Efficacy of Chemotherapeutic Agents Under Hypoxic Conditions in Pulmonary Adenocarcinoma Multidrug Resistant Cell Line

Abstract

Hypoxia is often observed in solid tumors. The aim of this study was to investigate the efficacy of seven cytotoxic drugs against the pulmonary adenocarcinoma multidrug-resistant cell line A549/MDR under hypoxia (3% O₂), and to explore the possible mechanisms for the change of efficacy. The efficacy of cytotoxic drugs under hypoxic conditions was different from that under normoxia. Proliferation of A549/MDR cells was enhanced under hypoxia and no close correlation was found between proliferation and cytotoxic effects. Under hypoxia, the efficacy of rhodamine 123 efflux was unchanged; the culture medium became more acidic and the generation of reactive oxygen species (ROS) was decreased. The intracellular fluorescence intensity of daunorubicin was much lower in this acidic microenvironment. These results indicate that susceptibility to drugs was greatly influenced by hypoxia and different intracellular drug concentrations induced by microenvironment acidification which may be the main cause of the change in drug efficacy. In addition, proliferation may change resistance to study drugs under hypoxia for A549/MDR cells. The decreased generation of ROS may be another reason for the resistance of A549/MDR cell line to daunorubicin under hypoxic conditions. Drug exclusion mediated by P-gp may not be the key reason.

Keywords:

• Pulmonary adenocarcinoma
• multidrug resistance
• cytotoxic drugs
• hypoxia
• normoxia