TY - JOUR
T1 - Synchrotron X-Ray Fluorescence Nanoprobe Reveals Target Sites for Organo-Osmium Complex in Human Ovarian Cancer Cells
AU - Sanchez-cano, Carlos
AU - Romero-canelón, Isolda
AU - Yang, Yang
AU - Hands-Portman, Ian J.
AU - Bohic, Sylvain
AU - Cloetens, Peter
AU - Sadler, Peter J.
PY - 2017/2/23
Y1 - 2017/2/23
N2 - A variety of transition metal complexes exhibit anticancer activity, but their target sites in cells need to be identified and mechanisms of action elucidated. Here, it was found that the sub‐cellular distribution of [Os(η6‐p‐cym)(Azpy‐NMe2)I]+ (p‐cym=p‐cymene, Azpy‐NMe2=2‐(p‐[dimethylamino]phenylazo)pyridine) (1), a promising drug candidate, can be mapped in human ovarian cancer cells at pharmacological concentrations using a synchrotron X‐ray fluorescence nanoprobe (SXRFN). SXRFN data for Os, Zn, Ca, and P, as well as TEM and ICP analysis of mitochondrial fractions suggest localization of Os in mitochondria and not in the nucleus, accompanied by mobilization of Ca from the endoplasmic reticulum, a signaling event for cell death. These data are consistent with the ability of 1 to induce rapid bursts of reactive oxygen species and especially superoxide formed in the first step of O2 reduction in mitochondria. Such metabolic targeting differs from the action of Pt drugs, offering promise for combatting Pt resistance, which is a current clinical problem.
AB - A variety of transition metal complexes exhibit anticancer activity, but their target sites in cells need to be identified and mechanisms of action elucidated. Here, it was found that the sub‐cellular distribution of [Os(η6‐p‐cym)(Azpy‐NMe2)I]+ (p‐cym=p‐cymene, Azpy‐NMe2=2‐(p‐[dimethylamino]phenylazo)pyridine) (1), a promising drug candidate, can be mapped in human ovarian cancer cells at pharmacological concentrations using a synchrotron X‐ray fluorescence nanoprobe (SXRFN). SXRFN data for Os, Zn, Ca, and P, as well as TEM and ICP analysis of mitochondrial fractions suggest localization of Os in mitochondria and not in the nucleus, accompanied by mobilization of Ca from the endoplasmic reticulum, a signaling event for cell death. These data are consistent with the ability of 1 to induce rapid bursts of reactive oxygen species and especially superoxide formed in the first step of O2 reduction in mitochondria. Such metabolic targeting differs from the action of Pt drugs, offering promise for combatting Pt resistance, which is a current clinical problem.
KW - bioinorganic chemistry
KW - elemental mapping
KW - metallodrugs
KW - organometallic complexes
KW - x-ray fluorescence
U2 - 10.1002/chem.201605911
DO - 10.1002/chem.201605911
M3 - Article
SN - 0947-6539
VL - 23
SP - 2512
EP - 2516
JO - Chemistry: A European Journal
JF - Chemistry: A European Journal
IS - 11
ER -