Activity of cyclosporins as resistance modifiers in primary cultures of human haematological and solid tumours

Fridborg, H; Jönsson, Bertil; Nygren, Peter; Csòka, Katalin; Nilsson, Kenneth; Öberg, Gunnar; Kristensen, Jörgen; Bergh, Jonas; Tholander, Bengt; Olsen, Lene Christin

doi:10.1038/bjc.1994.242

Cited by 28 publications

(10 citation statements)

References 25 publications

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“…[26][27][28][29] These modulators also markedly increased the accumulation and retention of DNR or the marker agents rhodamine 123 and DiOC 2 . [28][29][30][31][32] In adult AML, the sensitizing effect on drug resistance and the increase in drug accumulation and retention was often correlated with the expression of P-gp.…”

Section: Discussionmentioning

confidence: 99%

The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia

et al. 1998

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Resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL). Resistance to this class of drugs may (partly) be reversed by modulating agents, as has been demonstrated in a variety of cell lines. However, it is unknown which modulators may be of clinical benefit in childhood ALL. Therefore, we studied the modulating effect of PSC 833, cyclosporin A (CsA), verapamil (Vp) and genistein on daunorubicin (DNR) cytotoxicity, accumulation and retention in childhood ALL cells. DNR cytotoxicity was determined using the MTT assay; DNR accumulation, DNR retention and the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and major vault protein/lung resistance protein (LRP) were determined by flow cytometry. In the majority of samples PSC 833 (19/26), CsA (22/26) and Vp (15/18) sensitized the cells to DNR whereas genistein made 25 out of 26 samples more resistant to DNR. The sensitizing effect on the cytotoxicity of DNR was median 1.2-fold using 2 M PSC 833 (P = 0.025), 1.5-fold using 4 M CsA (P = 0.003) and 1.6-fold using 6 M Vp (P = 0.012) whereas the adverse effect of 25 M genistein was median 1.8-fold (P Ͻ 0.0001). No relationship was found between the sensitizing effect of PSC 833, CsA or Vp and the degree of DNR resistance. In contrast, the adverse effect of genistein was largest in DNR sensitive samples (P = 0.003). The effect of each modulator on the cytotoxicity of DNR did not differ between initial and relapse ALL samples although the latter were median 1.4-fold more resistant to DNR (P = 0.005). Modulation of DNR cytotoxicity was not correlated with changes in the accumulated and retained intracellular DNR content or with the expression of Pgp, MRP and LRP. Besides genistein, PSC 833, CsA and Vp incidentally made ALL cells more resistant to DNR. CsA stimulated the leukemic cell survival in seven out of 26 samples, a phenomenon that was not related to the degree of DNR resistance. In conclusion, PSC 833, CsA and Vp but not genistein may be used to sensitize cells to DNR in childhood ALL. The data also indicate that not all patients may have a therapeutic benefit from these modulators. Therefore, an in vitro culture assay may be necessary to screen for patients who may benefit by a modulator in their therapy.

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Section: Discussionmentioning

confidence: 99%

The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia

et al. 1998

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“…S2), suggesting that the potentiation effect observed with CsA may reflect an alternative mode of action of the latter. In addition to inhibiting calcineurin, CsA is also a well-known Pgp inhibitor (41)(42)(43). Thus, we reasoned that Pgp inhibition may be the mechanism underlying CsA-mediated enhancement of APO866 antileukemic activity and tested other, unrelated Pgp inhibitors in combination with APO866 to see whether they would recreate the effects of CsA.…”

Section: Nampt Is Overexpressed and Has Adverse Prognostic Relevance mentioning

confidence: 99%

APO866 Increases Antitumor Activity of Cyclosporin-A by Inducing Mitochondrial and Endoplasmic Reticulum Stress in Leukemia Cells

Cagnetta

Caffa

Acharya

et al. 2015

Clinical Cancer Research

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Purpose: The nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, APO866, has been previously shown to have antileukemic activity in preclinical models, but its cytotoxicity in primary leukemia cells is frequently limited. The success of current antileukemic treatments is reduced by the occurrence of multidrug resistance, which, in turn, is mediated by membrane transport proteins, such as P-glycoprotein-1 (Pgp). Here, we evaluated the antileukemic effects of APO866 in combination with Pgp inhibitors and studied the mechanisms underlying the interaction between these two types of agents.Experimental Design: The effects of APO866 with or without Pgp inhibitors were tested on the viability of leukemia cell lines, primary leukemia cells (AML, n ¼ 6; B-CLL, n ¼ 19), and healthy leukocytes. Intracellular nicotinamide adenine dinucleotide (NAD

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“…Although the concept of pharmacological drug resistance modulation seems to become less fruitful in the clinic than what might be expected from the basic research, it may certainly prove bene cial in some tumour types, probably in those already being drug sensitive (38).…”

Section: Optimisation Of the Use Of Currently Available Cytotoxic Drugsmentioning

confidence: 99%

What is cancer chemotherapy?

Nygren

2001

Acta Oncologica

117

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Activity of cyclosporins as resistance modifiers in primary cultures of human haematological and solid tumours

Abstract: S ary The semiautomated fluorimetric microculture cytotoxicity assay (FMCA)

Cited by 28 publications

References 25 publications

The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia

The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia

APO866 Increases Antitumor Activity of Cyclosporin-A by Inducing Mitochondrial and Endoplasmic Reticulum Stress in Leukemia Cells

What is cancer chemotherapy?

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