AG-825, a selective ErbB2 inhibitor with anti-cancer effect
Posted On 2019-11-18
The ErbB tyrosine kinase receptor (RTK) family has 4 members: ErbB1 (EGFR/HER1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). These receptors are cell surface receptors and play important roles in cell proliferation, survival, and growth signaling.
ErbB2 is an orphan receptor; it can associate with other ErbBs to enhances signaling intensity and dimer stability.
ErbB2 overpresses and amplifies in various malignancies. Noticeably, ErbB2 overexpression especially presents in breast cancer. As a result, targeting ErbB2 for breast cancer therapy is very necessary and indispensable.
Today, we will introduce a selective ErbB2 inhibitor, AG-825.
AG-825 leads to a decrease in ErbB2–nucleolin interaction, which suppresses tyrosine phosphorylation. It has anti-cancer activities.
Firstly, in vitro, AG-825 (40μM) has a negative impact on ErbB2–nucleoin complex formation in SKBR3 and MDCK cells. GroA (AS1411) is a G-rich oligonucleotide, reduces ErbB2 phosphorylation. Since GroA is beneficial in terms of cancer treatment, AG-825 combinates with it for treatment is researched for targeting breast cancer.
In SKBR3 and MDCK cells, AG-825 and GroA combination significantly decreases viable cells number. However, treatment alone is less effective. Furthermore, this combination erects a long-term effect on cell colony formation. They obviously decrease the total area of colonies in two cell lines.
Secondly, in MCF7 ErbB2-overexpressing clone cells, AG-825 (40μM) down-regulates ErbB2 phosphorylation expression. Moreover, AG-825 combines with GroA has a more prominent effect on the activation of ErbB2 than a single dose.
Thirdly, in the BrdU incorporation assay, co-treatment with GroA and AG-825 obviously enhances cell death when compares to the single-drug treatments.
Lastly, as we all know, Using a three-dimensional cell culture can allow the investigation of the anchorage-independent growth ability of the cells and the level of culture organization. In three-dimensional SKBR3 cell culture, GroA and AG-825 interfere with the ability of SKBR3 cells to grow in an anchorage-independent manner. However, combination treatment has no effect on growth morphology. AG-825 and GroA significantly decrease the number of cells which can invade through the Cultrex basement membrane.
In conclusion, AG-825, as a selective ErbB2 inhibitor, although it is not applicable in vivo at present, it has the potential for breast treatment when combines with GroA.
Wolfson E, et al. Cell Death Dis. 2018 Jan 19;9(2):47.