Cytotoxicity of Platinum and Palladium Chelates against Osteosarcoma

Abstract

This work reports the half maximal inhibitory concentrations, IC 50 , for conventional anti-cancer drug oxaliplatin (OXA) and potential new drugs Pt 2 Cl 2 Spm (Pt 2 Spm) and Pd 2 Cl 2 Spm (Pd 2 Spm) (Spm = Spermine) against osteosarcoma (OS). IC 50 values provided by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Alamar Blue (AB) viability assays and cell density Sulforhodamine B (SRB) test were compared. Values obtained with MTT and AB were generally in agreement, and a tendency for lower IC 50 values was noted by SRB, for OXA and Pd 2 Spm. The relative suitability of different assays is discussed for each chelate. The IC 50 trend: cisplatin (cDDP) � Pd 2 Spm < OXA < Pt 2 Spm, confirmed cDDP as the most cytotoxic Pt II -agent against OS and revealed a promising performance for Pd 2 Spm. Metal chelates were also tested in combination with doxorubicin and methotrexate, the results showing that, in general, cocktails achieved comparable endperformances to that of combined cDDP, indicating that drug combination may circumvent low single-drug cytotoxicity.

Novel Insights into Mice Multi-Organ Metabolism upon Exposure to a Potential Anticancer Pd(II)-Agent

“…Indeed, PAs form stable, flexible, and soluble complexes with Pd(II) [ 8 , 36 ], improving diffusion across cell membranes [ 35 , 40 ] and, therefore, promoting higher bioavailability of the complex to cancer cells [ 40 ]. Recent studies have focused on the biological performance of Pt/Pd complexes with PA regarding: (i) metal center (either Pt(II) or Pd(II)) [ 21 , 35 , 36 , 44 ] and (ii) type of ligand (either Spd or Spm) [ 39 , 40 ]. In particular, the antitumor properties of dinuclear Pd(II) complexes with biogenic polyamines such as spermine (Pd 2 Spm) have been studied mainly in vitro , in human cell lines of oral squamous carcinoma (HSC-3) [ 35 ], ovarian carcinoma (A2780) [ 36 ], osteosarcoma [ 44 ], and breast cancer (MCF-7 [ 19 ] and MDA-MB-231 [ 19 , 21 , 22 ]), generally exhibiting a tendency for enhanced cytotoxicity, compared to cDDP and its Pt(II) analog [ 35 , 36 ].…”

Preclinical Pharmacokinetics and Biodistribution of Anticancer Dinuclear Palladium(II)-Spermine Complex (Pd2Spm) in Mice

“…In particular, biogenic polyamines, such as spermidine (H 2 N(CH 2 ) 4 NH(CH 2 ) 3 NH 2 , Spd) and spermine (H 2 N(CH 2 ) 3 NH(CH 2 ) 4 NH(CH 2 ) 3 NH 2 , Spm), have been identified as suitable chelating ligands for both Pt and Pd-metal ions, allowing the formation of stable chelates with appropriate kinetic properties [ 17 ]. For instance, the dinuclear Pd(II) complex with spermine as a bridging ligand (Pd 2 Spm, Figure 1 d) has shown promising in vitro anticancer activity against osteosarcoma [ 18 ], breast [ 19 , 20 ] and ovarian cancers [ 21 ]. Pd 2 Spm´s antineoplastic activity is attributed to unconventional DNA interactions at more than one site in the double helix via the formation of long-range interstrand adducts that trigger more severe and less repairable cell damage than the clinically used mononuclear Pt(II) compounds (e.g., cisplatin) [ 17 , 22 , 23 ].…”

Response of Osteosarcoma Cell Metabolism to Platinum and Palladium Chelates as Potential New Drugs

“…In order to overcome these deleterious side effects and unveil new potential antineoplastic agents, other Pt(II) anticancer drugs such as oxaliplatin (OXA) and carboplatin, have been developed [ 5 ], although still associated to several often serious side effects [ 6 ]. Due to the chemical similarity between Pd(II) and Pt(II) ions, palladium chelates [ 7 ] have drawn increasing interest in this context [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. In spite of their favorable antiproliferative and cytotoxic activities [ 12 , 15 , 21 , 22 , 24 ], their high lability requires strongly coordinating ligands and reasonably nonlabile leaving groups to ensure stability.…”

“…These polynuclear agents allow the formation of long-range inter- and intra-strand crosslinks within DNA, leading to severe DNA damage and to improve in vitro antitumor efficacy, namely towards human metastatic breast cancer [ 13 , 14 , 18 , 19 , 24 ], ovarian cancer [ 10 ], oral cancer [ 9 ] and OS [ 21 ]. Interestingly, Pd 2 Spm has been shown to be more effective than its Pt(II) analogue against cell lines of triple negative breast [ 9 ] and ovarian [ 10 ] cancers, as well as of osteosarcoma [ 23 ]. Regarding the latter, Pd 2 Spm was observed to correspond to a lower IC 50 than Pt 2 Spm, cDDP or OXA [ 23 ].…”