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. cell incubations, anticancer agents, Xyloccensin K apoptosis, necrosis, viability, cyclin-dependent kinase inhibitor, alkylator, monoclonal antibody Introduction Although the growing range of treatment options for chronic lymphocytic leukemia and for other lymphoproliferative neoplasms has improved patient survival (1C4), these diseases remain incurable. 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. cell incubations, anticancer Xyloccensin K agents, apoptosis, necrosis, viability, cyclin-dependent kinase inhibitor, alkylator, monoclonal antibody Introduction Although the growing range of treatment options for chronic lymphocytic leukemia and for other lymphoproliferative neoplasms has improved patient survival (1C4), these diseases remain incurable. In addition, there are patients who do not respond to the applied therapy. The serious problems associated with the diagnostic procedure and the design of suitable treatments seem to be linked to the coexistence in patient peripheral blood of quiescent and cycling cells population; Xyloccensin K this constitutes a special challenge in predicting an effective approach for treating CLL patients (5,6). Differences in cell signaling trafficking, as well as in the expression of factors involved in apoptosis or microenvironmental factors, might contribute to differences (between patients) in the cell response to anticancer agents between patients. In addition, it is well accepted that diversity in the accumulation of genetic aberrations and epigenetic modifications could also account for heterogeneity in the clinical course of CLL (7C9) and the response to therapy (10,11). Moreover, another factor that could imply in the course of CLL as well as response to therapy is the expression of miR-155. This microRNA is associated with Xyloccensin K the progression of CLL and weak response to therapy (12). The presence of several factors important for disease development reveals the necessity for the use of personalized medicine, by testing the potential reaction of the patient’s cells to anticancer drugs before treatment, to avoid administration of an ineffective regimen (8,13C16). Therefore, it is very important to search for new anticancer agents with the potential to induce apoptosis in CLL cells (17C20). Cyclin-dependent kinases (CDK) are fundamental factors involved in the regulation of the cell-cycle, transcription and apoptosis. Their frequent deregulation in cancers provides novel targets for pharmacological intervention in oncology (21). Various small-molecule CDK inhibitors have been developed, including CDK4/CDK6-specific palbociclib and ribociclib, recently FDA-approved for multiple myeloma and breast cancer, respectively (22,23). Besides the cell cycle, CDKs play critical roles also in a non-proliferative CLL and in cell lines where the CDK inhibitor flavopiridol has been designed as Xyloccensin K an orphan drug for CLL (24). Flavopiridol however suffers several side effects, such as significant toxicity including high rates of major tumor lysis syndrome, cytokine release syndrome and secretory diarrhea (24). Other CDK inhibitors are therefore studied as new drugs for CLL, such as roscovitine, dinaciclib or SNS-032 (25). These compounds target multiple CDKs, including CDK1, CDK2, CDK5, CDK7 and CDK9, Rabbit Polyclonal to SF3B3 and trigger cytotoxic effects through interruption of the transcription of key antiapoptotic genes responsible for sustenance of the leukemia cell, such as MCL-1 (21,24). We have recently modified roscovitine to increase its potency and the optimization yielded new 2-substituted-6-biarylmethylamino-9-cyclopentylpurine derivatives BP14 and BP30, which display selective and potent inhibition of CDKs 1, 2, 7 and 9 with low nanomolar IC50 values (26). Both BP14 and BP30 exhibit strong cytotoxicity in human cancer cell lines that correlate with robust CDK1 and CDK2 inhibition and caspase activation. BP14 has demonstrated efficacy against xenografted human liver carcinomas, effectively repressing tumor growth (27). In addition, BP14 potently inhibited transcriptional regulator CDK9 and downregulated anti-apoptotic protein MCL-1 (27,28), key mediator of CLL-cell survival. The aim of the current work was to observe the importance of drug doses for anticancer response in leukemic cells. For this purpose we have compared the apoptosis induction potential of new CDK inhibitors as potential drugs for CLL and compare them with standard treatments. The present study compares the cytotoxicity (cell viability, apoptosis or necrosis level) of novel roscovitine derivatives BP14 and BP30 and anticancer drugs used in hematological clinics for treating CLL.