Ganoderic acid T, a triterpenic acid produced by Ganoderma lucidum, has demonstrated therapeutic potential for tumor disease. In the current work, ganoderic acid T was modified to produce more effective small-molecule inhibitors of cancer cell proliferation. Moreover, the anticancer effects of three new ganoderic acid T derivatives, i.e., (22S,24E)-3α,15α,22-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid ethyl ester (TLTO-Ee), (22S,24E)-3α,15α,22-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid propyl ester (TLTO-Pe), and (22S,24E)-3α,15α,22-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid amide (TLTO-A), and one known derivative, (22S,24E)-3α,15α,22-triacetoxy-5α-lanosta-7,9(11),24-trien-26-oic acid methyl ester (TLTO-Me), on the cervical cell line HeLa were investigated and compared. MTT assay indicated that, among the tested compounds, TLTO-A displayed the highest inhibitory effect on the growth of HeLa cells, whereas it showed less cytotoxicity to the non-tumorous cell line MCF-10A than ganoderic acid T. Flow cytometry analysis revealed that all the compounds caused cell cycle arrest at the G1 phase and induced apoptosis. Furthermore, they decreased the mitochondrial membrane potential and enhanced the activities of pro-apoptotic factors caspase-3 and caspase-9 in a dose-dependent manner. Accordingly, the apoptosis induction was presumed to occur through the endogenous pathway. The following order ranks both cytotoxic and pro-apoptotic effects of the compounds against HeLa cells: TLTO-A>ganoderic acid T≈TLTO-Me≈TLTO-Ee≈TLTO-Pe. This study suggests that the carboxyl group of ganoderic acid T is not the main active group and is suitable for its further structural modification. The current work presents valuable information on the design of ganoderic acid T derivatives to develop potential chemotherapy agents.
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