Detail
Článek
Článek online
FT
Medvik - BMČ
  • Je něco špatně v tomto záznamu ?

The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe

S. Drápela, P. Khirsariya, WM. van Weerden, R. Fedr, T. Suchánková, D. Búzová, J. Červený, A. Hampl, M. Puhr, WR. Watson, Z. Culig, L. Krejčí, K. Paruch, K. Souček

. 2020 ; 14 (10) : 2487-2503. [pub] 20200716

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc21026539

As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc21026539
003      
CZ-PrNML
005      
20230119094443.0
007      
ta
008      
211013s2020 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1002/1878-0261.12756 $2 doi
035    __
$a (PubMed)32579780
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Drápela, Stanislav $u Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Czech Republic $u Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic $7 xx0280838
245    14
$a The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe / $c S. Drápela, P. Khirsariya, WM. van Weerden, R. Fedr, T. Suchánková, D. Búzová, J. Červený, A. Hampl, M. Puhr, WR. Watson, Z. Culig, L. Krejčí, K. Paruch, K. Souček
520    9_
$a As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC.
650    _2
$a zvířata $7 D000818
650    _2
$a buněčná smrt $x účinky léků $7 D016923
650    _2
$a nádorové buněčné linie $7 D045744
650    _2
$a proliferace buněk $x účinky léků $7 D049109
650    _2
$a checkpoint kinasa 1 $x antagonisté a inhibitory $x metabolismus $7 D000071877
650    _2
$a deoxycytidin $x analogy a deriváty $x farmakologie $7 D003841
650    _2
$a docetaxel $x farmakologie $7 D000077143
650    _2
$a chemorezistence $x účinky léků $7 D019008
650    _2
$a lidé $7 D006801
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a myši SCID $7 D016513
650    12
$a mitóza $x účinky léků $7 D008938
650    _2
$a piperidiny $x chemie $x farmakologie $7 D010880
650    _2
$a nádory prostaty $x patologie $7 D011471
650    _2
$a pyrazoly $x chemie $x farmakologie $7 D011720
650    _2
$a pyrimidiny $x chemie $x farmakologie $7 D011743
650    _2
$a S fáze $x účinky léků $7 D016196
650    _2
$a xenogenní modely - testy protinádorové aktivity $7 D023041
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Khirsariya, Prashant $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Czech Republic $u Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic
700    1_
$a van Weerden, Wytske M $u Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
700    1_
$a Fedr, Radek $u Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Czech Republic
700    1_
$a Suchánková, Tereza $u Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Czech Republic
700    1_
$a Búzová, Diana $u Department of Adaptive Biotechnologies, Global Change Research Institute of the Czech Academy of Sciences, Brno, Czech Republic
700    1_
$a Červený, Jan $u Department of Adaptive Biotechnologies, Global Change Research Institute of the Czech Academy of Sciences, Brno, Czech Republic
700    1_
$a Hampl, Aleš $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Czech Republic $u Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
700    1_
$a Puhr, Martin $u Department of Urology, Experimental Urology, Medical University of Innsbruck, Austria
700    1_
$a Watson, William R $u School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland
700    1_
$a Culig, Zoran $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Czech Republic $u Department of Urology, Experimental Urology, Medical University of Innsbruck, Austria
700    1_
$a Krejčí, Lumír $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Czech Republic $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic $u National Centre for Biomolecular Research, Masaryk University, Brno, Czech Republic
700    1_
$a Paruch, Kamil $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Czech Republic $u Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic
700    1_
$a Souček, Karel $u Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic $u International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, Czech Republic $u Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
773    0_
$w MED00167281 $t Molecular oncology $x 1878-0261 $g Roč. 14, č. 10 (2020), s. 2487-2503
856    41
$u https://pubmed.ncbi.nlm.nih.gov/32579780 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20211013 $b ABA008
991    __
$a 20230119094437 $b ABA008
999    __
$a ok $b bmc $g 1715306 $s 1147046
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2020 $b 14 $c 10 $d 2487-2503 $e 20200716 $i 1878-0261 $m Molecular oncology $n Mol Oncol $x MED00167281
LZP    __
$a Pubmed-20211013

Najít záznam

Citační ukazatele

Pouze přihlášení uživatelé

Možnosti archivace