancer activity against pancreatic cancer xenografts (5,7).
The anti-cancer mechanism of ARTs is likely to be related to the cleavage of the iron- or heme-mediated peroxide bridge, followed by the generation of reactive oxygen species (ROS) (8-10). According to Efferth et al. (11), CCRF-CEM and U373 cells are sensitive to a combined treatment of ARTs and iron (II)-glycine sulfate or holotransferring. Pretreatment with deferoxamine mesylate salt (an iron chelator) visibly reduces DHA-induced apoptosis in HL-60 leukemia cells (2). The anti-cancer potential of ARTs is possibly connected to the expression of TfR. The synergism of artesunate and iron (II)-glycine sulfate co-treatment is unsuitable for all types of tumor cells (12). Endoplasmic reticulum stress is partially involved in some cases of ARTs-mediated anti-proliferation (13,14). ARTs induce cell cycle arrest in various cell types (1,13,15). For example, DHA and artesunate effectively mediate G1 phase arrest in HepG2 and Hep3B cells (1). DHA reduces cell number in the S phase in HCT116 colon cancer cells (13). Interestingly, DHA also arrests the G2 phase in OVCA-420 ovarian cancer cells (15). Thus, ART-mediated cell cycle arrest is possibly cell type dependent. ARTs also induce apoptotic cell death in a number of cell types, in which the mitochondrial-mediated apoptotic pathway plays a decisive role (2,4). For instance, DHA enhances Bax and reduces Bcl-2 expression in cancer cells (1,5). DHA-induced apoptosis is abrogated by the loss of Bak and is largely reduced in cells with siRNA-mediated downregulation of Bak or NOXA . However, DHA activates caspase-8, which is related to the death receptor-mediated apoptotic pathway in HL-60 cells (2). DHA enhances Fas expression and activates caspase-8 in ovarian cancer cells (17). DHA also enhances death receptor 5 and activates both mitochondrial- and death receptor-mediated apoptotic pathways in prostate cancer cells (18). ARTs-induced apoptosis in cancer cells may involve p38 MAPK rather than p53 (1,2).
ARTs inhibit angiogenesis which is a vital process in metastasis (19-22). DHA inhibits chorioallantoic membrane angiogenesis at low concentrations and decreases the levels of two major VEGF receptors on HUVEC (20). Conditioned media from K562 cells pre-treated with DHA inhibits VEGF expression and secretion in chronic myeloid leukemia K562 cells, leading to angiogenetic activity decrease (19,22). Artemisinin inhibits cell migration and concomitantly decreases the expression of MMP2 and the αvβ3 integrins in human melanoma cells (23). ARTs also regulate the levels of u-PA, MMP2, MMP7 and MMP9 all of which are related to metastasis ARTs exert synergistic effects with other compounds. Combination of DHA and caboplatin significantly reduces the development of ovarian cancer as compared with DHA only (17). Combined use of DHA or artesunate with gencitabine inhibits the growth of HepG2 and Hep3B transplanted tumors (1). Supra-additive inhibition of cell growth in some glioblastoma multiforme cells is observable when artesunate is in combined use with EGFR inhibitor OSI-774 (25). DHA not only up-regulates death receptor 5 expression but also cooperates with TNF-related apoptosis-inducing ligand (TRAIL) to induce apoptosis in human prostate cancer cells (18). Therefore, either used alone or in combination with other compounds, ARTs are promising compounds for chemotherapy.
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