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Selective Killing of Cancer Cells by Nonplanar Aromatic Hydrocarbon-Induced DNA Damage

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Selective Killing of Cancer Cells by Nonplanar Aromatic Hydrocarbon-Induced DNA Damage

Yan Zhou et al. Adv Sci (Weinh).

Abstract

A large number of current chemotherapeutic agents prevent the growth of tumors by inhibiting DNA synthesis of cancer cells. It has been found recently that many planar polycyclic aromatic hydrocarbons (PAHs) derivatives, previously known as carcinogenic, display anticancer activity through DNA cross-linking. However, the practical use of these PAHs is substantially limited by their low therapeutic efficiency and selectivity toward most tumors. Herein, the anticancer property of a nonplanar PAH named [4]helicenium, which exhibits highly selective cytotoxicity toward liver, lung cancer, and leukemia cells compared with normal cells, is reported. Moreover, [4]helicenium effectively inhibits tumor growth in liver cancer-bearing mice and shows little side effects in normal mice. RNA sequencing and confirmatory results demonstrate that [4]helicenium induces more DNA damage in tumor cells than in normal cells, resulting in tumor cell cycle arrest and apoptosis increment. This study reveals an unexpected role and molecular mechanism for PAHs in selectively killing tumor cells and provides an effective strategy for precision cancer therapies.

Keywords: DNA interstrand crosslinks; cancer therapy; helicene; nonplanar; polycyclic aromatic hydrocarbons.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Spectroscopy of [4]helicenium with DNA and in vitro cytotoxicity of PAHs in HCC cells. a) Molecular structure of [4]helicenium, Q, BQ, and NQ. b) UV–vis and CD spectra of DNA, [4]helicenium, and DNA/[4]helicenium complex, c [4]helicenium = 200 × 10−6 m, c DNA = 0.5 mg mL−1. c) Photoluminescence (PL) spectra of DNA, [4]helicenium, and DNA/[4]helicenium complex, c [4]helicenium = 200 × 10−6 m, c DNA = 0.5 mg mL−1. d) Cell viability analysis of normal hepatocyte HL7702, HCC cells including SK‐Hep1, SMMC7721, HuH7, and Hep G2 treated with [4]helicenium, Q, BQ, and NQ at 0–100 µg mL−1 for 24 h. e) Light microscopy images of SK‐Hep1 and HL7702 treated with 10 µg mL−1 [4]helicenium. Scale bar represents 100 µm.
Figure 2
Figure 2
In vitro cell apoptosis and cell cycle analysis in SK‐Hep1 and HL7702 cells. SK‐Hep1 and HL7702 were treated with 10 µg mL−1 [4]helicenium for 24 h. a,b) Flow cytometry analysis of apoptotic cell population of SK‐Hep1 and HL7702 before and after [4]helicenium treatment by Annexin V/PI staining. c,d) Flow cytometry analysis of cell cycle of SK‐Hep1 and HL7702 before and after [4]helicenium treatment by PI staining. e) Q‐PCR analysis of cyclin‐related genes (CCNA2, CCNB1, CCNB2) expressed in SK‐Hep1 and HL7702 before and after [4]helicenium treatment. GAPDH was used as an internal control. f) Western blot analysis of the protein expression levels of P53, P21, p‐CDC2, and CDC2 in SK‐Hep1 and HL7702 before and after [4]helicenium treatment. β‐actin was used as a loading control. Error bars represent mean ± S.D. ** p < 0.01, *** p < 0.001, **** p < 0.0001 (Student's t‐test).
Figure 3
Figure 3
In vivo antitumor efficacy of [4]helicenium on the HCC nude mouse model. a) Tumor growth profiles of SK‐Hep1 tumor‐bearing nude mice treated with normal saline, BQ, NQ, and [4]helicenium. b,c) Photographs and weight of the tumors extracted from the four groups of mice at the end of the experiments. d) Body weight profiles of SK‐Hep1 tumor‐bearing nude mice treated with normal saline, BQ, NQ, and [4]helicenium. e) HE staining of the major organs (i.e., heart, liver, spleen, lung, and kidney) of SK‐Hep1 tumor‐bearing nude mice treated with normal saline and [4]helicenium. f) Liver, kidney, and heart functions of SK‐Hep1 tumor‐bearing nude mice treated with normal saline and [4]helicenium. Error bars represent mean ± S.D. NS: not significant; ** p < 0.01, *** p < 0.001 (Student's t‐test).
Figure 4
Figure 4
Inhibition of [4]helicenium on DNA replication in SK‐Hep1. a) GO enrichment analysis of downregulated genes in SK‐Hep1 and HL7702 before and after [4]helicenium treatment. b) GSEA of the entire transcriptome of SK‐Hep1 before and after [4]helicenium treatment. c) Q‐PCR analysis of DNA replication‐related genes expressed in SK‐Hep1 and HL7702 before and after [4]helicenium treatment. d) MCM2 immunofluorescence staining of SK‐Hep1 and HL7702 before and after [4]helicenium treatment. Error bars represent mean ± S.D. * p < 0.05,** p < 0.01, *** p < 0.001, **** p < 0.0001 (Student's t‐test).
Figure 5
Figure 5
Inhibition of [4]helicenium on DNA ICLs repair and DSBs repair in SK‐Hep1. a) GSEA of ICLs repair and FA signaling pathway of SK‐Hep1 before and after [4]helicenium treatment. b) Comet assay images (right) and statistical results (left) of SK‐Hep1 and HL7702 before and after [4]helicenium treatment. c) Q‐PCR analysis of ICLs repair and FA signaling pathway‐related genes expressed in SK‐Hep1 and HL7702 before and after [4]helicenium treatment. d) Western blot analysis of the protein expression level of FANCA in SK‐Hep1 and HL7702 before and after [4]helicenium treatment. e) γH2AX immunofluorescence staining of SK‐Hep1 and HL7702 before and after [4]helicenium treatment. f) Western blot analysis of the protein expression level of γH2AX in SK‐Hep1 and HL7702 before and after [4]helicenium treatment. Histone H3 was used as a loading control. g) GSEA of DSBs repair of SK‐Hep1 before and after [4]helicenium treatment. h) Q‐PCR analysis of RAD51 expressed in SK‐Hep1 and HL7702 before and after [4]helicenium treatment. i) Western blot analysis of the protein expression level of RAD51 in SK‐Hep1 and HL7702 before and after [4]helicenium treatment. Error bars represent mean ± S.D. * p < 0.05,** p < 0.01, *** p < 0.001, **** p < 0.0001 (Student's t‐test).
Figure 6
Figure 6
In vitro cytotoxicity of PAHs in lung cancer cells. a) Cell viability analysis of normal lung epithelial cell Beas‐2B and lung cancer cell including H1975, Calu‐6, A549, and H1299 treated with Q, BQ, NQ, and [4]helicenium at 0–100 µg mL−1 for 24 h. b) Light microscopy images of H1975 and Beas‐2B treated with 10 µg mL−1 [4]helicenium. c) Cell viability analysis of proB cell line BaF3 and leukemia cell line BaF3‐BCR‐ABL‐P210 treated with [4]helicenium at 0–100 µg mL−1.
Figure 7
Figure 7
Molecular pattern of selective killing of cancer cells by [4]helicenium. In normal cells, [4]helicenium binds to the DNA of the S phase cells to induce ICLs, which triggers FA and HR repair to remove DNA lesions and then maintains normal cell cycle. In cancer cells, [4]helicenium leads to cell cycle arrest and apoptosis due to the lack of ability to repair ICLs‐related DNA damage.

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