Annonaceous Acetogenins Synergistically Inhibit Hepatocellular Carcinoma with Sorafenib

Sorafenib
was first approved as the standard treatment for advanced
hepatocellular carcinoma (HCC). Despite providing an advantage in
terms of patient survival, sorafenib has shown poor clinical efficacy
and severe side effects after long-term treatment. Thus, combination
treatment is a potential way to increase the effectiveness and reduce
the dose-limiting toxicity of sorafenib. Extracts of the seeds of Annona montana have shown synergistic antitumor activity
with sorafenib, and seven annonaceous acetogenins, including three
new acetogenins, muricin P (2), muricin Q (3), and muricin R (4), were isolated from the extracts
by bioguided fractionation and showed synergy with sorafenib. The
structures of these compounds were determined using spectroscopic
and chemical methods. Annonacin (1) and muricin P (2), which reduced intracellular ATP levels and promoted apoptosis,
exhibited synergistic cytotoxicity with sorafenib in vitro. In vivo, annonacin (1) displayed
synergistic antitumor activity by promoting tumor cell apoptosis.
Moreover, the potential mechanism of annonacin (1) was
predicted by transcriptomic analysis, which suggested that SLC33A1
is a potential target in HCC. Annonacin (1) might be
a novel candidate for combination therapy with sorafenib against advanced
HCC.