期刊
ONCOTARGET
卷 8, 期 1, 页码 490-505出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.13448
关键词
gold(III) complexes; bipyridine; cisplatin resistance; reactive oxygen species; p53
资金
- National Plan for Science and Technology and Innovation (MAARIFAH)-King Abdul Aziz city for Science and Technology-through the Science and Technology unit at King Fahd University of Petroleum and Minerals (KFUPM)- the Kingdom of Saudi Arabia [14-MED64-04]
- Italian Association for Cancer Research (AIRC) [IG 15844]
- Ministero della Salute, Ricerca Finalizzata FSN, I.R.C.C.S., Rome, Italy
- Fondazione Umberto Veronesi
- US National Institutes of Health [RO1 CA160687]
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.
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