# Novel C-2 Aromatic Heterocycle-Substituted Triterpenoids Inhibit Hedgehog Signaling in GLI1 Overexpression Cancer Cells

## TL;DR

Researchers developed new triterpenoids that block the Hedgehog signaling pathway in cancer cells overexpressing GLI1, showing potential for anticancer therapy.

## Contribution

A new series of C-2 aromatic heterocycle-substituted triterpenoids was designed and shown to inhibit Hedgehog signaling in cancer cells.

## Key findings

- Compounds 11a and 11b significantly inhibited proliferation and induced cell death in NSCLC and prostate cancer cells.
- These compounds reduced GLI1 protein and target genes like Cyclin D1, N-Myc, and Bcl-2 in cancer cells.
- The antiproliferative effects were mediated through inhibition of the Hedgehog signaling pathway.

## Abstract

The hedgehog signaling
pathway plays an important role in vertebrate
embryonic development, tissue homeostasis, and tumorigenesis. Constitutive
activation of Hh signaling in various human tumors leads to GLI-mediated
transcription and tumor progression. Based on the preliminary screening
of a large library of known triterpenes that exhibited interesting
Hh inhibitory activity, we designed and synthesized a new series of
triterpenoid analogues containing aromatic heterocyclic substituents
at position C-2 to enhance their interference with Hh signaling. In
this study, we evaluated the effect of 15 synthesized triterpenoids
on cell proliferation and Hh pathway activity in relevant cancer cell
lines. Among these compounds, two derivatives, 11a and 11b, both featuring a furan ring at position C-2, demonstrated
potent inhibitory effects on proliferation and induced cell death
in nonsmall cell lung cancer (NSCLC) and prostate cancer cell lines
exhibiting hyper-activated Hh signaling. Moreover, these compounds
significantly reduced GLI-mediated transcription in cell-based reporter
assays. Detailed immunoblot analyses revealed that compounds 11a and 11b decreased the expression of endogenous
GLI1 protein and its target genes associated with tumor progression
and proliferation, such as Cyclin D1, N-Myc, and Bcl-2, in A549 and
DU-145 cancer cells. These findings suggest that the antiproliferative
effects of 11a and 11b are mediated through
inhibition of the Hh signaling pathway and are promising candidates
for the development of new anticancer therapies targeting Hh-dependent
tumors.