Platinum (IV) Derivatives with Cinnamate Axial Ligands as Potent Agents Against Both Differentiated and Tumorigenic Cancer Stem Rhabdomyosarcoma Cells

Abstract

To design an anticancer drug capable of inhibiting not only the proliferation of the differentiated tumor cells but also reducing the tumorigenic capability of cancer stem cells (CSCs), the new PtIV prodrugs with axial cinnamate ligands were synthesized. We demonstrate their superior antiproliferative activity in monolayer and 3D spheroid antiproliferative activity tests using panel of cancer cell lines. An outstanding activity was found against rhabdomyosarcoma cells, one of the most problematic and poorly treatable pediatric tumors. The results also suggest that the released PtII compound inhibits antiproliferative activity of cancer cells by DNA‐damage mediated mechanism; the released cinnamic acid can trigger processes leading to differentiation, making the CSCs more sensitive to killing by the platinum part of the complex. PtIV complex with axial cinnamate ligands is the first PtIV prodrug capable of overcoming CSCs resistance and induce death in both CSCs and bulk cancer.

A Multi‐action PtIV Conjugate with Oleate and Cinnamate Ligands Targets Human Epithelial Growth Factor Receptor HER2 in Aggressive Breast Cancer Cells

“…This complex was designed to prepare ap rospective Pt-based drug acting efficiently in aggressive HER2-positive breast tumors, typical of poor prognosis.A sa na dded value,d ue to the biological activity of cinnamate ligand, the complex was supposed to kill both CSCs and bulk, differentiated cancer cells. [12] We demonstrate the superior antiproliferative activity of the complex against ap anel of breast cancer cell lines. Importantly,t here is as ignificant correlation of antiproliferative activity and HER2 overexpression;t he complex is markedly more active in the cells overexpressing HER2 receptor.T he results also confirm the hypothesis that both oleic and trans-cinnamic acids presented in axial positions of the molecule of the investigated Pt IV complex enter the cells altogether with the Pt-moiety and after intracellular reduction they can trigger processes leading to downregulation of HER2.…”

“…Platinum(IV) derivative of cisplatin with one axial ligand of trans-cinnamic acid and one axial ligand of oleic acid, cis,trans,cis-[Pt(NH 3 ) 2 (t-cinnamate)(oleate)Cl 2 ]( 1), was synthesized according to the standard procedures for the synthesis of mixed-carboxylato platinum(IV) complexes. [13] In brief,m onocarboxylated complex cis,trans,cis-[Pt-(NH 3 ) 2 (cinnamate)(OH)Cl 2 ]( prepared as already described [12] )w as reacted with an excess of the oleic anhydride (4 equiv.) in DMF.T he mixture was heated and stirred for 24 hi nt he dark, allowing the formation of an unsymmetrically biscarboxylated complex 1 (Supporting Information, Scheme S1).…”

“…[10] In addition, trans-CAh as been shown to affect differentiation of cancer stem cells (CSCs), making them more sensitive to cisplatin [11] so that the resulting Pt IV complex can possess anti-CSC activity. [12] Moreover, trans-CA may provide protection to normal cells from the toxic effects of cisplatin. [9a] However, the cellular accumulation of both these acids is low due to their anionic character under physiological conditions;t heir biological activity is observed only at their high concentrations.T herefore,t he conjugation of OA and trans-CA with platinum moiety represents ap romising approach.…”

Regulating Stem Cell-Related Genes Induces the Plastic Differentiation of Cancer Stem Cells to Treat Breast Cancer

“…Previous studies have shown that both small-molecule drugs (all-trans retinoic acid 32 and cinnamate 33 ) and macromolecule agents (bone morphogenetic proteins 34 ) are able to induce the differentiation of CSC into mature cancer cells, whereas the differentiated mature cancer cells can be more effectively killed by anticancer drugs. In this study, we reveal that the antibiotic salinomycin can induce the differentiation of CSCs as well.…”

Photoactivatable Platinum-Based Anticancer Drugs: Mode of Photoactivation and Mechanism of Action

“…This accidental finding provided a new strategy for the design of novel monoazido-containing Pt(IV) photoactivatable complexes. The conjugation of a bioactive ligand at the axial position of Pt(IV) prodrugs has been extensively studied as a strategy to potentiate the anticancer activity of platinum drugs, and the drugs were known as "dual-action" Pt(IV) prodrugs [51][52][53][54][55][56]. Recently, Kasparkova et al prepared complex 12 (Figure 3) by conjugating a histone deacetylase (HADC) inhibitor, suberoyl-bis-hydroxamic acid (Sub), to the axial position of the diazido Pt(IV) complex [57].…”