P-glycoprotein and survivin simultaneously regulate vincristine-induced apoptosis in chronic myeloid leukemia cells

Abstract

Abstract. Overexpression of P-glycoprotein (Pgp/ABCB1) in tumor cells is associated with a classic phenotype of multidrug resistance (MDR). Moreover, some members of the inhibitor of apoptosis protein (IAP) family, such as survivin, contribute to an apoptosis-resistant phenotype, by inhibiting chemotherapyinduced cell death and promoting MDR. By using Western blotting, qRT-PCR, Annexin V and immunofluorescence assays we have demonstrated a relationship between Pgp and survivin in a prior sensitive chronic myeloid leukemia (CML) cell line (K562). A high dose of vincristine induced a concomitant overexpression of Pgp and survivin, which was associated with a low apoptotic index in the K562 cell line. In addition, we observed a cytoplasmic co-localization of Pgp and survivin, suggesting a functional association between these two proteins in apoptosis control by a common mechanism. In summary, our data suggest that Pgp and survivin should be analyzed in aggregate because they may have significant impact on drug resistance in CML cells.

Expression of the multidrug transporter P-glycoprotein is inversely related to that of apoptosis-associated endogenous TRAIL

“…The concomitant expression of Pgp and apoptotic pathway proteins correlates with a multifactorial resistance phenotype in cancer cells [7, 21, 22, 29]. In the present study, we analyzed 95 apoptosis-linked genes, via TLDA, in both inducible Pgp cell lines and drug-resistant cell lines.…”

“…The procedures were performed as previously described [22] and cell staining was visualized in a Zeiss LSM 510 NLO Meta confocal microscope.…”

“…It has been reported that the co-expression of Pgp and anti-apoptotic proteins may contribute to the development of the MDR cancer phenotype, although those proteins might be modulated by chemotherapeutic agents [21, 22]. We hypothesized that Pgp, in addition to its function as a drug transporter, might actually play an additional role by modulating apoptotic protein expression.…”

The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia

“…Recently, we evaluated the resistance induced by the overexpression of both ABCB1 and survivin proteins [43]. In this work, we showed that K562 cells (ABCB1-negative) progressively became resistant to vincristine treatment by simultaneous overexpression of ABCB1 and survivin.…”

“…Studies have shown that the resistance induced by ABCB1 is also associated with the inhibition of cell death, and ABCB1 promotes additional protection to caspases-dependent apoptosis, UV radiation, serum starvation condition, and spontaneous apoptosis [39–42]. Recently, our group demonstrated that ABCB1 expression induced by drug treatment promotes resistance to apoptosis in BCR-ABL cells independently of its drug-efflux activity [43]. …”