Resistance modification by PSC-833, a novel non-immunosuppressive cyclosporin A

doi:10.1016/0277-5379(91)90435-G

European Journal of Cancer and Clinical Oncology

Volume 27, Issue 12, December 1991, Pages 1639-1642

European Journal of ...

https://doi.org/10.1016/0277-5379(91)90435-G Get rights and content

Abstract

A novel non-immunosuppressive cyclosporin A, PSC-833, has been tested for its ability to circumvent resistance to doxorubicin, vincristine and colchicine in human and murine multidrug resistantant (MDR) cell lines. This compound is shown to be a highly potent resistance modifier, being 7–10-fold more potent than the parent compound, cyclosporin A, whilst approximately equal to cyclosporin A in the growth inhibitory effects of compound alone. Reversal of the P-glycoprotein-associated MDR drug accumulation defect is a major component of resistance reversal for PSC-833, as it is for cyclosporin A.

References (21)

T Mosmann
Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays
J Immunol Meth
(1983)
D Boesch et al.
Restoration of daunomycin retention in multidrug resistant P388 cells by submicromolar concentrations of SDZ PSC 833, a nonimmunosuppressive cyclosporin derivative
Exp Cell Res
(1991)
WS Dalton et al.
Drug resistance in multiple myeloma and non-Hodgkin's lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy
J Clin Oncol
(1989)
TP Miller et al.
P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil
J Clin Oncol
(1991)
RD Jones et al.
A pilot study of quinidine and epirubicin in the treatment of advanced breast cancer
Br J Cancer
(1990)
P Sonneveld et al.
Reversal of drug-resistance by cyclosporin-A in a patient with acute myelocytic leukaemia
Br J Haematol
(1990)
LM Slater et al.
Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphocytic leukaemia in vitro
J Clin Invest
(1986)
M Naito et al.
Competitive inhibition by verapamil for ATP-dependent high affinity vincristine binding to the plasma membrane of multidrug resistance K562 cells without calcium ion involvement
Cancer Res
(1989)
PR Twentyman et al.
Cyclosporin A and its analogues as modifiers of adriamycin and vincristine resistance in a multidrug resistant human lung cancer cell line
Br J Cancer
(1987)
PR Twentyman
Modification of cytotoxic drug resistance by non-immunosuppressive cyclosporins
Br J Cancer
(1988)

There are more references available in the full text version of this article.

Cited by (226)

Re-evaluation of the hCMEC/D3 based in vitro BBB model for ABC transporter studies
2022, European Journal of Pharmaceutics and Biopharmaceutics
The blood–brain barrier (BBB) represents one of the biggest hurdles for CNS related drug delivery, preventing permeation of most molecules, and therefore poses a major challenge for researchers in finding effective treatments for CNS diseases. The low permeability of molecules through the BBB is linked on one hand to the extreme tightness by tight junction (TJ) formation limiting the paracellular transport, and on the other hand to the presence of ATP-driven efflux pumps which actively transport unwanted compounds out of the brain. In this study we evaluated the applicability of the immortalized human cell line hCMEC/D3 for ABC transporter studies, focusing on the most expressed ABC transporters at the human BBB: P-glycoprotein (PGP, ABCB1), multidrug resistance protein 4 (MRP4, ABCC4) and breast cancer resistance protein (BCRP, ABCG2). Therefore, a two-step screening method was applied, consisting of a regular uptake assay (96-well format) and bidirectional transport studies, using a transwell system as in vitro simulation of the human BBB. In conclusion, the hCMEC/D3 based in vitro BBB model is well suited to screen drug candidates for ABC transporter interactions on the basis of a regular uptake assay, but in terms of transcellular permeability studies the cell line is limited by a lack of sufficient junctional tightness.
Valspodar limits human cytomegalovirus infection and dissemination
2021, Antiviral Research
Citation Excerpt :
These inhibitors typically modulate ABC transporter function by competing for binding and transport of the substrate across the membrane or by binding to the protein and inducing allosteric changes, which hinder translocation. Valspodar, also known as PSC-833, was developed by Sandoz/Novartis (Twentyman, P.R. and N.M. Bleehen, 1991) as a chemosensitizer and studied thoroughly on hematological and solid tumors refractory to the classical anticancer drugs. Valspodar inhibits both the substrate export and basal ATPase activity of p-glycoprotein (Loor, 1999).
Human cytomegalovirus (HCMV) is a ubiquitous pathogen that establishes a life-long infection affecting up to 80% of the US population. HCMV periodically reactivates leading to enhanced morbidity and mortality in immunosuppressed patients causing a range of complications including organ transplant failure and cognitive disorders in neonates. Therapeutic options for HCMV are limited to a handful of antivirals that target late stages of the virus life cycle and efficacy is often challenged by the emergence of mutations that confer resistance. In addition, these antiviral therapies may have adverse reactions including neutropenia in newborns and an increase in adverse cardiac events in HSCT patients. These findings highlight the need to develop novel therapeutics that target different steps of the viral life cycle. To this end, we screened a small molecule library against ion transporters to identify new antivirals against the early steps of virus infection. We identified valspodar, a 2nd-generation ABC transporter inhibitor, that limits HCMV infection as demonstrated by the decrease in IE2 expression of virus infected cells. Cells treated with increasing concentrations of valspodar over a 9-day period show minimal cytotoxicity. Importantly, valspodar limits HCMV plaque numbers in comparison to DMSO controls demonstrating its ability to inhibit viral dissemination. Collectively, valspodar represents a potential new anti-HCMV therapeutic that limits virus infection by likely targeting a host factor. Further, the data suggest that specific ABC transporters may participate in the HCMV life-cycle.
Efflux pumps, NHE1, monocarboxylate transporters, and ABC transporter subfamily inhibitors
2020, pH-Interfering Agents as Chemosensitizers in Cancer Therapy
The transporter family of proteins play an essential role in normal physiology of the human body, as well as in many pathological states, generated by genetic or acquired diseases, including many forms of cancer. The chapter details the main classes of transporters, their natural substrates, and the drugs that can be transported in/out of various cells. It also details the classes of inhibitors developed against each type of transporter, their potency, selectivity and toxicity, alone and in combination with different other drugs, in vitro and in vivo. Whenever possible, we have presented the translational efforts made to move different transporter inhibitors into clinical use, as well as the representatives currently available in clinic, their advantages and limitations.
Identification of Smac mimetics as novel substrates for p-glycoprotein
2019, Cancer Letters
Multidrug resistance (MDR) in cancer patients undergoing chemotherapy is preventing effective treatment of multiple cancer types including pediatric tumors. Resistance to chemotherapeutic drugs in cancer cells is frequently associated with high expression of p-glycoprotein, a transporter in the plasma membrane that can mediate cellular drug export. Here, we generated pediatric cancer cells with acquired resistance to the chemotherapeutic drug vincristine (VCR). In these cells, acquired resistance is associated with increased expression of p-glycoprotein. VCR-resistant cells display an MDR phenotype and have acquired resistance to multiple other chemotherapeutic drugs including doxorubicin (DOXO) and etoposide (ETO). Notably, we discovered that these cells also display cross-resistance with several Smac mimetics, a novel class of experimental cancer therapeutics designed to induce apoptosis by inhibiting Inhibitor of Apoptosis (IAP) proteins. Resistance to Smac mimetics is reversible in the presence of p-glycoprotein inhibitors, highlighting Smac mimetics as novel substrates for p-glycoprotein. The identification of Smac mimetics as substrates for p-glycoproteins may influence the design of future clinical trials to prevent usage of Smac mimetics in the context of MDR or, alternatively, combine Smac mimetics with p-glycoprotein inhibitors to maximize their efficiency.
Understanding of human ATP binding cassette superfamily and novel multidrug resistance modulators to overcome MDR
2018, Biomedicine and Pharmacotherapy
Indeed, multi-drug resistance (MDR) is a significant obstacle to effective chemotherapy. The overexpression of ATP-binding cassette (ABC) membrane transporters is a principal cause of enhanced cytotoxic drug efflux and treatment failure in various types of cancers. At cellular level, the pumps of ABC family regulate the transportation of numerous substances including drugs in and out of the cells. In past, the overexpression of ABC pumps suggested a well-known mechanism of drug resistance in cancers as well as infectious diseases. In oncology, the search for new compounds for the inhibition of these hyperactive ABC pumps either genetically or functionally, growing interest to reverse multi-drug resistance and increase chemotherapeutic effects. Several ABC pump inhibitor/modulators has been explored to address the cancer associated MDR. However, the clinical results are still disappointing and conventional chemotherapies are constantly failed in successful eradication of MDR tumors. In this context, the structural and functional understanding of different ATP pumps is most important. In this concise review, we elaborated basic crystal structure of ABC transporter proteins as well as its critical elements such as different domains, motifs as well as some important amino acids which are responsible for ATP binding and drug efflux as well as demonstrated an ATP-switch model employed by various ABC membrane transporters. Furthermore, we briefly summarized different newly identified MDR inhibitors/modulators, deployed alone or in combination with cytotoxic agents to deal with MDR in different types of cancers.
Quercetin-glutamic acid conjugate with a non-hydrolysable linker; a novel scaffold for multidrug resistance reversal agents through inhibition of P-glycoprotein
2017, Bioorganic and Medicinal Chemistry
Previously, we have reported remarkable effect of a quercetin-glutamic acid conjugate to reverse multidrug resistance (MDR) of cancer cells to a broad spectrum of anticancer agents through inhibition of P-glycoprotein (Pgp)-mediated drug efflux. Due to the hydrolysable nature, MDR-reversal activity of the quercetin conjugate was attributed to its hydrolysis product, quercetin. However, several lines of evidence demonstrated that the intact quercetin-glutamic acid conjugate has stronger MDR-reversal activity than quercetin. In order to evaluate this hypothesis and to identify a novel scaffold for MDR-reversal agents, we prepared quercetin conjugates with a glutamic acid attached at the 7-O position via a non-hydrolysable linker. Pgp inhibition assay, Pgp ATPase assay, and MDR-reversal activity assay were performed, and the non-hydrolysable quercetin conjugates showed significantly higher activities compared with those of quercetin. Unfortunately, the quercetin conjugates were not as effective as verapamil in Pgp-inhibition and thereby reversing MDR, but it is worth to note that the structurally modified quercetin conjugates with a non-cleavable linker showed significantly improved MDR-reversal activity compared with quercetin. Taken together, the quercetin conjugates with appropriate structural modifications were shown to have a potential to serve as a scaffold for the design of novel MDR-reversal agents.

View all citing articles on Scopus

View full text

Article preview

European Journal of Cancer and Clinical Oncology

Abstract

References (21)

Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays

J Immunol Meth

Restoration of daunomycin retention in multidrug resistant P388 cells by submicromolar concentrations of SDZ PSC 833, a nonimmunosuppressive cyclosporin derivative

Exp Cell Res

Drug resistance in multiple myeloma and non-Hodgkin's lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy

J Clin Oncol

P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil

J Clin Oncol

A pilot study of quinidine and epirubicin in the treatment of advanced breast cancer

Br J Cancer

Reversal of drug-resistance by cyclosporin-A in a patient with acute myelocytic leukaemia

Br J Haematol

Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphocytic leukaemia in vitro

J Clin Invest

Competitive inhibition by verapamil for ATP-dependent high affinity vincristine binding to the plasma membrane of multidrug resistance K562 cells without calcium ion involvement

Cancer Res

Cyclosporin A and its analogues as modifiers of adriamycin and vincristine resistance in a multidrug resistant human lung cancer cell line

Br J Cancer

Modification of cytotoxic drug resistance by non-immunosuppressive cyclosporins

Br J Cancer

Cited by (226)

Re-evaluation of the hCMEC/D3 based in vitro BBB model for ABC transporter studies

Valspodar limits human cytomegalovirus infection and dissemination

Efflux pumps, NHE1, monocarboxylate transporters, and ABC transporter subfamily inhibitors

Identification of Smac mimetics as novel substrates for p-glycoprotein

Understanding of human ATP binding cassette superfamily and novel multidrug resistance modulators to overcome MDR

Quercetin-glutamic acid conjugate with a non-hydrolysable linker; a novel scaffold for multidrug resistance reversal agents through inhibition of P-glycoprotein

PaperResistance modification by PSC-833, a novel non-immunosuppressive cyclosporin A

Abstract

J Immunol Meth

Exp Cell Res

Drug resistance in multiple myeloma and non-Hodgkin's lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy

J Clin Oncol

P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil

J Clin Oncol

A pilot study of quinidine and epirubicin in the treatment of advanced breast cancer

Br J Cancer

Reversal of drug-resistance by cyclosporin-A in a patient with acute myelocytic leukaemia

Br J Haematol

Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphocytic leukaemia in vitro

J Clin Invest

Competitive inhibition by verapamil for ATP-dependent high affinity vincristine binding to the plasma membrane of multidrug resistance K562 cells without calcium ion involvement

Cancer Res

Cyclosporin A and its analogues as modifiers of adriamycin and vincristine resistance in a multidrug resistant human lung cancer cell line

Br J Cancer

Modification of cytotoxic drug resistance by non-immunosuppressive cyclosporins

Br J Cancer

Paper
Resistance modification by PSC-833, a novel non-immunosuppressive cyclosporin A