Anemarchalconyn, a natural alkyne ketone compound, inhibits HCC cell growth by suppressing Polθ and inducing synthetic lethality in Homologous recombination deficiency cells.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive liver cancer with limited treatment options. Dysfunction of DNA damage response (DDR) genes, including Polθ and BRCA1, is implicated in HCC development and progression, offering novel therapeutic targets.

OBJECTIVE: This study aimed to investigate the anticancer effects of anemarchalconyn (SL-001) on HCC and elucidate its underlying mechanisms.

METHODS: We leveraged The Cancer Genome Atlas (TCGA) data analysis to explore the potential of POLQ/BRCA1 as therapeutic targets in liver cancer, as well as their association with the prognostic clinicopathological features of hepatocellular carcinoma (LIHC). We have isolated SL-001 and then developed an innovative and efficient synthesis strategy for SL-001, a natural alkyne ketone compound isolated from Selaginella tamariscina, and assessed the anti-tumor effects of SL-001 through in vitro and in vivo studies.

RESULTS: TCGA analysis revealed significant upregulation of POLQ and BRCA1 in HCC tumors compared to normal tissues. Additionally, POLQ and BRCA1 expression demonstrated high accuracy in distinguishing tumor tissues and correlating with reduced overall survival. SL-001 exhibited robust anti-proliferative effects on hepatocellular carcinoma (HCC) cells, surpassing the efficacy of the current standard treatment, sorafenib. The anti-HCC effect of SL-001 was associated with downregulation of POLQ, a key protein involved in alternative DNA repair pathways. Importantly, SL-001 demonstrated enhanced inhibitory effects on Homologous recombination deficiency (HRD) HCC cells, suggesting a synthetic lethal interaction between SL-001 and HRD.

CONCLUSION: SL-001 represents a promising therapeutic candidate for HCC, particularly for patients with HRD tumors. Its mechanism involves inhibiting POLQ and disrupting DNA repair pathways, leading to increased DNA damage and cell death in HRD cells. This study provides a foundation for further investigation of SL-001 as a targeted therapy for HCC.