Anti-neoplastic effect of heterophyllin B on ovarian cancer via the regulation of NRF2/HO-1 in vitro and in vivo

Abstract

Background: Heterophyllin B (HB) is a cyclic peptide with anti-neoplastic effect on many cancers. However, its effect and mechanism of action in ovarian cancer cells are still unknown.

Purpose: The primary objective of this study was to assess the impact of HB on the proliferation of ovarian cancer (OC) cells and delve into the underlying mechanisms involved.

Methods: We performed CCK-8 assays, HE staining, KI67 staining, clonogenic formation assays, Annexin V-FITC/PI staining, tumor invasion assays, and migration assays to detect the effects of HB on cell viability, proliferation, apoptosis, migration, and invasion in ovarian cancer cells. Additionally, real-time fluorescent quantitative PCR (qPCR) and Western blotting were utilized for verification. The expression of NF-E2-related factor 2 (NRF2) and heme oxygenase 1 (HMOX1/HO-1) signaling molecules was detected using qPCR and Western blotting. A specific inducer, Hemin, was used to activate HO-1 and Nrf2 overexpression, in order to verify the pharmacological mechanism of HB on ovarian cancer cells. The binding relationship between HB and NRF2 was investigated through molecular docking.

Results: HB treatment inhibited the viability of OC cells, meanwhile it showed suppressive effect on the proliferation, migration, and invasion of OC cells, Meanwhile, HB could promote the apoptosis of tumor cells. For the mechanisms, we found that HB treatment could significantly down-regulate the levels of NRF2/HO-1. Consistent with the results of in vitro experiments, administration of HB significantly delayed tumor growth in OVCAR8 xenografted nude mice, and inhibited the expression of Ki67, Nrf2 and HO-1.

Conclusion: This study demonstrated that HB had anti-neoplastic effect on OC by inhibiting Nrf2/HO-1 signaling pathway and may be a potential drug for the treatment of OC.

Keywords: Apoptosis; Heterophyllin B; Molecular docking; NRF2/HO-1; Ovarian cancer.