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- Title
Pan-CDK inhibition augments cisplatin lethality in nasopharyngeal carcinoma cell lines and xenograft models.
- Authors
Syn, Nicholas L.; Lim, Pei Li; Kong, Li Ren; Wang, Lingzhi; Wong, Andrea Li-Ann; Lim, Chwee Ming; Loh, Thomas Kwok Seng; Siemeister, Gerhard; Goh, Boon Cher; Hsieh, Wen-Son
- 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. Cancer: Cell cycle–blocking drug active against throat cancer Nasopharyngeal carcinoma (NPC) is an uncommon malignancy arising from the nasopharynx epithelium, and is endemic to east and southeast parts of Asia where they account for 70% of worldwide incidence. Researchers from the Cancer Science Institute of Singapore examined the anti-tumor effects of roniciclib—a small-molecule drug that blocks a family of enzymes known as cyclin-dependent kinases (CDKs) which are classically involved in cell cycle progression and transcription—in cell lines and mouse models of nasopharyngeal carcinoma. Because CDK/cyclin complexes have a putative role in DNA repair, roniciclib was combined with cisplatin, a DNA-damaging agent which is currently used in chemotherapy of NPC. The authors found that roniciclib had potent anti-NPC effects when given alone, whereas the combination of roniciclib and cisplatin proved to be highly synergistic and restrained tumor growth to a greater extent than either drugs given alone. Interestingly, roniciclib appeared to selectively enhance the anti-cancer effects of cisplatin in cancerous cells while this "chemo-sensitizing" phenomenon was not seen in non-cancerous cells, suggesting that giving both drugs together could improve the effectiveness of standard chemotherapy without incurring additional toxicities. These findings suggest that roniciclib should be evaluated clinically in patients with NPC.
- Publication
Signal Transduction & Targeted Therapy, 2018, Vol 3, Issue 1, pN.PAG
- ISSN
2095-9907
- Publication type
Article
- DOI
10.1038/s41392-018-0010-0