Klin Farmakol Farm. 2006;20(4):197-201

BOHEMINE IN VITRO CYTOTOXIC ACTIVITY IN PRIMARY TUMOUR CELLS

Libuše Stýskalová², MUDr. Karel Cwiertka³, Věra Nosková², Anna Janošťáková², Lenka Radová², prof. MUDr. Vladimír Mihál CSc¹, Marián Hajdúch^2,3

¹ Dětská klinika LF UP a FN Olomouc

² Laboratoř experimentální medicíny při Dětské klinice LF UP a FN Olomouc

³ Onkologická klinika FN a LF UP, Olomouc

Background: Cyclin dependent kinases complexed with cyclins trigger eukaryotic cell cycle proliferation by phosphorylation of specific target protein. Synthetic inhibitors of cyclin dependent kinases (CDKIs) as olomoucine (OC), bohemine (BOH), R-roscovitine (ROSC, seliciclib, CYC202) etc., are typical representatives of drugs, which can be used for control of cellular proliferation and clinical treatment of tumours.

Aim: The purpose of this study was to assess the cytotoxic activity of the synthetic CDKI, bohemine, on human primary tumour cells and compare its potency with classic anti-cancer drugs.

Methods: Malignant cells were isolated, after mechanical and enzymatic digestion of tumour tissues, by gradient centrifugation. The cells were then incubated with ascendant concentrations of BOH or classical anti-cancer drugs in order to determine the concentrations lethal to 50 % of tumour cells (TCS50). TCS50 values were then mutually correlated in order to determine similarities/dissimilarities in the mechanism of action and/or drug resistance.

Results: In the course of study we have successfully analyzed 112 primary tumour samples for drug sensitivity to BOH. Our study showed a tendency for a higher sensitivity of the malignant versus the benignant tumours (20.94/51.57 µM, p = 0.162). The median value of BOH TCS50 in haematological/solid tumours (16.7/23.05 μM) indicates higher sensitivity of haematological malignancies (p = 0.0159).

Conclusion: There were only 20 BOH resistant patients compared to the resistance of classical anti-cancer drugs. Comparison of mechanism of action/resistance with other anti-cancer drugs revealed: 1. an association of BOH activity with antimetabolites, probably signifying common mechanisms of resistance due to their structural similarity, 2. a correlation of efficiency of BOH with drugs targeting RNA transcription (actinomycin D) and/or compounds causing DNA damage (topotecan, cisplatin, daunorubicin, mitoxantrone), which is evidently connected with BOH mediated inhibition of DNA repair and/or activating fosforylation of RNA polymerase II mediated by CDK7 and CDK9.

Keywords: Key words: synthetic inhibitors of cyclin dependent kinases, bohemine, primary human tumour cells.

Published: February 1, 2007  Show citation