Bortezomib prevents cytarabine resistance in MCL, which is characterized by down-regulation of dCK and up-regulation of SPIB resulting in high NF-κB activity

↓ Direkt till sidans innehåll
↓ Direkt till sidans sekundära innehåll (sidomenyn)

Search: WFRF:(Winther Kirsten) > Bortezomib prevents...

Bortezomib prevents cytarabine resistance in MCL, which is characterized by down-regulation of dCK and up-regulation of SPIB resulting in high NF-κB activity

Freiburghaus, Catja (author): Lund University,Lunds universitet,Institutionen för immunteknologi,Institutioner vid LTH,Lunds Tekniska Högskola,Department of Immunotechnology,Departments at LTH,Faculty of Engineering, LTH

Emruli, Venera Kuci (author): Lund University,Lunds universitet,Institutionen för immunteknologi,Institutioner vid LTH,Lunds Tekniska Högskola,Department of Immunotechnology,Departments at LTH,Faculty of Engineering, LTH

Johansson, Angelica (author): Lund University

Eskelund, Christian Winther (author): Copenhagen University Hospital

Grønbæk, Kirsten (author): Copenhagen University Hospital

Olsson, Roger (author): Lund University,Lunds universitet,Kemisk biologi med inriktning mot läkemedelsutveckling,Forskargrupper vid Lunds universitet,Chemical Biology and Therapeutics,Lund University Research Groups

Ek, Fredrik (author): Lund University,Lunds universitet,Kemisk biologi med inriktning mot läkemedelsutveckling,Forskargrupper vid Lunds universitet,Chemical Biology and Therapeutics,Lund University Research Groups

Jerkeman, Mats (author): Skåne University Hospital

Ek, Sara (author): Lund University,Lunds universitet,Institutionen för immunteknologi,Institutioner vid LTH,Lunds Tekniska Högskola,Department of Immunotechnology,Departments at LTH,Faculty of Engineering, LTH

show less...

(creator_code:org_t)

2018-04-25
2018
English.
In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 18:1

Related links:: http://dx.doi.org/10... (free); show more...; https://bmccancer.bi...; https://lup.lub.lu.s...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

BACKGROUND: The addition of high-dose cytarabine to the treatment of mantle cell lymphoma (MCL) has significantly prolonged survival of patients, but relapses are common and are normally associated with increased resistance. To elucidate the mechanisms responsible for cytarabine resistance, and to create a tool for drug discovery investigations, we established a unique and molecularly reproducible cytarabine resistant model from the Z138 MCL cell line.METHODS: Effects of different substances on cytarabine-sensitive and resistant cells were evaluated by assessment of cell proliferation using [methyl-14C]-thymidine incorporation and molecular changes were investigated by protein and gene expression analyses.RESULTS: Gene expression profiling revealed that major transcriptional changes occur during the initial phase of adaptation to cellular growth in cytarabine containing media, and only few key genes, including SPIB, are deregulated upon the later development of resistance. Resistance was shown to be mediated by down-regulation of the deoxycytidine kinase (dCK) protein, responsible for activation of nucleoside analogue prodrugs. This key event, emphasized by cross-resistance to other nucleoside analogues, did not only effect resistance but also levels of SPIB and NF-κB, as assessed through forced overexpression in resistant cells. Thus, for the first time we show that regulation of drug resistance through prevention of conversion of pro-drug into active drug are closely linked to increased proliferation and resistance to apoptosis in MCL. Using drug libraries, we identify several substances with growth reducing effect on cytarabine resistant cells. We further hypothesized that co-treatment with bortezomib could prevent resistance development. This was confirmed and show that the dCK levels are retained upon co-treatment, indicating a clinical use for bortezomib treatment in combination with cytarabine to avoid development of resistance. The possibility to predict cytarabine resistance in diagnostic samples was assessed, but analysis show that a majority of patients have moderate to high expression of dCK at diagnosis, corresponding well to the initial clinical response to cytarabine treatment.CONCLUSION: We show that cytarabine resistance potentially can be avoided or at least delayed through co-treatment with bortezomib, and that down-regulation of dCK and up-regulation of SPIB and NF-κB are the main molecular events driving cytarabine resistance development.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Publication and Content Type

art (subject category)
ref (subject category)

Find in a library

BMC Cancer (Search for host publication in LIBRIS)

To the university's database

Find more in SwePub

By the author/editor: Freiburghaus, Ca ...; Emruli, Venera K ...; Johansson, Angel ...; Eskelund, Christ ...; Grønbæk, Kirsten; Olsson, Roger; show more...; Ek, Fredrik; Jerkeman, Mats; Ek, Sara; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cancer and Oncol ...

Articles in the publication: BMC Cancer

By the university: Lund University

Search outside SwePub

Extend your search to:: Google; Google Book Search; Google Scholar

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

LIBRIS.kb.se