Modulation of Multidrug Resistance on the Same Single Cancer Cell in a Microfluidic Chip: Intended for Cancer Stem Cell Research

Abstract

A small population of cancer stem cells has been identified in a range of haematopoietic and solid tumours. These cells retain features of normal stem cells including self-renewal, pluripotency and altered gene expression, and might represent the cell of origin of these tumours (Dean et al., 2005)(Fallica et al., 2011). The possible eradication of cancer stem cells might offer revolutionary advances in the treatment of cancer. However, cancer stem cells are rare and are hard to destroy due to the occurrence of high level of multidrug resistance (MDR) proteins. Tumor cells carrying the MDR phenotype are often associated with the over-expression of drug efflux pumps, among which the membrane-bound energy-dependent P-glycoprotein (Pgp) is one of the important classes (Marthinet et al., 2000)(Persidis, 1999)(Locke et al., 2003). The Pgp efflux pump, which belongs to the superfamily of ATP binding cassette (ABC) transporters (i.e. ABCB1) (Higgins, 2007) and is encoded by the MDR1 class of genes (Gros et al., 1986), actively transports drugs out of the cancer cells. This has caused the intracellular drug concentration to be lower than the drug’s efficacy threshold within cancer cells (Marthinet et al., 2000), leading to the failure of many forms of chemotherapy (Higgins, 2007). Gaining a better insight into the mechanisms of cancer stem cell resistance to chemotherapy might lead to new therapeutic drug targets and better anti-cancer treatment strategies (Dean et al., 2005)(Shervington and Lu, 2008)(Dean, 2009)(Donnenberg and Donnenberg, 2005). To improve the chemotherapy sensitivity, Pgp inhibitors or MDR modulators have been employed, with their effects on MDR reversal studied (Ren and Wei, 2004)(Wang et al., 2000)(Efferth et al., 2002)(Medeiros et al., 2007)(Meaden et al., 2002). For instance, Ren et al. studied the efflux of doxorubicin in human carcinoma cells (Ren and Wei, 2004). But the assay conducted by a fluorescence plate reader is not amendable to the study of rare cells such as cancer stem cells. Wang et al. developed a method to quantitatively assess Pgp inhibitors by flow cytometry (Wang et al., 2000). While this method is widely used to study MDR modulation, it does not provide the information of an individual single cell, such as its time-dependent drug transport kinetics. In addition, flow cytometry requires a large