Understanding the role of drug efflux transporters in vincristine-resistant acute lymphoblastic leukaemia cells.

Cell proliferation is an integral process in ensuring leukemic cell survival. Microtubules, essential cytoskeleton components and important players in mitosis, makes them effective therapeutic target in leukaemia. The vinca alkaloid, vincristine (VCR), specifically disrupts microtubule dynamics, causing mitotic arrest and cell death. VCR treatment is one of the most commonly utilized in childhood Acute Lymphoblastic Leukaemia (ALL) due to its non-myelosuppressive nature and availability. In ALL, it has aggressive in vitro and in vivo activity but the mechanisms regulating VCR resistance remains unclear. To explore the possible role of efflux transporters in VCR displacement as a potential VCR resistant mechanism, we determined multi-drug resistance (MDR) transporter protein expression in VCR-resistant ALL cell lines generated via culture of REH and RS4 ALL cell lines by gradually increasing VCR concentrations. The resistant cell lines, REH-3 and RS4-1, show marked upregulation of Multidrug Resistance 1 (MDR1) as well as cross-resistance to known MDR1 substrate, prednisolone (PRED). This effect is prevented by MDR1 inhibitor, verapamil (VERA) contributing to the re-establishment of VCR sensitivity. Alternatively, in co-culture experiments, mesenchymal stem cells (MSCs) protected ALL cells from VCR cytotoxicity. Together, these data indicate that VCR is an effective treatment option for ALL but resistance mechanisms vary for different ALL subtypes.Bachelor of Science in Biological Science