Background:Mangrove plants produce polyisoprenoid compounds. Polyisoprenoids have been proven to have anticancer properties. This study investigated the inhibitory activity of polyisoprenoids derived from the leaves of mangrove plantsAvicennia albaandAvicennia lanataregarding the expression of PI3K, Akt1, mTOR, P53, and EGFR genes against human colorectal adenocarcinoma WiDr cells.Methods:Anticancer activity was tested through the MTT assay method performed on WiDr cells. The cell cycle and apoptosis were analysed by flow cytometry and double staining. Gene expression of PI3K, Akt1, mTOR, P53, and EGFR was observed using the RT-PCR method.Results:Cytotoxic activity against WiDr cells showed that the IC50 forA. albaandA. lanatawas 258.14 ug/mL and 243.32 ug/mL, respectively. This observation indicated the possibility to develop moderate anticancer agents. The cell cycle showed that inhibition ofA. albaandA. lanataoccurred in the late phase of apoptosis S (10.60 and 10.51%) and G2-M1 (22.05 and 23.84%), which was higher than negative and positive control cells. Furthermore, the polyisoprenoids derived fromA. albaandA. lanataleaves exhibited anticancer activity in WiDr cells through the downregulated gene expression of PI3K, Akt1, mTOR, and EGFR as well as the upregulated gene expression of P53.Conclusion:This study demonstrated that polyisoprenoids obtained fromA. albaandA. lanataleaves are promising chemopreventive agents for colon cancer.