Elsevier

Neoplasia

Volume 19, Issue 10, October 2017, Pages 830-841
Neoplasia

Chk1 Inhibitor SCH900776 Effectively Potentiates the Cytotoxic Effects of Platinum-Based Chemotherapeutic Drugs in Human Colon Cancer Cells

https://doi.org/10.1016/j.neo.2017.08.002Get rights and content
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Abstract

Although Chk1 kinase inhibitors are currently under clinical investigation as effective cancer cell sensitizers to the cytotoxic effects of numerous chemotherapeutics, there is still a considerable uncertainty regarding their role in modulation of anticancer potential of platinum-based drugs. Here we newly demonstrate the ability of one of the most specific Chk1 inhibitors, SCH900776 (MK-8776), to enhance human colon cancer cell sensitivity to the cytotoxic effects of platinum(II) cisplatin and platinum(IV)- LA-12 complexes. The combined treatment with SCH900776 and cisplatin or LA-12 results in apparent increase in G1/S phase–related apoptosis, stimulation of mitotic slippage, and senescence of HCT116 cells. We further show that the cancer cell response to the drug combinations is significantly affected by the p21, p53, and PTEN status. In contrast to their wt counterparts, the p53- or p21-deficient cells treated with SCH900776 and cisplatin or LA-12 enter mitosis and become polyploid, and the senescence phenotype is strongly suppressed. While the cell death induced by SCH900776 and cisplatin or LA-12 is significantly delayed in the absence of p53, the anticancer action of the drug combinations is significantly accelerated in p21-deficient cells, which is associated with stimulation of apoptosis beyond G2/M cell cycle phase. We also show that cooperative killing action of the drug combinations in HCT116 cells is facilitated in the absence of PTEN. Our results indicate that SCH900776 may act as an important modulator of cytotoxic response triggered by platinum-based drugs in colon cancer cells.

Abbreviations

CDDP
cisplatin
Chk1
checkpoint kinase 1
Chk2
checkpoint kinase 2
γ-H2AX
phosphorylated histone H2AX at Ser 139
LA-12
(OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)
PARP
poly (ADP-ribose) polymerase
PBS
phosphate-buffered saline
PTEN
phosphatase and tensin homolog
SEM
standard error of the mean
siRNA
small interfering RNA

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