Abstract
In addition to their canonical roles in regulating cell cycle transition and transcription, cyclin-dependent kinases (CDKs) have been shown to coordinate DNA damage response pathways, suggesting a rational pairing of CDK inhibitors with genotoxic chemotherapeutic agents in the treatment of human malignancies. Here, we report that roniciclib (BAY1000394), a potent pan-CDK inhibitor, displays promising anti-neoplastic activity as a single agent and potentiates cisplatin lethality in preclinical nasopharyngeal carcinoma (NPC) models. Proliferation of the NPC cell lines HONE-1, CNE-2, C666-1, and HK-1 was effectively curbed by roniciclib treatment, with IC50 values between 11 and 38 nmol/L. These anticancer effects were mediated by pleiotropic mechanisms consistent with successful blockade of cell cycle CDKs 1, 2, 3, and 4 and transcriptional CDKs 7 and 9, ultimately resulting in arrest at G1/S and G2/M, downregulation of the transcriptional apparatus, and repression of anti-apoptotic proteins. Considerably enhanced tumor cell apoptosis was achieved following combined treatment with 10 nmol/L roniciclib and 2.0 μmol/L cisplatin; this combination therapy achieved a response over 250% greater than either drug alone. Although roniciclib chemosensitized NPC cells to cisplatin, it did not sensitize untransformed (NP69) cells. The administration of 0.5 mg/kg roniciclib to BALB/c xenograft mice was well tolerated and effectively restrained tumor growth comparable to treatment with 6 mg/kg cisplatin, whereas combining these two agents produced far greater tumor suppression than either of the monotherapies. In summary, these data demonstrate that roniciclib has strong anti-NPC activity and synergizes with cisplatin chemotherapy at clinically relevant doses, thus justifying further evaluation of this combinatorial approach in clinical settings.
Highlights
The cyclin-dependent kinases (CDKs) are classically a family of serine/threonine kinases that orchestrate the precise spatiotemporal control of a multitude of biological functions related to cell cycle progression.[1,2]
We cultured human nasopharyngeal carcinoma cell lines (HONE-1, All animal experiments conformed to the guidelines set forth by CNE-2, C666-1, and HK-1) and human colorectal carcinoma cell lines (HCT-116-WT and HCT-116-p53−/−) in RPMI (Sigma-Aldrich, St Louis, MO, USA) + 10% fetal bovine serum at 37 °C in 5% CO2
HONE-1 and HK-1 cells were treated with combinations of roniciclib and cisplatin at effective concentrations below their respective 50% inhibition responses for 72 h, and combinatorial synergistic interactions were tested using the Bliss-additivity model (Supplementary Table S1)
Summary
The administration of 0.5 mg/kg roniciclib to BALB/c xenograft mice was well tolerated and effectively restrained tumor growth comparable to treatment with 6 mg/kg cisplatin, whereas combining these two agents produced far greater tumor suppression than either of the monotherapies. These data demonstrate that roniciclib has strong anti-NPC activity and synergizes with cisplatin chemotherapy at clinically relevant doses, justifying further evaluation of this combinatorial approach in clinical settings.
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