Conjugation of platinum(IV) complexes with chlorambucil to overcome cisplatin resistance via a joint action mode toward DNA

Two platinum(IV) complexes were designed and prepared by conjugation of cisplatin and oxaliplatin units with a DNA-damaging agent, chlorambucil, respectively. By taking a joint action to enhance the damage of DNA, the conjugates displayed potent antitumor activity against all the tested cancer cell lines comparable to cisplatin and oxaliplatin, and notably could overcome cisplatin resistance at certain degree. Complex 4, a hybrid of cisplatin and chlorambucil, arrested the cell cycle at the S and G2 phases, distinctive from those of cisplatin and oxaliplatin. Apoptosis studies revealed that complex 4 could induce cell apoptosis significantly in both SGC7901 and SGC7901/CDDP cells. Moreover, further investigation indicated that complex 4 suppressed the drug resistance by the improvement of the platinum uptake and the inhibition of PRAP-1 protein. These results show that the joint action on DNA is an effective strategy to overcome cisplatin resistance. (C) 2017 Elsevier Masson SAS. All rights reserved.