Abstract
Four new antimycin alkaloids (1–4) and six related known analogs (5–10) were isolated from the culture of a marine derived Streptomyces sp. THS-55, and their structures were elucidated by extensive spectroscopic analysis. All of the compounds exhibited potent cytotoxicity in vitro against HPV-transformed HeLa cell line. Among them, compounds 6–7 were derived as natural products for the first time, and compound 5 (NADA) showed the highest potency. NADA inhibited the proliferation, arrested cell cycle distribution, and triggered apoptosis in HeLa cancer cells. Our molecular mechanic studies revealed NADA degraded the levels of E6/E7 oncoproteins through ROS-mediated ubiquitin-dependent proteasome system activation. This is the first report that demonstrates antimycin alkaloids analogue induces the degradation of high-risk HPV E6/E7 oncoproteins and finally induces apoptosis in cervical cancer cells. The present work suggested that these analogues could serve as lead compounds for the development of HPV-infected cervical cancer therapeutic agents, as well as research tools for the study of E6/E7 functions.
Highlights
The sustained activation of cancer cell survive signaling through p53 and Rb, makes high-risk HPV E6/E7 oncoproteins potential drug targets for the treatment of cervical cancer[16]
Comparison of the NMR spectra of 2 with those of 1 revealed that the acetyl group attached to 8-O in the structure of 1 was replaced by an isobutyryl group in 2, which was further confirmed by analysis of the 1H-1H COSY and HMBC correlations of 2 (Fig. 2a)
We discovered the inhibition on the mitochondrial respiration and disruption on the membrane potential (MMP) in the presence of NADA (Fig. 5)
Summary
The sustained activation of cancer cell survive signaling through p53 and Rb, makes high-risk HPV E6/E7 oncoproteins potential drug targets for the treatment of cervical cancer[16]. We reported the isolation, structural determination, and cytotoxicity of these compounds. These studies focused on NADA with special emphasis to its cytotoxicity against HeLa cells and its effect on viral oncogenges E6/E7. Our results showed that NADA inhibited cell proliferation, arrested cell cycle, triggered apoptosis, and down-regulated E6/E7 through ROS-mediated UPS activation in HeLa cells. This is the first report that demonstrates antimycin-type analogue induces E6/E7 oncoproteins degradation via stimulation on UPS and induces apoptosis in HPV positive cervical cancer cells
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