Generic placeholder image

Current Molecular Pharmacology

Editor-in-Chief

ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Research Article

Promising Anticancer Activity of Multitarget Cyclin Dependent Kinase Inhibitors against Human Colorectal Carcinoma Cells

Author(s): Sonal M. Manohar* and Kalpana S. Joshi

Volume 15, Issue 7, 2022

Published on: 18 April, 2022

Article ID: e240122200482 Pages: 10

DOI: 10.2174/1874467215666220124125809

Price: $65

Abstract

Background: Colorectal cancer (CRC) is the third leading cause of cancer death worldwide, 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. Yet, efficacy of multitarget CDK inhibitors as therapeutic agents has not been much explored against CRC.

Objective: The anticancer potential of multitarget CDK inhibitor riviciclib (also known as P276-00), was investigated against CRC cell lines of varied genetic background.

Methods: Cytotoxicity of riviciclib - potent CDK1, CDK4 and CDK9-specific inhibitor was evaluated in vitro. Further, its effect on clonogenic potential, cell cycle, apoptosis and transcription was tested using colony forming assay, flow cytometry and western blot analysis, respectively. Also, efficacy of riviciclib in combination with standard chemotherapeutic agents was assessed. Dependency of CRC cells on specific CDKs for their survival was confirmed using siRNA studies.

Results: Riviciclib exerted significant cytotoxicity against CRC cells and inhibited their colony forming potential. It induced apoptosis along with inhibition of cell cycle CDKs and cyclins as well as transcriptional CDKs and cyclins. Moreover, dual combination of riviciclib with standard chemotherapeutic drugs exhibited synergism in CRC cells. siRNA studies indicated that CRC cells are dependent on specific CDKs for their survival which are targets of riviciclib.

Conclusion: This study provides evidence that multitarget CDK inhibitors can serve as promising therapeutic agents against CRC alone or in combination.

Keywords: CDKs, CDK inhibitors, colorectal cancer, cell cycle, apoptosis, drug combination.

Graphical Abstract
[1]
Colorectal cancer: Global drug forecast and market analysis to 2028. 2020. Available from: https://store.globaldata.com/report/gdhc182pidr- colorectal-cancer-global-drug-forecast-and-market-analysis-to-2028/ (accessed on December 25, 2020).
[2]
Arnold, M.; Sierra, M.S.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global patterns and trends in colorectal cancer incidence and mortality. Gut, 2017, 66(4), 683-691.
[http://dx.doi.org/10.1136/gutjnl-2015-310912] [PMID: 26818619]
[3]
Center, M.M.; Jemal, A.; Smith, R.A.; Ward, E. Worldwide variations in colorectal cancer. CA Cancer J. Clin., 2009, 59(6), 366-378.
[http://dx.doi.org/10.3322/caac.20038] [PMID: 19897840]
[4]
Ballantyne, G.H.; Quin, J. Surgical treatment of liver metastases in patients with colorectal cancer. Cancer, 1993, 71(12)(Suppl.), 4252-4266.
[http://dx.doi.org/10.1002/1097-0142(19930615)71:12+<4252::AID-CNCR2820711815>3.0.CO;2-6] [PMID: 8508388]
[5]
Salh, B.; Bergman, D.; Marotta, A.; Pelech, S.L. Differential cyclin-dependent kinase expression and activation in human colon cancer. Anticancer Res., 1999, 19(1B), 741-748.
[PMID: 10216486]
[6]
Benson, C.; Kaye, S.; Workman, P.; Garrett, M.; Walton, M.; de Bono, J. Clinical anticancer drug development: Targeting the cyclin-dependent kinases. Br. J. Cancer, 2005, 92(1), 7-12.
[http://dx.doi.org/10.1038/sj.bjc.6602229] [PMID: 15558073]
[7]
Shtutman, M.; Zhurinsky, J.; Simcha, I.; Albanese, C.; D’Amico, M.; Pestell, R.; Ben-Ze’ev, A. The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway. Proc. Natl. Acad. Sci. USA, 1999, 96(10), 5522-5527.
[http://dx.doi.org/10.1073/pnas.96.10.5522] [PMID: 10318916]
[8]
Sallam, H. Pharmacological and analytical studies of the cyclin dependent kinase inhibitors, 2009. h.D. Thesis, Karolinska Institute: Stockholm, Sweden.
[9]
Canavese, M.; Santo, L.; Raje, N. Cyclin dependent kinases in cancer: Potential for therapeutic intervention. Cancer Biol. Ther., 2012, 13(7), 451-457.
[http://dx.doi.org/10.4161/cbt.19589] [PMID: 22361734]
[10]
Mikhail, S.; Albanese, C.; Pishvaian, M.J. Cyclin-dependent kinase inhibitors and the treatment of gastrointestinal cancers. Am. J. Pathol., 2015, 185(5), 1185-1197.
[http://dx.doi.org/10.1016/j.ajpath.2015.01.008] [PMID: 25747534]
[11]
Joshi, K.S.; Rathos, M.J.; Joshi, R.D.; Sivakumar, M.; Mascarenhas, M.; Kamble, S.; Lal, B.; Sharma, S. In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00. Mol. Cancer Ther., 2007, 6(3), 918-925. a
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0613] [PMID: 17363486]
[12]
Joshi, K.S.; Rathos, M.J.; Mahajan, P.; Wagh, V.; Shenoy, S.; Bhatia, D.; Chile, S.; Sivakumar, M.; Maier, A.; Fiebig, H.H.; Sharma, S. P276-00, a novel cyclin-dependent inhibitor induces G1-G2 arrest, shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models. Mol. Cancer Ther., 2007, 6(3), 926-934. b
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0614] [PMID: 17363487]
[13]
Sharma, S.; Rathos, M.; Manohar, S.; Joshi, K.; Badhwar, A.; Kharas, F. Abstract P6-15-05: A Cyclin-Dependent Kinase inhibitor P276 inhibits growth of breast cancer cell lines including basal-Type/Triple-Negative alone and in combination with chemotherapeutic drugs. Cancer Res., 2010, 70(24)(Suppl.), 6-15.
[14]
Manohar, S.M.; Rathos, M.J.; Sonawane, V.; Rao, S.V.; Joshi, K.S. 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), 821-830.
[http://dx.doi.org/10.1016/j.leukres.2010.12.010] [PMID: 21216463]
[15]
Manohar, S.M.; Padgaonkar, A.A.; Jalota-Badhwar, A.; Rao, S.V.; Joshi, K.S. Cyclin-dependent kinase inhibitor, P276-00, inhibits HIF-1α and induces G2/M arrest under hypoxia in prostate cancer cells. Prostate Cancer Prostatic Dis., 2012, 15(1), 15-27.
[http://dx.doi.org/10.1038/pcan.2011.51] [PMID: 22083267]
[16]
Shirsath, N.P.; Manohar, S.M.; Joshi, K.S. 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.
[http://dx.doi.org/10.1186/1476-4598-11-77] [PMID: 23075291]
[17]
Rathos, M.J.; Joshi, K.; Khanwalkar, H.; Manohar, S.M.; Joshi, K.S. Molecular evidence for increased antitumor activity of gemcitabine in combination with a cyclin-dependent kinase inhibitor, P276-00 in pancreatic cancers. J. Transl. Med., 2012, 10, 161.
[http://dx.doi.org/10.1186/1479-5876-10-161] [PMID: 22873289]
[18]
Rathos, M.J.; Khanwalkar, H.; Joshi, K.; Manohar, S.M.; Joshi, K.S. Potentiation of in vitro and in vivo antitumor efficacy of doxorubicin by cyclin-dependent kinase inhibitor P276-00 in human non-small cell lung cancer cells. BMC Cancer, 2013, 13, 29.
[http://dx.doi.org/10.1186/1471-2407-13-29] [PMID: 23343191]
[19]
Mishra, P.B.; Lobo, A.S.; Joshi, K.S.; Rathos, M.J.; Kumar, G.A.; Padigaru, M. Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma. J. Transl. Med., 2013, 11, 42.
[http://dx.doi.org/10.1186/1479-5876-11-42] [PMID: 23414419]
[20]
Hirte, H.W.; Raghunadharao, D.; Baetz, T.; Hotte, S.; Rajappa, S.; Iacobucci, A. A phase 1 study of the selective cyclin dependent kinase inhibitor P276–00 in patients with advanced refractory neoplasms. Mol. Cancer Ther., 2007, 6(11), A112.
[21]
Blachly, J.S.; Byrd, J.C. Emerging drug profile: Cyclin-dependent kinase inhibitors. Leuk. Lymphoma, 2013, 54(10), 2133-2143.
[http://dx.doi.org/10.3109/10428194.2013.783911] [PMID: 23488658]
[22]
Cassaday, R.D.; Goy, A.; Advani, S.; Chawla, P.; Nachankar, R.; Gandhi, M.; Gopal, A.K. A phase II, single-arm, open-label, multicenter study to evaluate the efficacy and safety of P276-00, a cyclin-dependent kinase inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Clin. Lymphoma Myeloma Leuk., 2015, 15(7), 392-397.
[http://dx.doi.org/10.1016/j.clml.2015.02.021] [PMID: 25816934]
[23]
Whittaker, S.R.; Mallinger, A.; Workman, P.; Clarke, P.A. Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacol. Ther., 2017, 173, 83-105.
[http://dx.doi.org/10.1016/j.pharmthera.2017.02.008] [PMID: 28174091]
[24]
Chou, T.C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev., 2006, 58(3), 621-681.
[http://dx.doi.org/10.1124/pr.58.3.10] [PMID: 16968952]
[25]
Buch, K.; Peters, T.; Nawroth, T.; Sänger, M.; Schmidberger, H.; Langguth, P. Determination of cell survival after irradiation via clonogenic assay versus multiple MTT Assay- a comparative study. Radiat. Oncol., 2012, 7, 1.
[http://dx.doi.org/10.1186/1748-717X-7-1] [PMID: 22214341]
[26]
Balakrishnan, A.; Vyas, A.; Deshpande, K.; Vyas, D. Pharmacological cyclin dependent kinase inhibitors: Implications for colorectal cancer. World J. Gastroenterol., 2016, 22(7), 2159-2164.
[http://dx.doi.org/10.3748/wjg.v22.i7.2159] [PMID: 26900281]
[27]
Sánchez-Martínez, C.; Lallena, M.J.; Sanfeliciano, S.G.; de Dios, A. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015-2019). Bioorg. Med. Chem. Lett., 2019, 29(20), 126637.
[http://dx.doi.org/10.1016/j.bmcl.2019.126637] [PMID: 31477350]
[28]
Du, Q.; Guo, X.; Wang, M.; Li, Y.; Sun, X.; Li, Q. The application and prospect of CDK4/6 inhibitors in malignant solid tumors. J. Hematol. Oncol., 2020, 13(1), 41.
[http://dx.doi.org/10.1186/s13045-020-00880-8] [PMID: 32357912]
[29]
Schettini, F.; De Santo, I.; Rea, C.G.; De Placido, P.; Formisano, L.; Giuliano, M.; Arpino, G.; De Laurentiis, M.; Puglisi, F.; De Placido, S.; Del Mastro, L. CDK 4/6 inhibitors as single agent in advanced solid tumors. Front. Oncol., 2018, 8, 608.
[http://dx.doi.org/10.3389/fonc.2018.00608] [PMID: 30631751]
[30]
Ray, B.; Mehrotra, R. Nucleic acid binding mechanism of flavone derivative, riviciclib: Structural analysis to unveil anticancer potential. J. Photochem. Photobiol. B, 2020, 211, 111990.
[http://dx.doi.org/10.1016/j.jphotobiol.2020.111990] [PMID: 32858336]
[31]
Li, Y.; Wei, J.; Xu, C.; Zhao, Z.; You, T. Prognostic significance of cyclin D1 expression in colorectal cancer: A meta-analysis of observational studies. PLoS One, 2014, 9(4), e94508.
[http://dx.doi.org/10.1371/journal.pone.0094508] [PMID: 24728073]
[32]
Yan, M.; Song, M.; Bai, R.; Cheng, S.; Yan, W. Identification of potential therapeutic targets for colorectal cancer by bioinformatics analysis. Oncol. Lett., 2016, 12(6), 5092-5098.
[http://dx.doi.org/10.3892/ol.2016.5328] [PMID: 28105216]
[33]
Mastrogamvraki, N.; Zaravinos, A. Signatures of co-deregulated genes and their transcriptional regulators in colorectal cancer. NPJ Syst. Biol. Appl., 2020, 6(1), 23.
[http://dx.doi.org/10.1038/s41540-020-00144-8] [PMID: 32737302]
[34]
Costa-Cabral, S.; Brough, R.; Konde, A.; Aarts, M.; Campbell, J.; Marinari, E.; Riffell, J.; Bardelli, A.; Torrance, C.; Lord, C.J.; Ashworth, A. CDK1 is a synthetic lethal target for KRAS mutant tumours. PLoS One, 2016, 11(2), e0149099.
[http://dx.doi.org/10.1371/journal.pone.0149099] [PMID: 26881434]
[35]
Zhang, P.; Kawakami, H.; Liu, W.; Zeng, X.; Strebhardt, K.; Tao, K.; Huang, S.; Sinicrope, F.A. Targeting CDK1 and MEK/ERK overcomes apoptotic resistance in BRAF-mutant human colorectal cancer. Mol. Cancer Res., 2018, 16(3), 378-389.
[http://dx.doi.org/10.1158/1541-7786.MCR-17-0404] [PMID: 29233910]
[36]
Roskoski, R., Jr Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs. Pharmacol. Res., 2019, 139, 471-488.
[http://dx.doi.org/10.1016/j.phrs.2018.11.035] [PMID: 30508677]
[37]
Rahaman, M.H.; Lam, F.; Zhong, L.; Teo, T.; Adams, J.; Yu, M.; Milne, R.W.; Pepper, C.; Lokman, N.A.; Ricciardelli, C.; Oehler, M.K.; Wang, S. Targeting CDK9 for treatment of colorectal cancer. Mol. Oncol., 2019, 13(10), 2178-2193.
[http://dx.doi.org/10.1002/1878-0261.12559] [PMID: 31398271]
[38]
Tong, J.; Wang, P.; Tan, S.; Chen, D.; Nikolovska-Coleska, Z.; Zou, F.; Yu, J.; Zhang, L. Mcl-1 Degradation Is Required for Targeted Therapeutics to Eradicate Colon Cancer Cells. Cancer Res., 2017, 77(9), 2512-2521.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-3242] [PMID: 28202514]
[39]
He, S.B.; Yuan, Y.; Wang, L.; Yu, M.J.; Zhu, Y.B.; Zhu, X.G. Effects of cyclin-dependent kinase 8 specific siRNA on the proliferation and apoptosis of colon cancer cells. J. Exp. Clin. Cancer Res., 2011, 30(1), 109.
[http://dx.doi.org/10.1186/1756-9966-30-109] [PMID: 22104393]
[40]
Liu, X.; Gao, Y.; Shen, J.; Yang, W.; Choy, E.; Mankin, H.; Hornicek, F.J.; Duan, Z. Cyclin-Dependent Kinase 11 (CDK11) is required for ovarian cancer cell growth in vitro and in vivo, and its inhibition causes apoptosis and sensitizes cells to Paclitaxel. Mol. Cancer Ther., 2016, 15(7), 1691-1701.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0032] [PMID: 27207777]
[41]
Deep, G.; Agarwal, R. New combination therapies with cell-cycle agents. Curr. Opin. Investig. Drugs, 2008, 9(6), 591-604.
[PMID: 18516759]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy