-
Something wrong with this record ?
Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors
A. Sorf, S. Sucha, A. Morell, E. Novotna, F. Staud, A. Zavrelova, B. Visek, V. Wsol, M. Ceckova,
Language English Country Switzerland
Document type Journal Article
Grant support
PRIMUS/20/MED/010
Univerzita Karlova v Praze
SVV/260-414
Univerzita Karlova v Praze
grant No. 20-20414Y
Grantová Agentura České Republiky
EFSA-CDN (grant No. CZ.02.1.01/0.0/0.0/16_019/0000841)
Ministerstvo Školství, Mládeže a Tělovýchovy
NLK
Free Medical Journals
from 2009
PubMed Central
from 2009
Europe PubMed Central
from 2009
ProQuest Central
from 2009-01-01
Open Access Digital Library
from 2009-01-01
Open Access Digital Library
from 2009-01-01
ROAD: Directory of Open Access Scholarly Resources
from 2009
- Publication type
- Journal Article MeSH
Pharmacotherapy of acute myeloid leukemia (AML) remains challenging, and the disease has one of the lowest curability rates among hematological malignancies. The therapy outcomes are often compromised by the existence of a resistant AML phenotype associated with overexpression of ABCB1 and ABCG2 transporters. Because AML induction therapy frequently consists of anthracycline-like drugs, their efficiency may also be diminished by drug biotransformation via carbonyl reducing enzymes (CRE). In this study, we investigated the modulatory potential of the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib on AML resistance using peripheral blood mononuclear cells (PBMC) isolated from patients with de novo diagnosed AML. We first confirmed inhibitory effect of the tested drugs on ABCB1 and ABCG2 in ABC transporter-expressing resistant HL-60 cells while also showing the ability to sensitize the cells to cytotoxic drugs even as no effect on AML-relevant CRE isoforms was observed. All tested CDK4/6 inhibitors elevated mitoxantrone accumulations in CD34+ PBMC and enhanced accumulation of mitoxantrone was found with abemaciclib and ribociclib in PBMC of FLT3-ITD- patients. Importantly, the accumulation rate in the presence of CDK4/6 inhibitors positively correlated with ABCB1 expression in CD34+ patients and led to enhanced apoptosis of PBMC in contrast to CD34- samples. In summary, combination therapy involving CDK4/6 inhibitors could favorably target multidrug resistance, especially when personalized based on CD34- and ABCB1-related markers.
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc20019037
- 003
- CZ-PrNML
- 005
- 20201123124600.0
- 007
- ta
- 008
- 201103s2020 sz f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.3390/cancers12061596 $2 doi
- 035 __
- $a (PubMed)32560251
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a sz
- 100 1_
- $a Sorf, Ales $u Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy, Akademika Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
- 245 10
- $a Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors / $c A. Sorf, S. Sucha, A. Morell, E. Novotna, F. Staud, A. Zavrelova, B. Visek, V. Wsol, M. Ceckova,
- 520 9_
- $a Pharmacotherapy of acute myeloid leukemia (AML) remains challenging, and the disease has one of the lowest curability rates among hematological malignancies. The therapy outcomes are often compromised by the existence of a resistant AML phenotype associated with overexpression of ABCB1 and ABCG2 transporters. Because AML induction therapy frequently consists of anthracycline-like drugs, their efficiency may also be diminished by drug biotransformation via carbonyl reducing enzymes (CRE). In this study, we investigated the modulatory potential of the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib on AML resistance using peripheral blood mononuclear cells (PBMC) isolated from patients with de novo diagnosed AML. We first confirmed inhibitory effect of the tested drugs on ABCB1 and ABCG2 in ABC transporter-expressing resistant HL-60 cells while also showing the ability to sensitize the cells to cytotoxic drugs even as no effect on AML-relevant CRE isoforms was observed. All tested CDK4/6 inhibitors elevated mitoxantrone accumulations in CD34+ PBMC and enhanced accumulation of mitoxantrone was found with abemaciclib and ribociclib in PBMC of FLT3-ITD- patients. Importantly, the accumulation rate in the presence of CDK4/6 inhibitors positively correlated with ABCB1 expression in CD34+ patients and led to enhanced apoptosis of PBMC in contrast to CD34- samples. In summary, combination therapy involving CDK4/6 inhibitors could favorably target multidrug resistance, especially when personalized based on CD34- and ABCB1-related markers.
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Sucha, Simona $u Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy, Akademika Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
- 700 1_
- $a Morell, Anselm $u Department of Biochemical Sciences, Charles University, Faculty of Pharmacy, Akademika Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
- 700 1_
- $a Novotna, Eva $u Department of Biochemical Sciences, Charles University, Faculty of Pharmacy, Akademika Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
- 700 1_
- $a Staud, Frantisek $u Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy, Akademika Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
- 700 1_
- $a Zavrelova, Alzbeta $u 4th Department of Internal Medicine-Hematology, University Hospital Hradec Kralove, Charles University, Sokolska 581, 50005 Hradec Kralove, Czech Republic.
- 700 1_
- $a Visek, Benjamin $u 4th Department of Internal Medicine-Hematology, University Hospital Hradec Kralove, Charles University, Sokolska 581, 50005 Hradec Kralove, Czech Republic.
- 700 1_
- $a Wsol, Vladimir $u Department of Biochemical Sciences, Charles University, Faculty of Pharmacy, Akademika Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
- 700 1_
- $a Ceckova, Martina $u Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy, Akademika Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
- 773 0_
- $w MED00173178 $t Cancers $x 2072-6694 $g Roč. 12, č. 6 (2020)
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/32560251 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y a $z 0
- 990 __
- $a 20201103 $b ABA008
- 991 __
- $a 20201123124558 $b ABA008
- 999 __
- $a ind $b bmc $g 1585817 $s 1109235
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2020 $b 12 $c 6 $e 20200616 $i 2072-6694 $m Cancers $n Cancers $x MED00173178
- GRA __
- $a PRIMUS/20/MED/010 $p Univerzita Karlova v Praze
- GRA __
- $a SVV/260-414 $p Univerzita Karlova v Praze
- GRA __
- $a grant No. 20-20414Y $p Grantová Agentura České Republiky
- GRA __
- $a EFSA-CDN (grant No. CZ.02.1.01/0.0/0.0/16_019/0000841) $p Ministerstvo Školství, Mládeže a Tělovýchovy
- LZP __
- $a Pubmed-20201103