The cyclosporin PSC 833 increases survival and delays engraftment of human multidrug-resistant leukemia cells in xenotransplanted NOD-SCID mice

Abstract

Circumvention of chemoresistance in cancer may involve several modulator drugs with high affinity for the multidrug transporter P-glycoprotein (Pgp), which is expressed in a number of multi-resistant malignancies. Pgp acts as a membrane efflux pump with broad substrate specificity including antineoplastic drugs and endogenous substances such as certain cytokines and sphingolipids. Therefore, the consequence of Pgp blockade could be far more complex than intracellular drug retention. In the present study exposure of the Pgp inhibitor, PSC 833 (1200 ng/ml), to Pgp expressing KG1a/200 human leukemia cells provoked cell cycle arrest and apoptosis in vitro. This finding was put to test in vivo using a xenotransplant model of KG1a/200 human cells intravenously inoculated into non-obese diabetic severe combined immunodeficient (NOD-SCID) mice. The animals were randomly allocated to receive treatment with PSC 833 (n = 32) or placebo (n = 24). PSC 833 (30 mg/kg) was subcutaneously injected six or 12 times separated by 48-96 h. The overall mean whole blood concentration of PSC 833 was 1191 ± 60 ng/ml (s.e.m.) at 20 h after administration. Tumor engraftment was significantly reduced in the treatment group (P = 0.037), which also had prolonged survival compared to control animals (P = 0.0016). This is the first study that demonstrates antileukemic effects of a Pgp inhibitor as single agent therapy in vivo, and the present data raise the possibility of alternative exploitation of modulators in cancer chemotherapy.

Celastraceae Sesquiterpenes as a New Class of Modulators That Bind Specifically to Human P-Glycoprotein and Reverse Cellular Multidrug Resistance

“…It is also worth noting that the most efficient sesquiterpenes were less toxic than verapamil toward cultured drug-sensitive cells but were specifically more toxic toward P-glycoprotein-expressing cells (data not shown). This finding is very interesting, considering that P-glycoprotein is presumably involved in malignancy of cancer cells as well as drug resistance (41) and that inhibition of P-glycoprotein by PSC-833 led to a selective direct elimination of MDR cells (42).…”

ATP-binding-cassette transporters in hematopoietic stem cells and their utility as therapeutical targets in acute and chronic myeloid leukemia

“…In this context, it is noteworthy that an anti-apoptotic role for ABCB1 has been demonstrated recently promoting cell survival by inhibiting caspase activation. [42][43][44][45] Physiological function of other ABC transporters in HSC. Characterization of molecules with tightly controlled expression patterns during differentiation represents an important approach to understanding the regulation of HSC commitment.…”

P-glycoprotein as a therapeutic target: good news

“…1 Thus, uncontrolled Ig production with autoantibody formation could eventually lead to the development of clonal B cell disorders, as in the few cases in the literature and in our cases as well. 1,3,4 However, it should not be overlooked that T-LGLs with cytotoxic/suppressor phenotype might function as contrasuppressor T cells.…”

“…Furthermore, it can not be definitely excluded that the CBLPDs identified might share a common malignant precursor with T-LGL leukemias. Another, in our view more plausible, explanation might be that CBLPDs emerged secondarily due to B cell dysfunction in the setting of T-LGL leukemia; 1,5,6 in most cases, unlike…”

“…Documentation of the clonal T-LGL and B cell entities was based upon morphologic criteria (apart from case No. 8 in whom PB lymphocytes lacked typical LGL morphology; however, occasionally, clonally expanded lymphocytes with a characteristic CD3 + CD57 + phenotype may not have LGL morphology on PB smear 1 ), immunophenotypic analysis and genotypic profile. Their distribution in the tissues examined was immunophenotypically and genotypically discriminate.…”