Enhancing lipophilicity as a strategy to overcome resistance against platinum complexes?
- Author(s)
- Irina Buß, Dirk Garmann, Mathea Sophia Galanski, Günther Weber, Ganna V. Kalayda, Bernhard Keppler, Ulrich Jaehde
- Abstract
Decreased influx represents one of the major resistance mechanisms of platinum complexes. In order to address the question if this mechanism of resistance can be overcome by enhancing the lipophilicity of platinum complexes, we investigated the influence of lipophilicity on cellular accumulation and cytotoxicity in a panel of oxaliplatin analogues with different carrier ligands. Cellular accumulation, DNA platination and cytotoxicity were measured in a cisplatin-sensitive and -resistant ovarian carcinoma (A2780/A2780cis) and in an oxaliplatin-sensitive and -resistant ileocecal colorectal adenocarcinoma (HCT-8/HCT-8ox) cell line pair. Platinum concentrations were determined by flameless atomic absorption spectrometry or adsorptive stripping voltammetry. Passive diffusion represented the main influx mechanism of oxaliplatin analogues during the first minutes of incubation as indicated by a correlation between lipophilicity and early influx rate. Afterwards, the predominant influx mechanism was lipophilicity-independent. More lipophilic complexes showed a reduced cytotoxic activity, although the early influx rate was increased. The resistance profiles of the two cell line pairs were found to be different: HCT-8ox cells were less resistant against more lipophilic complexes, whereas A2780cis cells exhibited a comparable degree of resistance against all investigated compounds. However, the reduction in resistance factor of HCT-8ox cells cannot be explained by increased influx suggesting that other resistance mechanisms are circumvented upon exposure to more lipophilic compounds. Though resistance against more lipophilic platinum complexes analogues is lower we conclude that enhancing lipophilicity is not a successful strategy to overcome platinum resistance as higher lipophilicity is also associated with lower cytotoxic activity.
- Organisation(s)
- Department of Inorganic Chemistry
- External organisation(s)
- Rheinische Friedrich-Wilhelms-Universität Bonn, Institute for Analytical Sciences
- Journal
- Journal of Inorganic Biochemistry
- Volume
- 105
- Pages
- 709-717
- No. of pages
- 9
- ISSN
- 0162-0134
- Publication date
- 2011
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 301305 Medical chemistry
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/07492dc9-13fd-4193-bf81-040f4fdaff9a