Transcript Slajd 1 - Uniwersytet Warszawski

ANTHRACYCLINE MULTI-DRUG RESISTANCE REVERSAL BY
VERAPAMIL- MOLECULAR MECHANISM ELUCIDATION
Klara Chrzanowski
The objective of my work was to examine the molecular mechanism reversal of
cell resistance to anticancer drugs to verapamil. Making the mechanism clear
would create reliable ground to search for new more effecient drug reversing a
drug resistance to the chemotherapeutics.
2+
Ca
My hypothesis assumes verapamil molecules react with
ions in
cytoplasm forming stable, biligand complex. Hence, the inability of
reduction of oxidized glutathione (GS) to its reduced form excludes
removing of anthracyclines outside cell. It results in a higher level of
anthracyclines inside cell. Efficiency of this process depends on the
level of reduced glutathione inside the cell. The level of reduced
glutathione is dependent of the concentration of Ca2+ ions, since this
form of glutathione is created in the first stage of the pentose
phosphate pathway.
Ca
Glucose 6-phosphate +
+
NADP
2+
6-phospho-gloucono-δ- lactone
The mechanism of reversing DR to anthracycline may rely on the
2+
blocking of the Ca ions by verapamil.
Calcium ion- Verapamil Complex Structure
Verification of the hypothesis was done in two ways
1) using the quantum chemical method by which thermodynamic functions, enthalpy, and free enthalpy were calculated,
2) using MS method applying ‘soft’ ionization techniques APCI and ESI, which allow samples to be analysed in a liquid mobile phase, samples of verapamil and
calcium-verapamil complex solutions in methanol were studied.
The following values were obtained: ∆H = -36.27 kcal/mol and ∆G = -32.42 kcal/mol. These values prove that the reaction between verapamil and the calcium ion is
spontaneous and hence thermodynamically possible. The calculated values of ∆G give information whether the reaction is spontaneous and therefore
thermodynamically possible or not. The sign of ∆H gives account to whether the reaction produces energy or absorbs it.
2+
Ca
The complex compound of
ion with verapamil was synthesized and its identity confirmed by the mass spectrum. Through the Electrospray ionization technique
the molecular ions of Verapamil and the Calcium- Verapamil complex were detected. Many experiments were performed with different MS ionisations and changes in
the parameters of the sources were used to choose optimal conditions for the best results.