Shikonin is a novel and selective IMPDH2 inhibitor that target triple-negative breast cancer

Area of Science:

• Biochemistry
• Oncology
• Pharmacology

Background:

• Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to its heterogeneity and poor prognosis.
• Inosine 5'-monophosphate dehydrogenase 2 (IMPDH2), a key enzyme in guanine nucleotide synthesis, is frequently overexpressed in TNBC and represents a promising therapeutic target.

Purpose of the Study:

• To identify novel therapeutic agents targeting IMPDH2 for TNBC treatment.
• To investigate the anti-cancer activity and mechanism of action of shikonin, a natural product, against TNBC.

Main Methods:

• Screening of natural products to identify IMPDH2 inhibitors.
• Enzymatic assays (Lineweaver-Burk plot), biophysical techniques (thermal shift assay, fluorescence quenching), and molecular docking to characterize shikonin-IMPDH2 interaction.
• In vitro studies using human (MDA-MB-231) and murine (4T1) TNBC cell lines, including IMPDH2 knockdown experiments and rescue assays with guanosine supplementation.

Main Results:

• Shikonin was identified as a novel, selective, and competitive inhibitor of IMPDH2.
• Shikonin demonstrated dose-dependent inhibition of TNBC cell proliferation, which was reversible by guanosine.
• IMPDH2 knockdown conferred resistance to shikonin, confirming the enzyme's critical role in shikonin's efficacy.

Conclusions:

• The natural product shikonin exhibits selective IMPDH2 inhibition and possesses significant anti-TNBC activity.
• Shikonin represents a promising candidate for further preclinical and clinical investigation as a novel therapeutic strategy for triple-negative breast cancer.