TY - JOUR
T1 - New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status
AU - Altaf, Muhammad
AU - Monim-ul-Mehboob, Muhammad
AU - Kawde, Abdel Nasser
AU - Corona, Giuseppe
AU - Larcher, Roberto
AU - Ogasawara, Marcia
AU - Casagrande, Naike
AU - Celegato, Marta
AU - Borghese, Cinzia
AU - Siddik, Zahid H.
AU - Aldinucci, Donatella
AU - Isab, Anvarhusein A.
PY - 2017
Y1 - 2017
N2 - We synthesized, characterized and tested in a panel of cancer cell lines, nine new bipyridine gold(III) dithiocarbamate-containing complexes. In vitro studies demonstrated that compounds 1, 2, 4, 5, 7 and 8 were the most cytotoxic in prostate, breast, ovarian cancer cell lines and in Hodgkin lymphoma cells with IC50 values lower than the reference drug cisplatin. The most active compound 1 was more active than cisplatin in ovarian (A2780cis and 2780CP-16) and breast cancer cisplatin-resistant cells. Compound 1 determined an alteration of the cellular redox homeostasis leading to increased ROS levels, a decrease in the mitochondrial membrane potential, cytochrome-c release from the mitochondria and activation of caspases 9 and 3. The ROS scavenger NAC suppressed ROS generation and rescued cells from damage. Compound 1 resulted more active in tumor cells than in normal human Mesenchymal stromal cells. Gold compounds were active independent of p53 status: exerted cytotoxic effects on a panel of non-small cell lung cancer cell lines with different p53 status and in the ovarian A2780 model where the p53 was knocked out. In conclusion, these promising results strongly indicate the need for further preclinical evaluation to test the clinical potential of these new gold(III) complexes.
AB - We synthesized, characterized and tested in a panel of cancer cell lines, nine new bipyridine gold(III) dithiocarbamate-containing complexes. In vitro studies demonstrated that compounds 1, 2, 4, 5, 7 and 8 were the most cytotoxic in prostate, breast, ovarian cancer cell lines and in Hodgkin lymphoma cells with IC50 values lower than the reference drug cisplatin. The most active compound 1 was more active than cisplatin in ovarian (A2780cis and 2780CP-16) and breast cancer cisplatin-resistant cells. Compound 1 determined an alteration of the cellular redox homeostasis leading to increased ROS levels, a decrease in the mitochondrial membrane potential, cytochrome-c release from the mitochondria and activation of caspases 9 and 3. The ROS scavenger NAC suppressed ROS generation and rescued cells from damage. Compound 1 resulted more active in tumor cells than in normal human Mesenchymal stromal cells. Gold compounds were active independent of p53 status: exerted cytotoxic effects on a panel of non-small cell lung cancer cell lines with different p53 status and in the ovarian A2780 model where the p53 was knocked out. In conclusion, these promising results strongly indicate the need for further preclinical evaluation to test the clinical potential of these new gold(III) complexes.
KW - Bipyridine
KW - Cisplatin resistance
KW - Gold(III) complexes
KW - P53
KW - Reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=85009450645&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85009450645&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.13448
DO - 10.18632/oncotarget.13448
M3 - Article
C2 - 27888799
AN - SCOPUS:85009450645
SN - 1949-2553
VL - 8
SP - 490
EP - 505
JO - Oncotarget
JF - Oncotarget
IS - 1
ER -