The effects of proteasome inhibitor bortezomib on a P‐gp positive leukemia cell line K562/A02

Abstract

The aim of this study is to clarify the efficacy of proteasome inhibitor bortezomib to multidrug resistant (MDR) acute leukemia cells. We observed the effects of bortezomib on a P-glycoprotein (P-gp) positive leukemia line K562/A02. The results showed that bortezomib has significant effects on P-gp positive K562/A02 cells including cytotoxicity (48 h IC(50): 171.36 nM), induction of apoptosis (31.71 +/- 1.07% apoptotic cells after 24 h treatment at 100 nM), and inhibition of proteasome chymotrypsin-like activity (relative activity to untreated controls: 20.07 +/- 0.66% at 24 h with 10 nM bortezomib). These effects were lower than those observed in K562 cells (IC(50), percentage of apoptotic cells, relative chymotrypsin-like activity to untreated controls were 56.28 nM, 77.95 +/- 0.35%, 5.35 +/- 2.05% after the same treatments, respectively). No synergy between daunorubicin and bortezomib was shown in the killing of K562/A02 cells (synergistic ratios were <1). P-gp expression levels did not decrease in K562/A02 cells after bortezomib treatment. Pretreatment with bortezomib does not improve the intracellular anthracycline concentration in K562/A02 cells. Bortezomib shows a promising effect for the treatment of refractory/relapsed leukemia, but it does not improve the effect of anthracycline to MDR leukemia cells.

The interaction of bortezomib with multidrug transporters: implications for therapeutic applications in advanced multiple myeloma and other neoplasias

“…In the literature, results using one breast cancer cell line study suggests that bortezomib is a P-gp inhibitor [29], whereas other studies in leukaemia-derived cell lines refuted that finding [30, 31]. Here, we used the P-gp-overexpressing cell line DLKP-A and concluded that bortezomib is a weak inhibitor, at best and only at supra pharmacological concentrations.…”

CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy

“…It has previously been reported that bortezomib is transported by P-gp (Nakamura et al, 2007, Rumpold et al, 2007, Lu et al, 2010, O’Connor et al, 2013), primarily in the context of cancer multidrug resistance (Jung et al, 2004). Interestingly a silent polymorphism in P-gp, MDR1 C3435T, confers increased latency to relapse and higher bortezomib efficacy in human multiple myeloma (Buda et al, 2009, Buda et al, 2010).…”

“…Long term bortezomib treatment resulted in an improvement in motor function in SMA mice compared with vehicle treated animals; however survival was unaffected (Kwon et al, 2011). Pre-clinical studies have shown that bortezomib is unable to penetrate into the CNS, impeding its use for treating SMA and other neurological disorders (Nakamura et al, 2007, Rumpold et al, 2007, Lu et al, 2010). To overcome bortezomib’s low biodistribution in the CNS, we hypothesized that pre-treatment with an ABC transporter inhibitor would prevent bortezomib’s efflux at the blood-brain and -spinal cord barriers.…”

The resistance mechanisms of proteasome inhibitor bortezomib

“…The resistance-fold of K562/A02 to adriamycin and DNR were 139 and 67 compared with K562 cells, while the resistance-fold of K562/A02 to bortezomib was only 3 compared with K562 cells. These results showed only a slight cross-resistance of K562/A02 to bortezomib [53]. Lymphoid CEM/VLB cells with P-gp overexpression exhibited substantial resistance to carfilzomib (114-fold), whereas less resistance to bortezomib (4.5-fold) was observed [54].…”