Two highly oxygenated pentacyclic polyketides with two new carbon skeletons, trichopsistide A (1) and trichopsistide B (2), were isolated from the plant endophyte Trichoderma koningiopsis WZ-196 derived from the leaf of Rubia podantha Diels. The structures of these polyketides with full configurations were determined by comprehensive spectroscopic analysis, computer-assisted structure elucidation software, computational calculation, and X-ray crystal diffraction. Among them, 1 represented the first example of an unprecedented 5/6/6/6/5 pentacyclic ketalcontaining polyketide pyridine alkaloid, and 2 possessed a novel 6/ 6/6/6/5 pentacyclic ketal-containing polyketide scaffold fused with an α-pyrone. The plausible biosynthetic route for 1 and 2 was also proposed. Moreover, biological activity assays showed that 1 and 2 possessed inhibitory effects on the NF-κB signaling pathway with IC 50 values of 14.77 and 8.58 μM, respectively. Furthermore, 1 and 2 could also inhibit the expression of IκBα and p65 phosphorylation, decrease the expression of MCP-1, E-selectin, and IL-8 at the mRNA level, and inhibit the TNF-α-induced nuclear translocation of p65.
Background and Purpose: Colorectal cancer (CRC) is an exceptionally
deadly disease, whereas therapeutic drugs for CRC have presented a
serious shortage over the past few decades. Natural products have become
an inexhaustible source of anticancer drugs. Natural alkaloid
N-hydroxyapiosporamide (NHAP) exerts antitumor effects, but its effect
and mechanism in CRC remain unclear. This study aimed to reveal the
antitumor target of NHAP and identify NHAP as a promising leading
compound for CRC. Experimental Approach: The inhibitory effects of NHAP
on growth of CRC cells were determined by SRB and colony formation
assays. Various biochemical methods were used to investigate molecular
mechanisms of action for NHAP, including western blotting, RT-PCR, flow
cytometry, immunofluorescent staining, cell transfection and luciferase
assay, RNA-seq analysis, ELISA and immunoprecipitation analysis. Mouse
endotoxin shock model, CRC xenograft model and azoxymethane model were
used to assess the in vivo anti-tumor effect of NHAP against CRC. Key
Results: NHAP exhibited potent cytotoxicity, induced both apoptosis and
autophagic cell death of CRC cells, and inhibited the NF-κB signaling
pathway by blocking the interaction of TAK1-TRAF6 proteins. NHAP also
markedly inhibited CRC tumour growth in vivo without obvious toxicity
and possessed superior pharmacokinetic characteristics. Conclusion and
Implications: These findings identify, for the first time, that natural
alkaloid NHAP is a novel NF-κB inhibitor with potent anti-tumor activity
against CRC in vitro and in vivo. This study clarifies the anti-tumor
target of NHAP against CRC, which will contribute to the future
development of NHAP as a novel therapeutic leading compound for CRC.
Colorectal cancer (CRC) is an exceptionally deadly disease,
whereas
effective therapeutic drugs for CRC have declined over the past few
decades. Natural products have become a reliable source of anticancer
drugs. Previously we isolated an alkaloid named (−)-N-hydroxyapiosporamide (NHAP), which exerts potent antitumor
effects, but its effect and mechanism in CRC remain unclear. This
study aimed to reveal the antitumor target of NHAP and identify NHAP
as a promising lead compound for CRC. Various biochemical methods
and animal models were used to investigate the antitumor effect and
molecular mechanism for NHAP. These results showed that NHAP exhibited
potent cytotoxicity, induced both apoptosis and autophagic cell death
of CRC cells, and inhibited the NF-κB signaling pathway by blocking
the interaction of the TAK1–TRAF6 complex. NHAP also markedly
inhibited CRC tumor growth in vivo without obvious
toxicities and possessed good pharmacokinetic characteristics. These
findings identify, for the first time, that NHAP is an NF-κB
inhibitor with potent antitumor activity in vitro and in vivo. This study clarifies the antitumor
target of NHAP against CRC, which will contribute to the future development
of NHAP as a novel therapeutic lead compound for CRC.
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