Abstract
BackgroundEnvironment inside even a small tumor is characterized by total (anoxia) or partial oxygen deprivation, (hypoxia). It has been shown that radiotherapy and some conventional chemotherapies may be less effective in hypoxia, and therefore it is important to investigate how different drugs act in different microenvironments. In this study we perform a large screening of the effects of 19 clinically used or experimental chemotherapeutic drugs on five different cell lines in conditions of normoxia, hypoxia and anoxia.MethodsA panel of 19 commercially available drugs: 5-fluorouracil, acriflavine, bortezomib, cisplatin, digitoxin, digoxin, docetaxel, doxorubicin, etoposide, gemcitabine, irinotecan, melphalan, mitomycin c, rapamycin, sorafenib, thalidomide, tirapazamine, topotecan and vincristine were tested for cytotoxic activity on the cancer cell lines A2780 (ovarian), ACHN (renal), MCF-7 (breast), H69 (SCLC) and U-937 (lymphoma). Parallel aliquots of the cells were grown at different oxygen pressures and after 72 hours of drug exposure viability was measured with the fluorometric microculture cytotoxicity assay (FMCA).ResultsSorafenib, irinotecan and docetaxel were in general more effective in an oxygenated environment, while cisplatin, mitomycin c and tirapazamine were more effective in a low oxygen environment. Surprisingly, hypoxia in H69 and MCF-7 cells mostly rendered higher drug sensitivity. In contrast ACHN appeared more sensitive to hypoxia, giving slower proliferating cells, and consequently, was more resistant to most drugs.ConclusionsA panel of standard cytotoxic agents was tested against five different human cancer cell lines cultivated at normoxic, hypoxic and anoxic conditions. Results show that impaired chemosensitivity is not universal, in contrast different cell lines behave different and some drugs appear even less effective in normoxia than hypoxia.
Highlights
Environment inside even a small tumor is characterized by total or partial oxygen deprivation
Initial or moderate increase of HIF-1α levels could lead to cell adaptation, and in the absence of oxygen cancer cells adjust to their new microenvironment mainly by angiogenesis stimulation by vascular endothelial growth factor (VEGF) [9], inhibition of apoptosis via Bcl-2 [10], modifying the cellular glucose/energy metabolism [11], adapting to acidic extracellular pH [12] and up-regulation of proteins involved in metastasis [13]
The different cell lines were selected as representatives of various kinds of cancer types, including ovarian cancer (A2780), breast cancer (MCF-7), renal adenocarcinoma (ACHN), small cell lung cancer (H69) and a leukemic monocyte lymphoma (U937)
Summary
Environment inside even a small tumor is characterized by total (anoxia) or partial oxygen deprivation, (hypoxia). Neovascularization, or angiogenesis, is required to keep the growing tumor oxygenated and increased vascular density is correlated with increased metastasis and decreased patient survival in many cancers (reviewed by [6,7]). Initial or moderate increase of HIF-1α levels could lead to cell adaptation, and in the absence of oxygen cancer cells adjust to their new microenvironment mainly by angiogenesis stimulation by vascular endothelial growth factor (VEGF) [9], inhibition of apoptosis via Bcl-2 [10], modifying the cellular glucose/energy metabolism [11], adapting to acidic extracellular pH [12] and up-regulation of proteins involved in metastasis [13]. The delicate balance between activators and inhibitors regulate adaptation or cell death in growing tumor nodules
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