Rotundic acid induces Cas3-MCF-7 cell apoptosis through the p53 pathway.

In the present study, the functions and mechanisms of rotundic acid (RA) underlying its induction of apoptosis in caspase-3-transfected MCF-7 human breast cancer cells (Cas3-MCF-7 cells) were investigated. RA induced apoptosis in Cas3-MCF-7 cells more efficiently compared with that in MCF-7 cells transfected with control plasmid. The results from an MTT assay demonstrated that RA effectively inhibited Cas3-MCF-7 cell viability in a dose-dependent manner and induced cell apoptosis via caspase-3 activity within 12 to 48 h. Western blotting and fluorescence-activated cell sorting demonstrated that RA initiated Cas3-MCF-7 cell apoptosis via p53 activation. The silencing of the p53 gene in the Cas3-MCF-7 cell line led to decreased RA-induced Cas3-MCF-7 cell caspase-3 activity and cell apoptosis. Collectively, the results of the present study indicate that caspase-3 serves a critical function in rotundic acid-induced apoptosis, and suggest that caspase-3 deficiency may contribute to the chemotherapy-resistance of breast cancer. Reconstitution of caspase-3 sensitizes MCF-7 breast cancer cells to chemotherapy. RA has the potential for development as a novel drug combined with reconstitution of caspase-3 gene therapy for the treatment of human breast cancer with caspase-3 deficiency.

Design, synthesis and evaluation of antitumor activity of new rotundic acid acylhydrazone derivatives.

In light of the important antitumor activity of acylhydrazone compounds and based on our previous study, 18 new rotundic acid (RA) acylhydrazone derivatives were synthesized. All of the compounds were characterized by their spectroscopic data. The antiproliferative activity of the compounds was evaluated in vitro via the MTT method in three tumor cell lines, including A-375 (human malignant melanoma cells), SPC-A1 (human lung adenocarcinoma) and NCI-H446 (small cell lung cancer). The results showed that the antiproliferative activity of all of the compounds on the NCI-H446 cell line did not increase compared to RA, however, most of the derivatives exhibited higher activity against the A375 and SPC-A1 cell lines as compared to RA. Importantly, the antiproliferative activities of compounds 5a and 5b were the highest among the compounds, with IC(50) values <10 µM. Collectively, compounds 5a and 5b may act as potential anti-tumor agents in the future.

Synthesis, characterization and cytotoxicity of new rotundic acid derivatives.

Rotundic acid (RA, 1), a natural compound, exhibits potent tumor cell growth inhibiting properties. To date there are no reports on derivatives of RA. Furthermore, the 28-COOH position of RA might make it unstable and induced serious gastrointestinal side effects when it was applied in vivo. Therefore, in order to explore and make use of this compound, eight new amino acid derivatives of RA at the 28-COOH position were synthesized and evaluated for their cytotoxicities in vitro on three tumor cell lines including A375, HepG2 and NCI-H446. As a result, a few of these new amino acid derivatives showed stronger cytotoxicity. Compound 5a was found to have the best inhibition activity on the three tested human tumor cell lines with IC(50) values of less than 10 µM compared with RA treatment. Meanwhile, the cytotoxicity of compound 6b was significantly higher than that of RA on the A375 cell line and almost the same as RA on the HepG2 and NCI-H446 cell lines. Hence, compounds 5a and 6b may serve as potential lead compounds for the development of new anti-tumor drugs.