Abstract
Tumor hypoxia is one main biological factor that drives resistance to chemotherapy and radiotherapy. To develop a novel strategy for overcoming hypoxia-induced therapy resistance, we examined the anti-neoplastic activity of the reactive oxygen donor dihydroartemisinin (DHA) in human colon cancer cell lines in normoxia and severe hypoxia. In addition, we analyzed the involvement of the intrinsic apoptosis pathway for DHA-mediated cytotoxicity in HCT116 cells in short-term and long-term in vitro assays. When applied at lower concentrations (≤25 μM), DHA induced apoptosis in Colo205, HCT15, and HCT116 cells, whereas necrotic cell death was increased when cells were treated with higher DHA concentrations (50 μM). However, no preference for DHA-induced apoptosis or necrosis could be detected between the treatment under normoxic or hypoxic conditions. Moreover, DHA potently reduced clonogenic survival of HCT116 cells in normoxia and hypoxia. Treatment of HCT116 cells with 25 μM DHA resulted in activation of Bax under normoxic and hypoxic conditions. Interestingly, cytochrome c release from the mitochondria and caspase-activation were observed only under normoxic conditions, whereas, under hypoxic conditions DHA induced a caspase-independent apoptosis-like cell death. However, under both conditions, generation of reactive oxygen species was an important mediator of DHA-induced toxicity. Further molecular analysis suggests that DHA-mediated cell death involves different sets of pro-apoptotic Bcl-2 family members. The pronounced cytotoxic activity of DHA in severe hypoxia as well as normoxia offers new perspectives for targeting the hypoxic tumor cell fraction to improve treatment outcome for cancer patients.
Highlights
Tumor cell resistance to classical chemotherapy and radiotherapy remains a major obstacle in the treatment of solid human tumors [1]
DHA significantly reduced the number of viable HCT15, HCT116, and Colo 205 colon cancer cells in a concentration-dependent manner under normoxic (Figure 1, upper panel) as well as under hypoxic conditions (Figure 1, lower panel)
Whereas HCT15 cells turned out to be highly sensitive in normoxia and hypoxia with almost 50% reduction in the number of viable cells upon treatment with 10 μM DHA under both conditions, the sensitivity of HCT116 cells was higher in hypoxia
Summary
Tumor cell resistance to classical chemotherapy and radiotherapy remains a major obstacle in the treatment of solid human tumors [1]. Genetic or epigenetic alterations in the tumor cells that affect cellular death and survival signaling can allow the tumor cells to escape the cytotoxic action of standard genotoxic therapies and molecularly targeted agents. Specific conditions within the tumor microenvironment and the intimate dialog between tumor cells and their surrounding stroma by soluble growth- and survival-promoting factors provide a multitude of mechanisms for therapy resistance. Current research activities focus on the identification of drugs that are active under adverse environmental conditions to counteract environment-mediated resistance to therapies. Tumor hypoxia is a common characteristic of solid human tumors and is mostly associated with poor prognosis [2].
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