Valuable insight into the anticancer activity of the platinum-histone deacetylase inhibitor conjugate, cis-[Pt(NH3)2malSAHA-2H)]
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
22591133
DOI
10.1021/mp300038f
Knihovny.cz E-resources
- MeSH
- Cisplatin pharmacology MeSH
- DNA metabolism MeSH
- Histone Deacetylase Inhibitors pharmacology MeSH
- Hydroxamic Acids poisoning MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Organoplatinum Compounds pharmacology MeSH
- Antineoplastic Agents pharmacology MeSH
- Vorinostat MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Cisplatin MeSH
- DNA MeSH
- Histone Deacetylase Inhibitors MeSH
- Hydroxamic Acids MeSH
- Organoplatinum Compounds MeSH
- Antineoplastic Agents MeSH
- Vorinostat MeSH
cis-[Pt(II)(NH3)2(malSAHA-2H)], a cisplatin adduct conjugated to a potent histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA), was previously developed as a potential anticancer agent. This Pt-HDACi conjugate was demonstrated to have comparable cytotoxicity to cisplatin against A2780 ovarian cancer cells but significantly reduced cytotoxicity against a representative normal cell line, NHDF. Thus, with a view to (i) understanding more deeply the effects that may play an important role in the biological (pharmacological) properties of this new conjugate against cancer cells and (ii) developing the next generation of Pt-HDACi conjugates, the cytotoxicity, DNA binding, cellular accumulation and HDAC inhibitory activity of cis-[Pt(II)(NH3)2(malSAHA-2H)] were investigated and are reported herein. cis-[Pt(II)(NH3)2(malSAHA-2H)] was found to have marginally lower cytotoxicity against a panel of cancer cell lines as compared to cisplatin and SAHA. cis-[Pt(II)(NH3)2(malSAHA-2H)] was also found to accumulate better in cancer cells but bind DNA less readily as compared to cisplatin. DNA binding experiments indicated that cis-[Pt(II)(NH3)2(malSAHA-2H)] bound DNA more effectively in cellulo as compared to in cell-free media. Activation of the Pt-HDACi conjugate was therefore investigated. The binding of cis-[Pt(II)(NH3)2(malSAHA-2H)] to DNA was found to be enhanced by the presence of thiol-containing molecules such as glutathione and thiourea, and activation occurred in cytosolic but not nuclear extract of human cancer cells. The activity of cis-[Pt(NH3)2(malSAHA-2H)] as a HDAC inhibitor was also examined; the conjugate exhibited no inhibition of HDAC activity in CH1 cells. In light of these results, novel Pt-HDACi conjugates are currently being developed, with particular emphasis, through subtle structural modifications, on enhancing the rate of DNA binding and enhancing HDAC inhibitory activity.
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