TY - JOUR
T1 - Mechanism of cytotoxicity and cellular uptake of lipophilic inert dinuclear polypyridylruthenium(II) complexes
AU - Pisani, Michelle J.
AU - Fromm, Phillip Dieter
AU - Mulyana, Yanyan
AU - Clarke, Ronald James
AU - Körner, Heinrich
AU - Heimann, Kirsten Ruth
AU - Collins, Grant
AU - Keene, Richard Richard
PY - 2011/5/2
Y1 - 2011/5/2
N2 -
The accumulation, uptake mechanism, cytotoxicity, cellular localisation of-and mode of cell death induced by-dinuclear ruthenium(II) complexes ΔΔ/ΛΛ-[{Ru(phen)
2
}
2
{μ-bb
n
}]
4+
(Rubb
n
), where phen is 1,10-phenanthroline, bb
n
is bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (n=2, 5, 7, 10, 12 or 16), and the corresponding mononuclear complexes containing the bb
n
ligands, were studied in L1210 murine leukaemia cells. Cytotoxicity increased with linker chain length, and the ΔΔ-Rubb
16
complex displayed the highest cytotoxicity of the series, with an IC
50
value of 5μM, similar to that of carboplatin in the L1210 murine leukaemia cell line. Confocal microscopy and flow cytometry studies indicated that the complexes accumulate in the mitochondria of L1210 cells, with the magnitude of cellular uptake and accumulation increasing with linking chain length in the bb
n
bridge of the metal complex. ΔΔ-Rubb
16
entered the L1210 cells by passive diffusion (with a minor contribution from protein-mediated active transport), inducing cell death via apoptosis. Additionally, metal-complex uptake in leukaemia cells was approximately 16-times that observed in healthy Bcells highlighting that the bb
n
series of complexes may have potential as selective anticancer drugs. Quick on the uptake! Inert dinuclear polypyridylruthenium complexes with ligand bridges containing long alkyl chains exhibit high cellular uptake in L1210 cells, selectively accumulating in the mitochondria and inducing cell death by apoptosis. These novel complexes have potential applications as cancer therapeutics.
AB -
The accumulation, uptake mechanism, cytotoxicity, cellular localisation of-and mode of cell death induced by-dinuclear ruthenium(II) complexes ΔΔ/ΛΛ-[{Ru(phen)
2
}
2
{μ-bb
n
}]
4+
(Rubb
n
), where phen is 1,10-phenanthroline, bb
n
is bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (n=2, 5, 7, 10, 12 or 16), and the corresponding mononuclear complexes containing the bb
n
ligands, were studied in L1210 murine leukaemia cells. Cytotoxicity increased with linker chain length, and the ΔΔ-Rubb
16
complex displayed the highest cytotoxicity of the series, with an IC
50
value of 5μM, similar to that of carboplatin in the L1210 murine leukaemia cell line. Confocal microscopy and flow cytometry studies indicated that the complexes accumulate in the mitochondria of L1210 cells, with the magnitude of cellular uptake and accumulation increasing with linking chain length in the bb
n
bridge of the metal complex. ΔΔ-Rubb
16
entered the L1210 cells by passive diffusion (with a minor contribution from protein-mediated active transport), inducing cell death via apoptosis. Additionally, metal-complex uptake in leukaemia cells was approximately 16-times that observed in healthy Bcells highlighting that the bb
n
series of complexes may have potential as selective anticancer drugs. Quick on the uptake! Inert dinuclear polypyridylruthenium complexes with ligand bridges containing long alkyl chains exhibit high cellular uptake in L1210 cells, selectively accumulating in the mitochondria and inducing cell death by apoptosis. These novel complexes have potential applications as cancer therapeutics.
KW - Apoptosis
KW - Bioinorganic chemistry
KW - Cellular uptake
KW - Cytotoxicity
KW - Ruthenium polypyridyl complexes
UR - http://www.scopus.com/inward/record.url?scp=79955004094&partnerID=8YFLogxK
U2 - 10.1002/cmdc.201100053
DO - 10.1002/cmdc.201100053
M3 - Article
SN - 1860-7179
VL - 6
SP - 848
EP - 858
JO - ChemMedChem
JF - ChemMedChem
IS - 5
ER -