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. 2023 Apr 24;15(5):1325.
doi: 10.3390/pharmaceutics15051325.

Modulation of Transcription Profile Induced by Antiproliferative Thiosemicarbazone Metal Complexes in U937 Cancer Cells

Serena Montalbano  1 , Franco Bisceglie  1   2 , Giorgio Pelosi  1   2 , Mirca Lazzaretti  1 , Annamaria Buschini  1   2
Affiliations

Modulation of Transcription Profile Induced by Antiproliferative Thiosemicarbazone Metal Complexes in U937 Cancer Cells

Serena Montalbano et al. Pharmaceutics. .

Abstract

Since the discovery of cisplatin, the search for metal-based compounds with therapeutic potential has been a challenge for the scientific community. In this landscape, thiosemicarbazones and their metal derivatives represent a good starting point for the development of anticancer agents with high selectivity and low toxicity. Here, we focused on the action mechanism of three metal thiosemicarbazones [Ni(tcitr)2], [Pt(tcitr)2], and [Cu(tcitr)2], derived from citronellal. The complexes were already synthesized, characterized, and screened for their antiproliferative activity against different cancer cells and for genotoxic/mutagenic potential. In this work, we deepened the understanding of their molecular action mechanism using an in vitro model of a leukemia cell line (U937) and an approach of transcriptional expression profile analysis. U937 cells showed a significant sensitivity to the tested molecules. To better understand DNA damage induced by our complexes, the modulation of a panel of genes involved in the DNA damage response pathway was evaluated. We analyzed whether our compounds affected cell cycle progression to determine a possible correlation between proliferation inhibition and cell cycle arrest. Our results demonstrate that metal complexes target different cellular processes and could be promising candidates in the design of antiproliferative thiosemicarbazones, although their overall molecular mechanism is still to be understood.

Keywords: DNA damage response pathway; expression profile study; molecular action mechanism; ribonucleotide reductase; thiosemicarbazone metal complexes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the synthesized metal complexes [Ni(tcitr)2], [Pt(tcitr)2], and [Cu(tcitr)2].
Figure 2
Figure 2
Flow cytometric cell cycle analysis by NovoCyte TM flow cytometry. U937 cells were treated for 4 (A) and 24 (B) h with the GI50 values of [Pt(tcitr)2] (A) and [Cu(tcitr)2]. Data are expressed as percentage of cells in G1, S, and G2 phases of cell cycle. DMSO: negative control; [Pt(tcitr)2]: cells treated with [Pt(tcitr)2] at 7.0 µM for 4 (A) and 24 h (B); [Cu(tcitr)2]: cells treated with [Cu(tcitr)2] at 33.0 µM for 4 (A) and 24 h (B).
Figure 3
Figure 3
Effects of [Ni(tcitr)2], [Pt(tcitr)2], and [Cu(tcitr)2] on the expression of RRM1, RRM2, and p53R2. U937 cells were seeded (2 × 106 cells/flask) into 25 cm2 flasks with complete medium and then treated with GI50 value for each metal complex for 1–4–24 h. Total RNA was extracted, quantified, and 1 μg was reverse-transcribed. The complementary DNA (cDNA) was used as a template for qRT-PCR reactions. Data are expressed as fold change ± standard deviation in target gene expression in treated cells normalized to the internal control gene (GAPDH) and relative to the DMSO negative control.
Figure 4
Figure 4
Effects of [Ni(tcitr)2], [Pt(tcitr)2], and [Cu(tcitr)2] on the expression of ATM, ATR; Chk2 and Chk1. U937 cells were seeded (2 × 106 cells/flask) into 25 cm2 flasks with complete medium and then treated with GI50 value for each metal complex for 1–4–24 h. Total RNA was extracted, quantified, and 1 μg was reverse-transcribed. The complementary DNA (cDNA) was used as a template for qRT-PCR reactions. Data are expressed as fold change ± standard deviation in target gene expression in treated cells normalized to the internal control gene (GAPDH) and relative to the DMSO negative control.
Figure 5
Figure 5
Effects of [Ni(tcitr)2], [Pt(tcitr)2], and [Cu(tcitr)2] on the expression of cyclin A1 and cyclin B. U937 cells were seeded (2 × 106 cells/flask) into 25 cm2 flasks with complete medium and then treated with GI50 value for each metal complexes for 1–4–24 h. Total RNA was extracted, quantified, and 1 μg was reverse-transcribed. The complementary DNA (cDNA) was used as a template for qRT-PCR reactions. Data are expressed as fold change ± standard deviation in target gene expression in treated cells normalized to the internal control gene (GAPDH) and relative to the DMSO negative control.
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