New Platinum (Pt)-based Anticancer Agents, Bearing a PtN2SO Coordination Core, For Treating Advanced Melanoma
Refereed conference paper presented and published in conference proceedings


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AbstractThe aim of this project is to demonstrate the potential utility of a new series of platinum (Pt) compounds having a PtN2SO coordination core in treating advanced melanoma. There is currently an unsatisfied medical need for a more effective treatment of advanced melanoma, which is notorious for its prominent resistance to conventional chemotherapeutic drugs due to elevated DNA repair capacity and dysregulation of cancer apoptotic pathways. Platinum (Pt)-based anticancer drugs, exemplified by cisplatin, are key component in combination chemotherapy. They bind to DNA and form mainly the Pt-GG crosslink, subsequently leading to apoptosis to mediate cell death. A series of new Pt(II) compounds possessing a bidentate ligand modified from oxaliplatin has been synthesized, with one of the oxygen ligating atom substituted for a sulfur atom (resulting in a PtN2SO coordination core structure). This novel design is to minimize competition from protein and other bionucleophiles for the Pt drug but maximize drug-DNA interaction. We hypothesize that the unique features of the new PtN2SO compounds may make them good candidates for treating advanced melanoma by (i) overcoming DNA repair-mediated drug resistance; and (ii) generating excess reactive oxygen species (ROS) to selectively trigger apoptosis in melanoma cells. The new compounds were found to be more cytotoxic than cisplatin in a panel of human and mouse melanoma cell lines. Importantly, the new compounds were also found to be minimally affected by Pt resistance, which is presumably caused by the formation of unique Pt-G monoadduct and reduced DNA repair. DNA-platination study in melanoma cell lines revealed that the new PtN2SO compounds are able to form more DNA-Pt adducts and there was less repair than treatment with cisplatin. The new compounds were also found to cause a greater induction of the MAPKs (p38, JNK and ERK) than cisplatin to mediate apoptosis. On the other hand, at equipotent concentration, some of the new Pt compounds were found to generate more ROS than cisplatin as indicated by a general fluorescent dye-based oxidative stress indicator. Interestingly, the cytotoxicity of the new compounds were blocked to a greater extent than cisplatin by ROS scavengers, suggesting a more prominent role played by ROS in mediating the cytotoxicity of the new compounds. Our study thus advocates further investigation of the new PtN2SO compounds in treating advanced melanoma.
All Author(s) ListTo KKW, CHONG, Shu Xian, AU-YEUNG Chik Fun Steve
Name of ConferenceAmerican Association for Cancer Research 2016 Annual Meeting
Start Date of Conference20/04/2016
End Date of Conference20/04/2016
Place of ConferenceNew Orleans, LA
Country/Region of ConferenceUnited States of America
Proceedings TitleAmerican Association for Cancer Research 2016 Annual Meeting
Detailed descriptionorganized by American Association for Cancer Research ,
Year2016
Month4
Day20
Volume Number76
Issue Number14
Place of PublicationUnited States of America, New Orleans
Pages1
ISSN0008-5472
LanguagesEnglish-United Kingdom
KeywordsPlatinum, Melanoma, Drug resistance

Last updated on 2020-20-10 at 03:33