ABSTRACT
Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is one of the most common genetic lesions in acute myeloid leukemia patients (AML). Although FLT3 tyrosine kinase inhibitors initially exhibit clinical activity, resistance to treatment inevitably occurs within months. PIM kinases are thought to be major drivers of the resistance phenotype and their inhibition in relapsed samples restores cell sensitivity to FLT3 inhibitors. Thus, simultaneous PIM and FLT3 inhibition represents a promising strategy in AML therapy. For such reasons, we have developed SEL24-B489 - a potent, dual PIM and FLT3-ITD inhibitor. SEL24-B489 exhibited significantly broader on-target activity in AML cell lines and primary AML blasts than selective FLT3-ITD or PIM inhibitors. SEL24-B489 also demonstrated marked activity in cells bearing FLT3 tyrosine kinase domain (TKD) mutations that lead to FLT3 inhibitor resistance. Moreover, SEL24-B489 inhibited the growth of a broad panel of AML cell lines in xenograft models with a clear pharmacodynamic-pharmacokinetic relationship. Taken together, our data highlight the unique dual activity of the SEL24-B489 that abrogates the activity of signaling circuits involved in proliferation, inhibition of apoptosis and protein translation/metabolism. These results underscore the therapeutic potential of the dual PIM/FLT3-ITD inhibitor for the treatment of AML.
ABSTRACT
The phenomenon of cancer cell resistance to chemotherapeutics is the main cause of insensitivity to anticancer therapy. Thus, the current challenge remains searching for substances sensitising the activity of cytostatic drugs. In this respect, resveratrol is a very promising therapeutic agent. It has pleiotropic effect on cancer cells, which can play a key role in numerous resistance mechanisms, both classical and atypical. The purpose of the present study was to assess the effect of resveratrol on the inhibition of human pancreatic cancer cell proliferation and on the level of cytostatic resistance-associated proteins. The study was performed on human pancreatic cancer cell lines EPP85-181P (control), EPP85-181RDB (daunorubicin resistance) and EPP85-181PRNOV (mitoxantrone resistance). The effect of resveratrol on the viability and proliferation of the studied cell lines was evaluated by SRB assay, whereas cell cycle arrest and cytostatic accumulation by FACS. Western blot analysis was used to determine the level of P-glycoprotein, topoisomerase II α and ß and immunofluorescence technique to visualise the proteins in the cells. Resveratrol inhibited proliferation of all studied cell lines. Phase-specific cell cycle arrest depended on the type of cancer cells. Resveratrol decreased the level and activity of P-gp in EPP85-181RDB cells. In EPP85-181PRNOV cells, expression of both TopoII isoforms increased in a statistically significant manner. The results of in vitro studies support the possibility of potential use of resveratrol in breaking cancer cell resistance to chemotherapeutic drugs.