Drug resistance in cancer

Interactions of cyclin dependent kinase inhibitors with drug efflux transporters

This line of our research follows the path of drug interactions on drug efflux transporters and their role in drug resistance of cancer treatment.

Beside playing an important physiological role in tissue protection, drug efflux transporters from the family of ATP-binding cassette (ABC) transporters, i.e., P‑glycoprotein (ABCB1), breast cancer resistance protein (BCRP, ABCG2), and multidrug resistance proteins (MRPs, ABCCs), are responsible for multidrug resistance in cancer when pumping cytotoxic drugs out of the cancer cells, diminishing thereby the intracellular concentration of the drugs under the lethal level.

Cyclin-dependent kinases (CDK) contribute to the control of cell cycle progression, proliferation and RNA transcription. Abnormalities in their regulation and expression can cause pathogenic changes resulting in different malignancies. Therefore, the CDK are logical targets for inhibition, which can lead to therapeutically beneficial cytostasis and apoptosis. CDK inhibitors (CDKi) have become a novel approach in cancer therapeutics as they effectively stop cellular proliferation and induce apoptosis. Many of these compounds are currently undergoing preclinical and clinical testing.

Synergistic cytotoxic effect of combination of CDKi with other cytostatic drugs

Synergistic cytotoxic effect of combination of CDKi with other cytostatic drugs (modified from Hofman et al., Pharm Res, 2012)

Although much attention has been devoted to the pharmacodynamic properties of these drugs, the pharmacokinetic aspects and mainly interactions with drug efflux transporters have not been evaluated in detail to date. Therefore, we aim to identify possible interactions of these novel compounds with drug efflux transporters to evaluate possible pharmacokinetic interactions and/or dual benefit of these drugs in cancer therapy. Currently, this project is partly running in cooperation with the laboratory of Assoc. Prof. Vladimir Krystof of the Laboratory of Growth Regulators, Palackeho University in Olomouc, Czech Republic.

 

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