Reversal of Multidrug Resistance in Murine Lymphoma Cells by Amphiphilic Dihydropyridine Antioxidant Derivative

Background: Multidrug resistance, the principal mechanism by which cancer cells develop resistance to chemotherapy drugs, is a major factor in the failure of many forms of chemotherapies. Aim: The aim of the study was to investigate the effect of K-2-11 on the reversal of multidrug resistance. Materials and Methods: The effects of amphiphilic dihydropyridine derivative K-2-11 were tested on MDR1-expressing mouse lymphoma cells and their parental control. The effects of K-2-11 with and without doxorubicin were studied by determination of cell viability, cell proliferation and production of reactive oxygen species. Results: K-2-11 caused complete reversal of multidrug resistance of the MDR cells, being much more efficient than the positive control verapamil. Accordingly, the cytotoxic effects of doxorubicin were enhanced by K-2-11, both in the MDR and in parental cell line, while K-2-11 alone did not affect cell viability. K-2-11 also acted as an antioxidant, reducing the cellular generation of reactive oxygen species. Conclusion: Our results indicate the high potential of K-2-11 as a novel antioxidant with potent MDR-blocking ability that should be studied further for development in adjuvant anticancer treatments. Besides late diagnosis, resistance to multiple chemotherapies can be considered as major source of failure in cancer treatment. There may be several mechanisms involved in the development of multidrug resistance (MDR) and the best characterized involves the membrane localized P- glycoprotein (P-gp). MDR of cancer cells is associated with a large number of chemotherapeutic medicaments due to P- gp overexpression. This protein accomplishes drug resistance through its action as a drug efflux-pump by reducing the intracellular concentration of anticancer drugs (1). P- glycoprotein belongs to the group of the most important efflux pumps and causes resistance to various classes of cytostatic compounds such as the vinca alkaloids, anthracycline derivatives, podophyllotoxins and fluorouracil derivatives (2). Expression of MDR1 (multi-drug resistance protein 1) protein, which belongs to the P-gp family, is up- regulated during stressful stimuli such as chemotherapy. The enhancement of MDR1 expression by reactive oxygen species (ROS) in tumor cells is of particular interest because many anticancer treatments (e.g. radiotherapy and doxorubicin chemotherapy) rely on the cytotoxicity of ROS. Moreover, cancer cells themselves produce more ROS than normal cells, mainly due to alterations in metabolic pathways and an inadequate tumor vascular network. Cellular antioxidant mechanisms that in normal conditions scavenge ROS, under such excessive oxidative stress, are unable to prevent ROS impact on vital cellular functions (3). DNA damage and changes in signal transduction pathways lead to mutations resulting in malignant transformation, while ROS generated during the inflammation that accompanies carcinogenesis have been shown to facilitate tumor promotion (4). Hence, oxidative stress plays a role in tumor progression. Thereby, MDR inhibitors with antioxidant potential would be useful in treating cancer patients whose tumors are resistant to multiple chemotherapies. Such chemicals might prevent ROS increase in tumor cells and