C-Myc Protein Level Affected by Unsymmetrical Bisacridines Influences Apoptosis and Senescence Induced in HCT116 Colorectal and H460 Lung Cancer Cells.

Monika Pawłowska,Ewa Augustin,Jolanta Kulesza

doi:10.3390/ijms23063061

Monika Pawłowska, Ewa Augustin + Show 1 more

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https://doi.org/10.3390/ijms23063061

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Abstract

Unsymmetrical bisacridines (UAs) are highly active antitumor compounds. They contain in their structure the drugs previously synthesized in our Department: C-1311 and C-1748. UAs exhibit different properties than their monomer components. They do not intercalate to dsDNA but stabilize the G-quadruplex structures, particularly those of the MYC and KRAS genes. Since MYC and KRAS are often mutated and constitutively expressed in cancer cells, they can be used as therapeutic targets. Herein, we investigate whether UAs can affect the expression and protein level of c-Myc and K-Ras in HCT116 and H460 cancer cells, and if so, what are the consequences for the UAs-induced cellular response. UAs did not affect K-Ras, but they strongly influenced the expression and translation of the c-Myc protein, and in H460 cells, they caused its full inhibition. UAs treatment resulted in apoptosis, as confirmed by the morphological changes, the presence of sub-G1 population and active caspase-3, cleaved PARP, annexin-V/PI staining and a decrease in mitochondrial potential. Importantly, apoptosis was induced earlier and to a greater extent in H460 compared to HCT116 cells. Moreover, accelerated senescence occurred only in H460 cells. In conclusion, the strong inhibition of c-Myc by UAs in H460 cells may participate in the final cellular response (apoptosis, senescence).

Highlights

Unsymmetrical bisacridines (UAs) are a group of new, promising antitumor compounds among acridine derivatives, developed at Gdansk University of Technology
The cytotoxicity of new unsymmetrical bisacridines was evaluated in four cell lines: two cancer, colorectal HCT116 and lung H460, and two normal colon epithelial CCD 841 CoN and lung fibroblast MRC-5
We evaluated the influence of bisacridine compounds on cytotoxicity, expression and protein level of c-Myc and K-Ras, cell cycle progression and cellular response triggered in HCT116 colon and H460 lung cancer cells, as well as in normal cells—human colon CCD 841 CoN and lung MRC-5 cells

Summary

Introduction

Unsymmetrical bisacridines (UAs) are a group of new, promising antitumor compounds among acridine derivatives, developed at Gdansk University of Technology They exhibit high cytotoxic activity against a lot of tumor cells in vitro, as well as high antitumor efficacy against several types of human cancer xenografts in nude mice, including lung and colorectal cancers [1–3]. G-quadruplexes (G4) are present in specific human guanine-rich sequences with functional significance, such as telomeres, oncogene-promoter regions, including MYC, RAS, KIT, BCL2, VEGF genes and 5 - and 3 -untranslated region (UTR) of mRNA [4]. They have been shown to be a regulatory motif in a number of critical cellular processes, such as gene transcription, translation, replication and genomic stability

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