Tuning the metabolism of the anticancer drug cisplatin with chemoprotective agents to improve its safety and efficacy

Abstract

Numerous in vivo studies have shown that the severe toxic side-effects of intravenously administered cisplatin can be significantly reduced by the co-administration of sulfur-containing 'chemoprotective agents'. Using a metallomics approach, a likely biochemical basis for these potentially useful observations was only recently uncovered and appears to involve the reaction of chemoprotective agents with cisplatin-derived Pt-species in human plasma to form novel platinum-sulfur complexes (PSC's). We here reveal aspects of the structure of two PSC's and establish the identification of an optimal chemoprotective agent to ameliorate the toxic side-effects of cisplatin, while leaving its antineoplastic activity largely intact, as a feasible research strategy to transform cisplatin into a safer and more effective anticancer drug.

Fig. 1. Conceptual depiction of the chemical reactions that occur between cisplatin (CP) and chemoprotective agents in human plasma in vitro as well as the repercussions that these Pt-species will exert in the whole organism in vivo. CPHP refers to all CP-derived hydrolysis products and PP refers to plasma proteins.

Fig. 2. X-ray absorption spectroscopy-derived structure of the [Pt(S₂O₃)₄]^6– that was isolated from PBS-buffer (STS : CP = 400 : 1). (A) Shows the Pt L_III EXAFS oscillations and (B) the Pt–S phase corrected Fourier transforms, for data (red lines), together with the best fit (blue lines). Best fits indicated four equivalent Pt–S at distance R of 2.31 Å, with σ ², the mean square deviation in R, of 0.0031 Ų. The inset shows the energy minimized geometry optimized density functional theory structure for [Pt(S₂O₃)₄]^6– constrained to S ₄ point group symmetry to assist with convergence. The computed Pt–S bond-lengths were 2.33 Å, in excellent agreement with the EXAFS results, and both are in agreement with the Pt–S distance of the sole reported crystal structure of a terminal thiosulfate bound to a Pt(ii) ion.

Fig. 3. A LC-ESI-MS spectrum (negative mode) obtained when PBS-buffer was spiked with CP, incubated at 37 °C for 10 min and then spiked with NAC and analyzed 50 min later. NAC : CP molar ratio 400 : 1, CP: cisplatin, NAC: N-acetylcysteine.

Melani Sooriyaarachchi

Graham N. George

Ingrid J. Pickering

Aru Narendran

Jürgen Gailer