Chronic lymphocytic leukemia (CLL) treatment is improving; however, some patients do not respond to therapy. Due to the high heterogeneity in disease development, there is an urgent need for personalization of therapy. In the present study, the response of leukemic mononuclear cells to anticancer drugs used for CLL treatment (cladribine + mafosfamide; CM or CM combined with rituximab; RCM) was compared with the response to new cyclin‑dependent kinase (CDK) inhibitors: BP14 and BP30. Viable apoptotic and necrotic cells were quantified by flow cytometry using propidium iodide and Yo‑Pro stains. CDK inhibitors were studied in several doses to determine the reduction of necrosis and simultaneous increase of apoptosis in leukemic cell incubations with anticancer agents. The distinct cell response to applied doses/anticancer agents was observed. Results obtained in the current manuscript confirmed that modulation of doses is important. This was particularly indicated in results obtained at 24 h of cells incubation with anticancer agent. While an important time for analysis of anticancer response efficacy (monitoring of apoptosis induction potential) seems to be 48 h of cells exposition to anticancer agents. High variability in response to the drugs revealed that both the nature and the dose of the anticancer agents could be important in the final effect of the therapy. The present findings support the thesis that personalized medicine, before drug administration in the clinic, could be important to avoid the application of ineffective therapy.

Department of Chemical Biology and Genetics Centre of the Region Haná for Biotechnological and Agricultural Research Faculty of Science Palacký University 78371 Olomouc Czech Republic

Department of Cytobiochemistry Faculty of Biology and Environmental Protection University of Lodz 90‑236 Lodz Poland

Department of Experimental Hematology Medical University of Lodz 93‑510 Lodz Poland

Department of Hematology Medical University of Lodz 93‑510 Lodz Poland

Laboratory of Growth Regulators Faculty of Science Palacký University and Institute of Experimental Botany AS CR 78371 Olomouc Czech Republic

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Besbes S, Mirshahi M, Pocard M, Billard C. Strategies targeting apoptosis proteins to improve therapy of chronic lymphocytic leukemia. Blood Rev. 2015;29:345–350. doi: 10.1016/j.blre.2015.03.005. PubMed DOI

Cramer P, Eichhorst B, Reinhardt HC, Hallek M. Current strategies to create tailored and risk-adapted therapies for CLL patients. Best Pract Res Clin Haematol. 2016;29:111–121. doi: 10.1016/j.beha.2016.08.010. PubMed DOI

Visentin A, Facco M, Frezzato F, Castelli M, Trimarco V, Martini V, Gattazzo C, Severin F, Chiodin G, Martines A, et al. Integrated CLL scoring system, a new and simple index to predict time to treatment and overall survival in patients with chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2015;15:612–620.e1-5. doi: 10.1016/j.clml.2015.06.001. PubMed DOI

Koffman B, Schorr A. The 21st century revolution in CLL: Why this matters to patients. Best Pract Res Clin Haematol. 2016;29:122–132. doi: 10.1016/j.beha.2016.08.008. PubMed DOI

Klein U, Dalla-Favera R. Germinal centres: Role in B-cell physiology and malignancy. Nat Rev Immunol. 2008;8:22–33. doi: 10.1038/nri2217. PubMed DOI

Hallek M. Chronic lymphocytic leukemia: 2013 update on diagnosis, risk stratification and treatment. Am J Hematol. 2013;88:803–816. doi: 10.1002/ajh.23491. PubMed DOI

Martin-Subero JI, López-Otín C, Campo E. Genetic and epigenetic basis of chronic lymphocytic leukemia. Curr Opin Hematol. 2013;20:362–368. doi: 10.1097/MOH.0b013e32836235dc. PubMed DOI

Rogalińska M, Franiak-Pietryga I, Błoński JZ, Góralski P, Maciejewski H, Janus A, Robak P, Mirowski M, Piekarski H, Robak T, Kiliańska ZM. Toward personalized therapy for chronic lymphocytic leukemia: DSC and cDNA microarray assessment of two cases. Cancer Biol Ther. 2013;14:6–12. doi: 10.4161/cbt.22623. PubMed DOI PMC

Rodriquez-Vicente AE, Díaz MG, Hernández-Rivas JM. Chronic lymphocytic leukemia: A clinical and molecular heterogenous disease. Cancer Genet. 2013;206:49–62. doi: 10.1016/j.cancergen.2013.01.003. PubMed DOI

Rogalinska M, Goralski P, Wozniak K, Bednarek JD, Blonski JZ, Robak T, Piekarski H, Hanausek M, Walaszek Z, Kilianska ZM. Calorimetric study as a potential test for choosing treatment of B-cell chronic lymphocytic leukemia. Leuk Res. 2009;33:308–314. doi: 10.1016/j.leukres.2008.06.032. PubMed DOI

Jeyakumar D, O'Brien S. B cell receptor inhibition as a target for CLL therapy. Best Pract Res Clin Haematol. 2016;29:2–14. doi: 10.1016/j.beha.2016.08.004. PubMed DOI

Ferrajoli A, Shanafelt TD, Ivan C, Shimizu M, Rabe KG, Nouraee N, Ikuo M, Ghosh AK, Lerner S, Rassenti LZ, et al. Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia. Blood. 2013;122:1891–1899. doi: 10.1182/blood-2013-01-478222. PubMed DOI PMC

Rogalińska M, Kiliańska ZM. Personalised therapy versus targeted therapy, differences in meaning. Glo J Res Anal. 2015;4:5–8.

Rogalińska M, Błoński JZ, Góralski P, Wawrzyniak E, Hartman M, Rogalska A, Robak P, Koceva-Chyła A, Piekarski H, Robak T, Kiliańska ZM. Relationship between in vitro drug sensitivity and clinical response of patients to treatment in chronic lymphocytic leukemia. Int J Oncol. 2015;46:1259–1267. doi: 10.3892/ijo.2015.2823. PubMed DOI

Rogalińska M, Góralski P, Błoński JZ, Robak P, Barciszewski J, Koceva-Chyła A, Piekarski H, Robak T, Kilianska ZM. Personalized therapy tests for the monitoring of chronic lymphocytic leukemia development. Oncol Let. 2017;13:2079–2084. doi: 10.3892/ol.2017.5725. PubMed DOI PMC

Montserrat E, Bauman T, Delgado J. Present and future of personalized medicine in CLL. Best Pract Res Clin Haematol. 2016;29:100–110. doi: 10.1016/j.beha.2016.08.009. PubMed DOI

Piggin A, Bayly E, Tam CS. Novel agents versus chemotherapy as frontline treatment of CLL. Leuk Lymph. 2017;58:1320–1324. doi: 10.1080/10428194.2017.1280606. PubMed DOI

Rogalińska M, Kiliańska ZM. Potential new agents for chronic lymphocytic leukemia treatment. Anticancer Agents Med Chem. 2010;10:666–682. doi: 10.2174/187152010794479799. PubMed DOI

Robak T, Stilgenbauer S, Tedeschi A. Front-line treatment of CLL in the era of novel agents. Cancer Treat Rev. 2017;53:70–78. doi: 10.1016/j.ctrv.2016.12.007. PubMed DOI

Hallek M. Role and timing of new drugs in CLL. Hematol Oncol. 2017;35(Suppl 1):S30–S32. doi: 10.1002/hon.2397. PubMed DOI

Whittaker S, Mallinger A, Workman P, Clarke PA. Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacol Ther. 2017;173:83–105. doi: 10.1016/j.pharmthera.2017.02.008. PubMed DOI PMC

Niesvizky R, Badros AZ, Costa LJ, Ely SA, Singhal SB, Stadtmauer EA, Haideri NA, Yacoub A, Hess G, Lentzsch S, et al. Phase 1/2 study of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Leuk Lymph. 2015;56:3320–3328. doi: 10.3109/10428194.2015.1030641. PubMed DOI

Edessa D, Sisay M. Recent advances of cyclin-dependent kinases as potential therapeutic targets in HR+/HER2-metastatic breast cancer: A focus on ribociclib. Breast Cancer (Dove Med Press) 2017;9:567–579. PubMed PMC

Blachly JS, Byrd JC, Grever M. Cyclin-dependent kinase inhibitors for the treatment of chronic lymphocytic leukemia. Semin Oncol. 2016;43:265–273. doi: 10.1053/j.seminoncol.2016.02.003. PubMed DOI

Chen Y, Germano S, Clements C, Samuel J, Shelmani G, Jayne S, Dryer MJ, Macip S. Pro-survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia. Br J Haematol. 2016;175:641–651. doi: 10.1111/bjh.14285. PubMed DOI

Gucký T, Jorda R, Zatloukal M, Bazgier V, Berka K, Řezníčková E, Béres T, Strnad M, Kryštof V. A novel series of highly potent 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitors. J Med Chem. 2013;56:6234–6247. doi: 10.1021/jm4006884. PubMed DOI

Haider C, Grubinger M, Řezníčková E, Weiss TS, Rotheneder H, Miklos W, Berger W, Jorda R, Zatloukal M, Gucky T, et al. Novel inhibitors of cyclin-dependent kinases combat hepatocellular carcinoma without inducing chemoresistance. Mol Cancer Ther. 2013;12:1947–1957. doi: 10.1158/1535-7163.MCT-13-0263. PubMed DOI

Allegri L, Baldan F, Mio C, Puppin C, Russo D, Kryštof V, Damante G. Effects of BP-14, a novel cyclin-dependent kinase inhibitor, on anaplastic thyroid cancer cells. Oncol Rep. 2016;35:2413–2418. doi: 10.3892/or.2016.4614. PubMed DOI

Rodriguez D, Bretones G, Arango JR, Valdespino V, Campo E, Quesada V, López-Otín C. Molecular pathogenesis of CLL and its evolution. Int J Hematol. 2015;101:219–228. doi: 10.1007/s12185-015-1733-0. PubMed DOI

Tong WG, Chen R, Plunkett W, Siegel D, Sinha R, Harvey RD, Badros AZ, Popplewell L, Coutre S, Fox JA, et al. Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. J Clin Oncol. 2010;28:3015–3022. doi: 10.1200/JCO.2009.26.1347. PubMed DOI PMC

Ge Y, Lei W, Ma Y, Wang Y, Wei B, Chen X, Ru G, He X, Mou X, Wang S. Synergistic antitumor effects of CDK inhibitor SNS-032 and an oncolytic adenovirus co-expressing TRAIL and Smac in pancreatic cancer. Mol Med Rep. 2017;15:3521–3528. doi: 10.3892/mmr.2017.6472. PubMed DOI PMC

Flynn J, Jones J, Johnson AJ, Andritsos L, Maddocks K, Jaglowski S, Hessler J, Grever MR, Im E, Zhou H, et al. Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia. Leukemia. 2015;29:1524–1529. doi: 10.1038/leu.2015.31. PubMed DOI PMC

Robak P, Robak T. Novel synthetic drugs currently in clinical development for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017;26:1249–1265. doi: 10.1080/13543784.2017.1384814. PubMed DOI

Awan FT, Kay NE, Davis ME, Wu W, Geyer SM, Leung N, Jelinek DF, Tschumper RC, Secreto CR, Lin TS, et al. Mcl-1 expression predicts progression-free survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and rituximab. Blood. 2009;113:535–537. doi: 10.1182/blood-2008-08-173450. PubMed DOI PMC

Kozako T, Suzuki T, Yoshimitsu M, Arima N, Honda S, Soeda S. Anticancer agents targeted to sirtuins. Molecules. 2014;19:20295–20313. doi: 10.3390/molecules191220295. PubMed DOI PMC

Albayrak A, Halici Z, Cadirci E, Polat B, Karakus E, Bayir Y, Unal D, Atasoy M, Dogrul A. Inflammation and peripheral 5-HT7 receptors: The role of 5-HT7 receptors in carrageenan induced inflammation in rats. Eur J Pharmacol. 2013;715:270–279. doi: 10.1016/j.ejphar.2013.05.010. PubMed DOI

Polat B, Halici Z, Cadirci E, Albayrak A, Karakus E, Bayir Y, Bilen H, Sahin A, Yuksel TN. The effect of alpha-lipoic acid in ovariectomy and inflammation-mediated osteoporosis on the skeletal status of rat bone. Eur J Pharmacol. 2013;718:469–474. doi: 10.1016/j.ejphar.2013.07.033. PubMed DOI

Rogalinska M. The role of mitochondria in cancer induction, progression and changes in metabolism. Mini Rev Med Chem. 2016;16:524–530. doi: 10.2174/1389557515666151016124331. PubMed DOI