TY - JOUR
T1 - Cellular trafficking, accumulation and DNA platination of a series of cisplatin-based dicarboxylato Pt(IV) prodrugs
AU - Ravera, Mauro
AU - Gabano, Elisabetta
AU - Zanellato, Ilaria
AU - Bonarrigo, Ilaria
AU - Alessio, Manuela
AU - Arnesano, Fabio
AU - Galliani, Angela
AU - Natile, Giovanni
AU - Osella, Domenico
N1 - Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved. v.
PY - 2015/5/30
Y1 - 2015/5/30
N2 - A series of Pt(IV) anticancer prodrug candidates, having the equatorial arrangement of cisplatin and bearing two aliphatic carboxylato axial ligands, has been investigated to prove the relationship between lipophilicity, cellular accumulation, DNA platination and antiproliferative activity on the cisplatin-sensitive A2780 ovarian cancer cell line. Unlike cisplatin, no facilitated influx/efflux mechanism appears to operate in the case of the Pt(IV) complexes under investigation, thus indicating that they enter by passive diffusion. While Pt(IV) complexes having lipophilicity comparable to that of cisplatin (negative values of log Po/w) exhibit a cellular accumulation similar to that of cisplatin, the most lipophilic complexes of the series show much higher cellular accumulation (stemming from enhanced passive diffusion), accompanied by greater DNA platination and cell growth inhibition. Even if the Pt(IV) complexes are removed from the culture medium in the recovery process, the level of DNA platination remains very high and persistent in time, indicating efficient storing of the complexes and poor detoxification efficiency.
AB - A series of Pt(IV) anticancer prodrug candidates, having the equatorial arrangement of cisplatin and bearing two aliphatic carboxylato axial ligands, has been investigated to prove the relationship between lipophilicity, cellular accumulation, DNA platination and antiproliferative activity on the cisplatin-sensitive A2780 ovarian cancer cell line. Unlike cisplatin, no facilitated influx/efflux mechanism appears to operate in the case of the Pt(IV) complexes under investigation, thus indicating that they enter by passive diffusion. While Pt(IV) complexes having lipophilicity comparable to that of cisplatin (negative values of log Po/w) exhibit a cellular accumulation similar to that of cisplatin, the most lipophilic complexes of the series show much higher cellular accumulation (stemming from enhanced passive diffusion), accompanied by greater DNA platination and cell growth inhibition. Even if the Pt(IV) complexes are removed from the culture medium in the recovery process, the level of DNA platination remains very high and persistent in time, indicating efficient storing of the complexes and poor detoxification efficiency.
KW - Cell growth inhibition
KW - Cellular accumulation
KW - DNA platination
KW - Lipophilicity
KW - Pt(IV) complexes
UR - http://www.scopus.com/inward/record.url?scp=84930664461&partnerID=8YFLogxK
U2 - 10.1016/j.jinorgbio.2015.05.012
DO - 10.1016/j.jinorgbio.2015.05.012
M3 - Article
SN - 0162-0134
VL - 150
SP - 1
EP - 8
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
ER -
