| Reference | 1. Mol Cancer Ther. 2016 Nov;15(11):2758-2766. Epub 2016 Aug 22.
<br>
Dinaciclib Induces Anaphase Catastrophe in Lung Cancer Cells via Inhibition of
Cyclin-Dependent Kinases 1 and 2.
<br>
Danilov AV(1)(2), Hu S(3), Orr B(2)(4), Godek K(2)(4), Mustachio LM(3), Sekula
D(3), Liu X(5), Kawakami M(5), Johnson FM(5), Compton DA(2)(4), Freemantle
SJ(3)(4), Dmitrovsky E(6)(3)(5)(7).
<br>
Author information: <br>
(1)Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, New
Hampshire.
(2)Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover,
New Hampshire, and Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
(3)Department of Pharmacology and Toxicology, Geisel School of Medicine at
Dartmouth, Hanover, New Hampshire.
(4)Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover,
New Hampshire.
(5)Department of Thoracic/Head and Neck Medical Oncology, The University of Texas
MD Anderson Cancer Center, Houston, Texas.
(6)Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover,
New Hampshire, and Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
[email protected].
(7)Department of Cancer Biology, The University of Texas MD Anderson Cancer
Center, Houston, Texas.
<br>
Despite advances in targeted therapy, lung cancer remains the most common cause
of cancer-related mortality in the United States. Chromosomal instability is a
prominent feature in lung cancer and, because it rarely occurs in normal cells,
it represents a potential therapeutic target. Our prior work discovered that lung
cancer cells undergo anaphase catastrophe in response to inhibition of
cyclin-dependent kinase 2 (CDK2), followed by apoptosis and reduced growth. In
this study, the effects and mechanisms of the multi-CDK inhibitor dinaciclib on
lung cancer cells were investigated. We sought to determine the specificity of
CDK-dependent induction of anaphase catastrophe. Live cell imaging provided
direct evidence that dinaciclib caused multipolar cell divisions resulting in
extensive chromosome missegregation. Genetic knockdown of dinaciclib CDK targets
revealed that repression of CDK2 and CDK1, but not CDK5 or CDK9, triggered
anaphase catastrophe in lung cancer cells. Overexpression of CP110, which is a
mediator of CDK2 inhibitor-induced anaphase catastrophe (and a CDK1 and 2
phosphorylation substrate), antagonized anaphase catastrophe and apoptosis
following dinaciclib treatment. Consistent with our previous findings,
acquisition of activated KRAS sensitized lung cancer cells to dinaciclib-mediated
anaphase catastrophe and cell death. Combining dinaciclib with the mitotic
inhibitor taxol augmented anaphase catastrophe induction and reduced cell
viability of lung cancer cells. Thus, the multi-CDK inhibitor dinaciclib causes
anaphase catastrophe in lung cancer cells and should be investigated as a
potential therapeutic for wild-type and KRAS-mutant lung cancer, individually or
in combination with taxanes. Mol Cancer Ther; 15(11); 2758-66. ©2016 AACR.
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2. Biochem Pharmacol. 2015 Dec 1;98(3):465-72. doi: 10.1016/j.bcp.2015.08.099. Epub
2015 Aug 20.
<br>
Dinaciclib, a cyclin-dependent kinase inhibitor, is a substrate of human ABCB1
and ABCG2 and an inhibitor of human ABCC1 in vitro.
<br>
Cihalova D(1), Ceckova M(2), Kucera R(3), Klimes J(4), Staud F(5).
<br>
Author information: <br>
(1)Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec
Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove,
Czech Republic. Electronic address: [email protected].
(2)Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec
Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove,
Czech Republic. Electronic address: [email protected].
(3)Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy
in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec
Kralove, Czech Republic. Electronic address: [email protected].
(4)Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Pharmacy
in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec
Kralove, Czech Republic. Electronic address: [email protected].
(5)Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec
Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove,
Czech Republic. Electronic address: [email protected].
<br>
Dinaciclib is a novel cyclin-dependent kinase inhibitor (CDKI) with significant
activity against various cancers in vitro and in vivo. ABC efflux transporters
play an important role in drug disposition and are responsible for multidrug
resistance in cancer cells. Inhibitors and substrates of these transporters may
participate in pharmacokinetic drug-drug interactions (DDIs) that alter drug
disposition during pharmacotherapy. To assess such risks associated with
dinaciclib we evaluated its possible effects on efflux activities of ABCB1, ABCC1
and ABCG2 transporters in vitro. Monolayer transport, XTT cell proliferation,
ATPase and intracellular accumulation assays were employed. Here, we show that
the transport ratio of dinaciclib was far higher across monolayers of
MDCKII-ABCB1 and MDCKII-ABCG2 cells than across MDCKII parental cell layers,
demonstrating that dinaciclib is a substrate of ABCB1 and ABCG2. In addition,
overexpression of ABCB1, ABCG2 and ABCC1 conferred resistance to dinaciclib in
MDCKII cells. In ATPase assays, dinaciclib decreased stimulated ATPase activity
of ABCB1, ABCG2 and ABCC1, confirming it has interactive potential toward all
three transporters. Moreover, dinaciclib significantly inhibited ABCC1-mediated
efflux of daunorubicin (EC50=18 μM). The inhibition of ABCC1 further led to a
synergistic effect of dinaciclib in both MDCKII-ABCC1 and human cancer T47D
cells, when applied in combination with anticancer drugs. Taken together, our
results suggest that ABC transporters can substantially affect dinaciclib
transport across cellular membranes, leading to DDIs. The DDIs of dinaciclib with
ABCC1 substrate chemotherapeutics might be exploited in novel cancer therapies.
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3. Leukemia. 2015 Jul;29(7):1524-9. doi: 10.1038/leu.2015.31. Epub 2015 Feb 24.
<br>
Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical
activity in relapsed and refractory chronic lymphocytic leukemia.
<br>
Flynn J(1), Jones J(1), Johnson AJ(2), Andritsos L(1), Maddocks K(1), Jaglowski
S(1), Hessler J(1), Grever MR(1), Im E(3), Zhou H(3), Zhu Y(3), Zhang D(3), Small
K(3), Bannerji R(4), Byrd JC(2).
<br>
Author information: <br>
(1)Division of Hematology and Oncology, Department of Internal Medicine,
Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
(2)1] Division of Hematology and Oncology, Department of Internal Medicine,
Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA [2]
Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University,
Columbus, OH, USA.
(3)Merck & Co., Inc., Oncology Clinical Research, Whitehouse Station, NJ, USA.
(4)1] Merck & Co., Inc., Oncology Clinical Research, Whitehouse Station, NJ, USA
[2] Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical
School, New Brunswick, NJ, USA.
<br>
Dinaciclib (SCH727965) is a selective CDKi chosen for clinical development based
upon a favorable therapeutic index in cancer xenograft models. We performed a
phase I dose escalation study of dinaciclib in relapsed and refractory chronic
lymphocytic leukemia (CLL) patients with intact organ function and WBC<200 ×
10(9) /l. Five separate dose levels (5 mg/m(2), 7 mg/m(2), 10 mg/m(2), 14 mg/m(2)
and 17 mg/m(2)) were explored dosing on a weekly schedule × 3 with 1 week off
(4-week cycles) using a standard 3+3 design with expansion cohorts to optimize
safety. Fifty-two patients were enrolled with relapsed and refractory CLL.
Escalation through cohorts occurred with two dose-limiting toxicity (DLTs) at the
17 mg/m(2) dose (tumor lysis syndrome (TLS) and pneumonia). The phase II
expansion occurred at 14 mg/m(2) with 16 patients receiving this dose with one
DLT (TLS). Additional stepped up dosing to the maximum tolerated dose was
examined in 19 patients at this dose. Adverse events included cytopenias,
transient laboratory abnormalities and TLS. Responses occurred in 28 (54%) of
patients independent of del(17)(p13.1) with a median progression-free survival of
481 days. Dinaciclib is clinically active in relapsed CLL including those
patients with high risk del(17)(p13.1) disease and warrants future study.
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