Abstract
Cisplatin is an important anti-cancer agent widely used in the clinic; however, it has several notable limitations. To develop novel platinum analogues, key characteristics were considered that may result in more effective platinum analogues. In this study, we present comprehensive molecular dynamics simulation studies using a 12-mer DNA (5’-CCTCTggTCTCC-3’, gg= the site of platination) oligonucleotide which was platinated with cisplatin (1), oxaliplatin_1R_2R (2), and BNP3029 (3, a novel substituted cyano platinum analogue, PtCl2[N≡C(CH2)3(C6H5)]2), and analyzed the large data output using the Kolmogorov-Smirnov statistical analyses. In summary, data indicated that BNP3029-DNA had less A-like DNA morphology in comparison to cisplatin-DNA and oxaliplatin-DNA thus maintaining a more B-like DNA form. BNP3029 demonstrated more potent cytotoxic activity, relative to cisplatin and oxaliplatin, in a variety of human cancer cell lines, including several platinum-resistant cell lines.
Highlights
For more than 35 years, cisplatin has been an effective anticancer agent against a variety of tumors including germ cell tumors, ovarian and bladder carcinomas, squamous cell tumors of the head and neck, esophageal cancers, and non-small cell lung tumors either as a single agent or in combination with other chemotherapy drugs (Figure 1) [1,2,3]
Crystallographic studies have previously been carried out on 12-mer DNA oligonucleotide adducts of cisplatin, oxaliplatin and JM118 (JM118 is the active metabolite of Satraplatin) by Lippard and coworkers [14,15,16]
Studies from cisplatin-DNA crystal structure indicated that: (a) platinum coordination bends the DNA (12-mer) by 35-400 towards major groove; (b) DNA takes on A-form morphology on the 5’-side of the platinum adduct with a widened minor groove and adopts B-form morphology on the 3’-side of the platinum adduct; (c) the two guanines which are coordinated to platinum (g6g7, the numbering is based on the 12-mer DNA sequence: 5’-CCTCTggTCTCC-3’) have a roll angle of 260; (d) the 5’-NH3 hydrogen of cisplatin is in hydrogenbond contact with the g6 phosphate backbone oxygen atom [14]
Summary
For more than 35 years, cisplatin has been an effective anticancer agent against a variety of tumors including germ cell tumors, ovarian and bladder carcinomas, squamous cell tumors of the head and neck, esophageal cancers, and non-small cell lung tumors either as a single agent or in combination with other chemotherapy drugs (Figure 1) [1,2,3]. Tumors can develop platinum resistance rendering the drug ineffective [1] Analogues of platinum such as carboplatin and oxaliplatin [4] (Figure 1) have been developed and approved, but their use is limited compared to cisplatin. The postulated mechanism of action of cisplatin involves the initial replacement of one of the two chlorine atoms in cisplatin by water intracellularly, resulting in the formation of a reactive monoaquomonochloro species [3]. This reactive monoaquo species attacks the exposed imidazole N7 atom of guanine on DNA, initially yielding a mono-platinum-DNA adduct. Some patients develop resistance to cisplatin due to: (i) increased drug efflux from the cell; (ii) decreased accumulation of the drug; (iii) increased inactivation of cisplatin by thiol containing proteins or by glutathione (GSH); (iv) increased repair of the platinum-DNA adducts by nucleotide excision repair (NER) proteins; (v) defects in mismatch repair which may lead to reduced apoptotic activity upon treatment with platinum agents; and (vi) increased replicative bypass (or trans- lesion synthesis)
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