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

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.

Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer

“…Moreover, the combination of the platinum compound, cisplatin and the CHK1 inhibitor, rabusertib did not have a toxic effect on non-tumorigenic breast tissue-derived cells, which suggests that the high efficacy of the combination of CHK1 inhibitors and DNA-damaging agents is restricted to cancer cells. A similar antiproliferative effect was observed for PARP inhibitors, reinforcing the concept that inhibition of CHK1 allows cells to enter apoptosis when a relevant genetic instability is present, in this case due to alterations of DNA repair mechanisms or an increase in DNA damage [25]. Therefore, we found that agents that induced DNA damage, like gemcitabine or platinum compounds or to a less extent doxorubicin and topotecan, were synergistic in breast cancer cell lines.…”

<p>Synergism of cisplatin-oleanolic acid co-loaded calcium carbonate nanoparticles on hepatocellular carcinoma cells for enhanced apoptosis and reduced hepatotoxicity</p>

“…As shown in Figure 7, p53 pathway proapoptotic proteins, such as p53, Bax, cytochrome C, and caspase-3 were upregulated, while the anti-apoptotic Bcl-2 expression was decreased. P53, a major regulator in CDDP-induced cancer cell apoptosis57 via a transcription-dependent or independent pathway. Increased Bax can rupture the outer mitochondrial membrane to induce the cytochrome C release to activate the generation of caspase-3 and ultimately induces extrinsic apoptosis, while downregulated Bcl-2 leads to the intrinsic apoptosis through reduced formation of Bcl-2/Bax heterodimers which promotes the cytochrome C release for the initiation of apoptosis through caspase activation 58.…”

Scutellarin Increases Cisplatin-Induced Apoptosis and Autophagy to Overcome Cisplatin Resistance in Non-small Cell Lung Cancer via ERK/p53 and c-met/AKT Signaling Pathways

“…Accumulating evidence has shown that p53 serves as a key tumor suppressor, which is essential for induction of cisplatin-induced apoptosis ( Yang et al, 2012 ). It has been proposed that the presence of functional p53 facilitates the cytotoxic effects of chemotherapeutic drugs including cisplatin ( Herudkova et al, 2017 ). For instance, in head and neck squamous cell carcinoma, small molecules targeted p53-reactivation have been shown to induce apoptosis and enhance chemotherapeutic cytotoxicity ( Roh et al, 2011 ).…”