Monoterpenes as drug shuttles: cytotoxic (6-aminomethylnicotinate)dichloridoplatinum(II) complexes with potential to overcome cisplatin resistance.
(6-Aminomethylnicotinate)dichloridoplatinum(II) complexes 4 esterified with terpene alcohols were tested on a panel of five human tumor cell lines. While they were accumulated in all cell lines more readily than cisplatin (CDDP), their cytotoxicities were tumor-specific and structure-dependent. Cell lines known to feature elevated levels of antiapoptotic, ion-channel-affecting proteins or otherwise impaired caspase-9 activation responded better to 4 than to CDDP, e.g., the HL-60 leukemia to the fenchyl and bornyl derivatives 4a,b at an IC90 < or = 10 microM. The (-)-menthyl complex 4g was far better accumulated and more efficacious in CDDP-resistant 1411HP male germ cell tumor cells than in the congenerous CDDP-sensitive H12.1 cell line. 4g also broke the CDDP resistance of 518A2 melanoma cells. Cell decay in each case was apoptotic as to TUNEL and Annexin V fluorescence assays. Some complexes 4 seem to positively modulate the permeability of the cell membrane and of blocked mitochondrial anion channels.
Schobert
Rainer
R
Organic Chemistry Laboratory, University of Bayreuth, Universitaetsstrasse 30, 95440 Bayreuth, Germany. Rainer.Schobert@uni-bayreuth.de
Biersack
Bernhard
B
Dietrich
Andrea
A
Grotemeier
Antje
A
Müller
Thomas
T
Kalinowski
Bernd
B
Knauer
Sebastian
S
Voigt
Wieland
W
Paschke
Reinhard
R
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D015180:Electrophoresis, Gel, Two-Dimensional; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D039821:Monoterpenes / Q000737:chemistry*; D009336:Necrosis; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010957:Plasmids; D013054:Spectrophotometry, Atomic
D000970:Antineoplastic Agents; D039821:Monoterpenes; D009944:Organoplatinum Compounds; D004247:DNA; D002945:Cisplatin