Abstract
The differences in efficacy and molecular mechanisms of platinum anti-cancer drugs cisplatin (CP) and oxaliplatin (OX) are thought to be partially due to the differences in the DNA conformations of the CP and OX adducts that form on adjacent guanines on DNA, which in turn influence the binding of damage-recognition proteins that control downstream effects of the adducts. Here we report a comprehensive comparison of the structural distortion of DNA caused by CP and OX adducts in the TGGT sequence context using nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations. When compared to our previous studies in other sequence contexts, these structural studies help us understand the effect of the sequence context on the conformation of Pt-GG DNA adducts. We find that both the sequence context and the type of Pt-GG DNA adduct (CP vs. OX) play an important role in the conformation and the conformational dynamics of Pt-DNA adducts, possibly explaining their influence on the ability of many damage-recognition proteins to bind to Pt-DNA adducts.
Highlights
Cisplatin (CP), carboplatin and oxaliplatin (OX) are platinum based drugs widely used in the treatment of many cancers [1]
The binding of the mismatch repair complex appears to increase the cytotoxicity of Pt-DNA adducts [8,12,13,14], either by activating downstream signaling pathways that lead to apoptosis [15,16,17] or by causing ‘‘futile cycling’’ during translesion synthesis past Pt-DNA adducts [18]
The average solution structures of OX-DNA and undamaged DNA in the TGGT sequence context were computed from the nuclear magnetic resonance (NMR) data essentially as described previously for OX-DNA, CP-DNA and undamaged DNA in the AGGC sequence context [45,46]
Summary
Cisplatin (CP), carboplatin and oxaliplatin (OX) are platinum based drugs widely used in the treatment of many cancers [1]. Cells and tumors resistant to CP are often not cross resistant to OX [5,6], and many DNA damage recognition proteins that bind to Pt-GG adducts discriminate between CP- and OX-GG adducts [7,8,9,10,11], even though they form chemically similar adducts. The effectiveness of OX in CP-resistant cell lines is thought to be due to repair or damage-recognition processes that discriminate between CP and OX DNA adducts. This has been best established for mismatch repair. The binding of the mismatch repair complex appears to increase the cytotoxicity of Pt-DNA adducts [8,12,13,14], either by activating downstream signaling pathways that lead to apoptosis [15,16,17] or by causing ‘‘futile cycling’’ during translesion synthesis past Pt-DNA adducts [18]
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