Ptxplatin: a multifunctional Pt(IV) antitumor prodrug

A series of Pt(IV) prodrugs containing a microtubule inhibitor paclitaxel (PTX) were synthesized and characterized and their antitumor activity was evaluated. Prodrugs 5-12 exhibited the most potent antitumor activity against the tested cancer lines, and simultaneously displayed lower toxicity toward the human normal cells MRC-5 and HL-7702 compared to mono- and co-therapy, respectively. As a representative, compound 5 (named Ptxplatin), conjugating cisplatin (CDDP) with one PTX, effectively entered the cancer cells in a time-dependent manner, significantly induced DNA damage, arrested the cell cycle at the G2/M stage, activated the expression of p53, and inhibited the migration of MCF-7 cells. Moreover, Ptxplatin induced mitochondrial dysfunction via the loss of the mitochondrial membrane potential (Delta psi(m)), increase of reactive oxygen species (ROS) content, promotion of Bax expression and inhibition of Bcl-2 expression. Besides, Ptxplatin induced excessive accumulation of intracellular ROS to trigger endoplasmic reticulum (ER) stress, leading to the significant exaltation of Ca2+ levels and upregulation of the ER-related protein PERK, ATF4 and CHOP. These findings indicated that Ptxplatin intervened in several cellular processes including the p53 apoptosis pathway, mitochondrial damage and ER stress to kill cancer cells.