Novel Palladium(II) Complexes that Influence Prominin-1/CD133 Expression and Stem Cell Factor Release in Tumor Cells.

Eva Fischer-Fodor,Roman Mikláš,Mihai Cenariu,Natalia Miklášová,Ioana Georgeta Grosu,Ferdinand Devínsky,Ciprian Tomuleasa,Ioana Berindan-Neagoe,Maria Perde-Schrepler,Lucia Rišiaňová,Piroska Virag

doi:10.3390/molecules22040561

Abstract

New Pd(II) complexes of 1,7-bis(2-methoxyphenyl)hepta-1,6-diene-3,5-dione were synthesized and structurally characterized. The complexes were tested in vitro on human colon and hepatic carcinoma cell lines, normal hepatic cells and hematopoietic progenitor cells. Biological tests proved that Pd(II) complexes 1 and 2 (containing a curcumin derivative) exhibit a strong in vitro antitumor effect against the cells derived from human colorectal carcinoma and the hepatic metastasis of a colorectal carcinoma. Complex 1 has an outstanding inhibitory effect against BRAF-mutant colon carcinoma and hepatocarcinoma cell growth; 1 and 2 are both more active than the free ligand and have the capacity to trigger early apoptotic processes. By flow cytometric measurements, an important decrease of prominin-1 (CD133) molecule expression on tumor cells membrane was identified in cell populations subjected to 1 and 2. Quantitative immune enzymatic assay proved restrictions in stem cell factor (SCF) release by treated tumor cells. Although less cytotoxic, the free ligand inhibits the surface marker CD133 expression in hepatocarcinoma cells, and in HT-29 colon carcinoma. The new synthesized Pd(II) complexes 1 and 2 exhibit an important potential through their selective cytotoxic activity and by targeting the stem-like tumor cell populations, which leads to the tumor growth arrest and prevention of metastasis.

Highlights

In the last decades, modern cancer treatment modalities have extended the survival of patients with solid tumors, but the mortality rate remains unchanged [1]
CD133+ expression; while in DLD-1 cell line we found the lowest expression among all the studied cell lines (Figure 2, Table 2)
The cytotoxicity of complex 1 was prominent and the fact that complex 1 downregulates the CD133 expression in cancer cells along with the strong reduction of the stem cell factor (SCF) secretion in two aggressive tumor cell lines suggests a potential applicability as prodrug

Summary

Introduction

Modern cancer treatment modalities have extended the survival of patients with solid tumors, but the mortality rate remains unchanged [1]. Recent studies have described the major importance of cancer stem-like cells within a tumor; these cells drive the tumor growth and evade therapy [3] through asymmetric division, self-renewal and differentiation ability, the evidence of these cells required improvements in standard cancer treatment [4]. The anti-cancer drugs and other treatment methods should eliminate the rapidly dividing and terminally differentiated cell populations, but they should target the dormant stem-like cancer cells, which confer chemoresistance. The up-regulation of CD133 in colorectal cancer strongly correlates with a poor prognosis [5]. It is presumed that a targeted therapy which focuses on CD133, prevents the tumor re-growth and metastasis [6] rather than shrinkage of tumor size in short term

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Conclusion