A New Platinum-Based Prodrug Candidate for Chemotherapy and Its Synergistic Effect With Hadrontherapy: Novel Strategy to Treat Glioblastoma

Abstract

Glioblastoma (GBM) is the most common tumor of the central nervous system. Current therapies, often associated with severe side effects, are inefficacious to contrast the GBM relapsing forms. In trying to overcome these drawbacks, (OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato)platinum(IV), also called Pt(IV)Ac-POA, has been recently synthesized. This new prodrug bearing as axial ligand (2-propynyl)octanoic acid (POA), a histone deacetylase inhibitor, has a higher activity due to (i) its high cellular accumulation by virtue of its high lipophilicity and (ii) the inhibition of histone deacetylase, which leads to the increased exposure of nuclear DNA, permitting higher platination and promoting cancer cell death. In the present study, we investigated the effects induced by Pt(IV)Ac-POA and its potential antitumor activity in human U251 glioblastoma cell line using a battery of complementary techniques, i.e., flow cytometry, immunocytochemistry, TEM, and Western blotting analyses. In addition, the synergistic effect of Pt(IV)Ac-POA associated with the innovative oncological hadrontherapy with carbon ions was investigated, with the aim to identify the most efficient anticancer treatment combination. Our in vitro data demonstrated that Pt(IV)Ac-POA is able to induce cell death, through different pathways, at concentrations lower than those tested for other platinum analogs. In particular, an enduring Pt(IV)Ac-POA antitumor effect, persisting in long-term treatment, was demonstrated. Interestingly, this effect was further amplified by the combined exposure to carbon ion radiation. In conclusion, Pt(IV)Ac-POA represents a promising prodrug to be incorporated into the treatment regimen for GBM. Moreover, the synergistic efficacy of the combined protocol using chemotherapeutic Pt(IV)Ac-POA followed by carbon ion radiation may represent a promising approach, which may overcome some typical limitations of conventional therapeutic protocols for GBM treatment.

Medicinal inorganic chemistry – challenges, opportunities and guidelines to develop the next generation of radioactive, photoactivated and active site inhibiting metal-based medicines

“…The presence of POA enhances the DNA exposure to the active Pt 2+ complex after the reduction mechanism in the tumor environment. 22 Complex 29 is another good example of a multifunctional Pt 4+ prodrug by incorporation of 4-PBA and a targeting moiety with the biotin group (Fig. 10, middle).…”

“…Other de novo complexes have been developed and tested, primarily using metals Ru, Ir, Os, Re, and Pt. Most notably, Ru complex TLD-1433 (22), is the first Ru 2+ based photosensitizer to undergo human clinical trials. Its main photoexcitation occurs between 300-550 nm, thereby, it can be excited by green light.…”

Synthesis and anticancer activity of two highly water-soluble and ionic Pt(iv) complexes as prodrugs for Pt(ii) anticancer drugs

“…Platinum(IV) complexes are almost always six-coordinated with octahedron geometries, the saturated, kinetically much more inert coordination sphere is less susceptible to ligand substitution reactions than four-coordinate platinum(II) centers, thus minimizing undesired side reactions with biomolecules prior to DNA binding [9]. In addition, the two extra axial ligands of low-spin d6 platinum(IV) centers provide a means to endow and ne-tune desired biological properties such as lipophilicity, redox stability, cancer-cell targeting, orthogonal or complementary bioactivity, and improved cellular uptake [10][11][12][13][14][15]. However, although platinum(IV) complexes can platinate DNA in their oxidized form, the formation of cytotoxic lesions by ligand substitution occurs on the scale of weeks [16], therefore, reduction of the platinum(IV) center to homologous platinum(II), accompanied by the loss of two axial ligands, is thought to be essential for these agents to exert anticancer activity [17].…”

“…10 In addition, two extra axial ligands coordinated to platinumIJIV) centers can endow or fine-tune the desired properties of these complexes, such as lipophilicity, redox properties, bioactivity, cancer-cell targeting, and enhanced cellular uptake. [11][12][13][14][15][16] However, although platinumIJIV) complexes can directly platinate DNA in this oxidized form, the formation of cytotoxic lesions through ligand substitution reactions often demands a scale of several weeks; 17 therefore, the reduction of platinumIJIV) complexes to homologous platinumIJII), accompanied by the loss of two axial ligands, is considered to be an essential process for these platinumIJIV) agents to exert their anticancer activity. 18 So far, four PtIJIV) complexes, namely iproplatin, satraplatin, tetraplatin and LA-12 (Fig.…”

Application of the anthraquinone drug rhein as an axial ligand in bifunctional Pt(iv) complexes to obtain antiproliferative agents against human glioblastoma cells

“…In fact, they should be designed to be specifically reduced in the hypoxic tumor tissue, to give the cytotoxic Pt(II) metabolite with the concomitant loss of the two axial ligands (activation by reduction). [15][16][17][18][19][20][21] In this regard, two bifunctional Pt(IV) complexes, containing 2-(2-propynyl)octanoate and a methyltetrahydropyridin derivative, respectively, were reported to be effective against GBM in both in vitro [22][23][24] and in vivo 25 models. In addition, a recent review discussed the anticancer effects and advantages of platinum-based drugs in the field of brain tumors.…”