Multitarget CDK inhibitors roscovitine and UCN‑01 induce apoptosis in colorectal cancer cells by inhibiting cell cycle progression and transcription
DOI:
https://doi.org/10.1590/Keywords:
CDK inhibitors, Roscovitine, UCN-01, Colorectal cancer, Cell cycle, Apoptosis, Transcription inhibition, Drug combinationAbstract
Colorectal cancer (CRC) is the third leading cause of cancer death in the world, and its incidence is steadily rising in developing nations. Cell cycle aberrations due to deregulation of cyclin dependent kinases (CDKs) and cyclins are common events during colorectal carcinogenesis. Herein, we investigate the anticancer potential of two multitarget CDK inhibitors viz. roscovitine (specific inhibitor of CDK1, 2, 7, and 9) and UCN-01 (pan CDK inhibitor) against three CRC cell lines. Both the drugs exerted cytotoxicity and inhibited clonogenic potential of human CRC cell lines. These drugs induced apoptosis, downregulated cell cycle regulatory and transcriptional CDKs and cyclins’ protein expression as well as their activity. Moreover, dual combination of either of these CDK inhibitors with standard chemotherapeutic drugs was found to be synergistic in CRC cells. Thus, we demonstrate that multiple CDK inhibition offers promising therapeutic strategy against CRC.
Downloads
References
Bhonde MR, Hanski ML, Magrini R, Moorthy D, Müller A, Sausville EA, et al. The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-x(L) protein. Oncogene 2005;24(1):148-56.
Blagosklonny M.V. Flavopiridol, an inhibitor of transcription: implications, problems and solutions. Cell Cycle. 2004;3(12):1537-42.
Bonelli P, Tuccillo FM, Borrelli A, Schiattarella A, Buonaguro FM. CDK/CCN and CDKI alterations for cancer prognosis and therapeutic predictivity. Biomed Res Int. 2014;2014: 361020.
Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-63.
Bteich F, Mohammadi M, Li T, Bhat MA, Sofianidi A, Wei N, et al. Targeting KRAS in Colorectal Cancer: A Bench to Bedside Review. Int J Mol Sci. 2023;24(15):12030.
Canavese M, Santo L, Raje N. Cyclin dependent kinases in cancer-Potential for therapeutic intervention. Cancer Biol Ther. 2012;13(7):451-7.
Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58(3):621-81.
Costa NR, Gil Da Costa RM, Medeiros R. A viral map of gastrointestinal cancers. Life Sci. 2018;199:188-200.
Crescenzi E, Palumbo G, Brady HJ. Roscovitine Modulates DNA Repair and Senescence: Implications for combination chemotherapy. Clin Cancer Res. 2005;11(22):8158-71.
Damato A, Astarita C, Sun A, Pesce A, Pinto C, Giordano A. Sequential inhibition of DNA methyltransferase (DNMT) and CDK 4/6 in a panel of colon cancer cells. J Clin Oncol. 2018;36(15):e15704.
Delehouzé C, Godl K, Loaëc N. Bruyère C, Desban N, Oumata N, et al. CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells. Oncogene 2014;33(50):5675-87.
Galons H, Oumata N, Gloulou O, Meijer L. Cyclin-dependent kinase inhibitors closer to market launch? Expert Opin. Ther Patents 2013;23(8):945-63.
Gartel AL. Transcriptional inhibitors, p53 and apoptosis. Biochim Biophys Acta 2008;1786(2):83-6.
Ghafouri-Fard S, Khoshbakht T, Hussen BM, Dong P, Gassler N, Taheri M, et al. A review on the role of cyclin dependent kinases in cancers. Cancer Cell Int. 2022;22(1):325.
Graf F, Wuest F, Pietzsch J. Cyclin-Dependent Kinases (Cdk) as Targets for Cancer Therapy and Imaging. Gali-Muhtasib H (ed.) Advances in Cancer Therapy, Rijeka: InTech; 2011,265-88 pp.
Handa K, Yamakawa M, Takeda H, Kimura S, Takahashi T. Expression of the cell cycle markers in colorectal carcinoma: Superiority of cyclin A as an indicator of poor prognosis. Int J Cancer. 1999;84(3):225-33.
Joshi KS, Padganokar A, Rathos M, Wagh V, Manohar S, Bhatia D, et al. P1446A-05: a new oral cyclin-dependent kinase inhibitor with potent preclinical antitumor activity. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012;72(8 Suppl): Abstract no. 3054.
Korenaga D, Takesue F, Yasuda M, Honda M, Nozoe T, Inutsuka S. The relationship between cyclin B1 overexpression and lymph node metastasis in human colorectal cancer. Surgery 2002;131:S114-S120.
Krystof V, Baumli S, Fürst R. Perspective of Cyclin-dependent kinase 9 (CDK9) as a Drug Target. Current Pharm Des. 2012;18(20):2883-90.
Lee SY, Oh SC. Advances of targeted therapy in treatment of unresectable metastatic colorectal cancer. Biomed Res Int . 2016;2016:7590245.
Li J, Wang Y, Wang X, Yang Q. CDK1 and CDC20 overexpression in patients with colorectal cancer are associated with poor prognosis: evidence from integrated bioinformatics analysis. World J Surg Oncol. 2020;18(1):50.
Lien WC, Chen TY, Sheu SY, Lin TC, Kang FC, Yu CH, et al. 7-hydroxy-staurosporine, UCN-01, induces DNA damage response, and autophagy in human osteosarcoma U2-OS cells. J Cell Biochem. 2018;119(6):4729-41.
Ma CX, Ellis MJ, Petroni GR, Guo Z, Cai SR, Ryan CE, et al. A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer. Breast Cancer Res Treat. 2013;137(2):483-92.
MacCallum DE, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A, et al. Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA Polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res. 2005;65(12):5399-407.
Maeda K, Chung Y-S, Kang S-M, Ogawa M, Onoda N, Nakata B, et al. Overexpression of cyclin D1 and p53 associated with disease recurrence in colorectal adenocarcinoma. Int J Cancer . 1997;74(3):310-5.
Manohar S, Shah P, Biswas S, Mukadam A, Joshi M, Viswanathan G. Combining fluorescent cell barcoding and flow cytometry-based phospho-ERK1/2 detection at short time scales in adherent cells. Cytometry A. 2019;95:192-200.
Manohar SM, Joshi KS. Molecular pharmacology of multitarget cyclin-dependent kinase inhibitors in human colorectal carcinoma cells. Expert Opin Ther Targets. 2023;27(3):1-11.
Manohar SM, Joshi KS. Promising anticancer activity of multitarget cyclin dependent kinase inhibitors against human colorectal carcinoma cells. Curr Mol Pharmacol. 2022;15(7):1024-33.
Manohar SM, Rathos MJ, Sonawane V, Rao SV, Joshi KS. Cyclin-dependent kinase inhibitor, P276-00 induces apoptosis in multiple myeloma cells by inhibition of Cdk9-T1 and RNA polymerase II-dependent transcription. Leuk Res. 2011;35(6):821-30.
Manohar SM. Cyclin-dependent kinases as potential targets for colorectal cancer: past, present and future. Future Med Chem. 2022;14(14):1087-105.
Meijer L, Borgne A, Mulner O, Chong JPJ, Blow J, Inagaki N, Delcros J-G, Moulinoux J-P. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem. 1997;243:527-536.
Mull BB, Livingston JA, Patel N, Bui T, Hunt KK, Keyomarsi K. Specific, reversible G1 arrest by UCN-01 in vivo provides cytostatic protection of normal cells against cytotoxic chemotherapy in breast cancer. Br J Cancer 2020; 122(6): 812-822.
Raje N, Kumar S, Hideshima T, Roccaro A, Ishitsuka K, Yasui H, et al. Seliciclib (CYC-02 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood 2005;106(3):1042-7.
Ramani S, Samant S, Manohar SM. The story of EGFR: from signaling pathways to a potent anticancer target. Future Med Chem . 2022;14(17):1267-88.
Rathos MJ, Joshi K, Khanwalkar H, Manohar SM, Joshi KS. Molecular evidence for increased antitumor activity of gemcita-bine in combination with a cyclin-dependent kinase inhibitor, P276-00 in pancreatic cancers. J Transl Med. 2012;10:161.
Rathos MJ, Khanwalkar H, Joshi K, Manohar SM, Joshi KS. Potentiation of in vitro and in vivo antitumor efficacy of doxo-rubicin by cyclin-dependent kinase inhibitor P276-00 in human non-small cell lung cancer cells. BMC Cancer. 2013;13:29.
Raynaud FI, Whittaker SR, Fischer PM, McClue S, Walton MI, Barrie SE, et al. In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202. Clin Cancer Res . 2005;11(13):4875-87.
Salh B, Bergman D, Marotta A, Pelech SL. Differential cyclin-dependent kinase expression and activation in human colon cancer. Anticancer Res. 1999;19(1B):741-8.
Senderowicz AM. The cell cycle as a target for cancer therapy: basic and clinical findings with the small molecule inhibitors Flavopiridol and UCN-01. Oncologist 2002;7:12-9.
Shirsath NP, Manohar SM, Joshi KS. P276-00, a cyclin-dependent kinase inhibitor, modulates cell cycle and induces apoptosis in vitro and in vivo in mantle cell lymphoma cell lines. Mol Cancer 2012;11:77.
Tong J, Tan X, Hao S, Ermine K, Lu X, Liu Z, et al. Inhibition of multiple CDKs potentiates colon cancer chemotherapy via p73-mediated DR5 induction. Oncogene 2023;42(12):869-80.
Tong J, Wang P, Tan S, Chen D, Nikolovska-Coleska Z, Zou F, et al. Mcl-1 Degradation is required for targeted therapeutics to eradicate colon cancer cells. Cancer Res . 2017;77(9): 2512-21.
Whittaker SR, Walton MI, Garrett MD, Workman P. The cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits RB phosphorylation, causes loss of cyclin D1 and activates the mitogen activated protein kinase pathway. Cancer Res . 2004;64(1):262-72.
Wu G, Xu L, Lin N, Feitelson MA. UCN-01 induces S and G2/M cell cycle arrest through the p53/p21waf1or CHK2/CDC25C pathways and can suppress invasion in human hepatoma cell lines. BMC Cancer 2013;13:167.
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Brazilian Journal of Pharmaceutical Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content of the journal, except where identified, is licensed under a Creative Commons attribution-type BY.
The on-line journal has open and free access.
