Abstract

Cervical cancer is a significant health issue in Indonesia, with 36,633 cases reported in 2020. Chemotherapy, especially with doxorubicin, is a primary treatment but causes adverse effects such as cardiotoxicity, hair loss, nausea, vomiting, and immunosuppression. Combining chemotherapy with chemopreventive agents can enhance efficacy and reduce side effects. Selaginella doederleinii, known for its biflavonoid compounds, has potential chemopreventive activity. This study investigated the chemopreventive mechanism of Selaginella doederleinii ethanol extract (EESD) as a co-chemotherapy agent for HeLa cells through in silico and in vitro approaches. High-performance liquid chromatography analysis identified amentoflavone and 2,3-dihydro-3,3-diphenylapigenin as key compounds in EESD. Protein–protein interaction network analysis revealed 24 target receptors associated with cervical cancer, with ESR2 and HSP90AA1 being upregulated and involved in chemical carcinogenesis, estrogen signaling, cancer pathways, and endocrine resistance. EESD exhibited moderate cytotoxic activity (IC50 = 367.89 μg/ml) and demonstrated chemopreventive properties. The mechanism of EESD is presumed to involve the inhibition of key regulatory proteins in cervical cancer, namely ESR2 and HSP90AA1. Furthermore, EESD exhibited a slight synergistic effect with doxorubicin, with a combination index value of 0.85870. This study is the first to explore the chemopreventive potential of EESD along with its underlying mechanism, highlighting its role as a co-chemotherapy agent.

Key words: Selaginella doederleinii, Network Pharmacology, Co-Chemotherapy, Cervical Cancer, Mechanism