Apoptotic Properties of Platinum Antitumor Agents Phosphaplatins

Phosphaplatins are a group of non-DNA binding platinum compounds that exhibit excellent in vivo and in vitro efficacies against a variety of cisplatin- and carboplatin-sensitive and resistant ovarian cancers. Although, combinations of cis- or carbo-platin and paclitaxel therapies continue to be the choice of treatment for ovarian cancer, many patients develop resistance to the treatment. Phosphaplatins are pyrophosphate bound platinum-(II) and (IV)-platinum complexes that are bi-negatively charged at or near neutral pH. Both Platinum (II) and platinum (IV) complexes do not induce the overexpress of any DNA repair genes, consistent with the no-DNA binding property of phosphaplatins. In this report, we show the apoptotic properties of two representative compounds, (R, R-1,2-cyclohexanediamine)-(dihydrogen pyrophosphato)platinum (II) (RRD2) and (R,R-1,2-cyclohexanediamine)-trans-dihydroxo(dihydrogen pyrophosphato)platinum (IV) (RRD4) through a variety of experiments as described below.
Phosphaplatins are found to activate and upregulate death receptors on cell surface such as FAS, DR5, and TNFR1. These three death receptors follow the common signaling path to trigger apoptosis by an extrinsic pathway via Death Inducing Signaling Complex (DISC) by recruiting FADD and procaspase-8 and activating caspase-8. A direct binding of FAS by platinum is implicated as the platinum compound was found to be co-localized in the lipid rafts. The PTEN-PI3K pathway involvement was confirmed by the down regulation of both PI3K and p-AKT. Phosphoplatins also upregulate tumor suppression genes P53 and PTEN. Apoptosis by p53 signaling follows intrinsic pathways involving BCL-proteins. In particular upregulation of BAX, PUMA, and downregulation of BCL2 were observed. To further confirm p53-signailng, we have identified a number of p53 target genes that include AEN, CYFIP2, TP53I3, TP53INP1, DPYSL4, LRDD, DRAM1, and a few others. Our data shows that phosphaplatins have the potential to not only treat resistant but also advanced metastatic ovarian cancers.