C-phycocyanin to overcome the multidrug resistance phenotype in human erythroleukemias with or without interaction with ABC transporters

The phenotype of multidrug resistance (MDR) is one of the main causes of chemotherapy failure. Our study investigated the effect of C-phycocyanin (C-PC) in three human erythroleukemia cell lines with or without the MDR phenotype: K562 (non-MDR; no overexpression of drug efflux proteins), K562-Lucena (MDR; overexpression of ATP-binding cassette, sub-family B/ABCB1), and FEPS (MDR; overexpression of ABCB1 and ATP-binding cassette, sub-family C/ABCC1). Using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, we showed that 20 and 200 μg/mL C-PC decreased K562 viable cells after 24 h and 200 μg/mL C-PC decreased K562-Lucena cell proliferation after 48 h. C-PC did not decrease viable cells of FEPS cells. On the other hand, the MTT assay showed that exposure of 2, 20, and 200 μg/mL C-PC for 24 or 48 h was not cytotoxic to peritoneal macrophages. At 72 h, the trypan blue exclusion assay showed that 20 μg/mL C-PC decreased K562 and K562-Lucena cell proliferation and in FEPS cells, only 200 μg/mL C-PC decreased proliferation. In addition, protein-protein docking showed differences in energy and binding sites of ABCB1 and ABCC1 for C-PC, and these results were confirmed by the efflux protein activity assay. Only ABCC1 activity was altered in the presence of C-PC and FEPS cells showed lower C-PC accumulation, suggesting C-PC extrusion by ABCC1, conferring C-PC resistance. In combination with chemotherapy (vincristine [VCR] and daunorubicin [DNR]), the sensitivity of K562-Lucena cells for C-PC + VCR did not increase, whereas FEPS cell sensitivity for C-PC + DNR was increased. In molecular docking experiments, the estimated free energies of binding for C-PC associated with chemotherapy were similar (VCR: -6.9 kcal/mol and DNR: -7.2 kcal/mol) and these drugs were located within the C-PC cavity. However, C-PC exhibited specificity for tumor cells and K562 cells were more sensitive than K562-Lucena cells, followed by FEPS cells. Thus, C-PC is a possible chemotherapeutic agent for cells with the MDR phenotype, both alone in K562-Lucena cells (resistance due to ABCB1), or in combination with other drugs for cells similar to FEPS (resistance due to ABCC1). Moreover, C-PC did not damage healthy cells (peritoneal macrophages of Mus musculus).