Novel shikonin derivatives suppress cell proliferation, migration and induce apoptosis in human triple-negative breast cancer cells via regulating PDK1/PDHC axis.

Aims: PDK1 is one of the key enzymes in the glucose metabolism pathway, which is abnormally high expressed in breast cancer tissues and can promote tumor proliferation and metastasis. PDK1 and the PDHC/PDK axis are important targets for regulating glucose metabolism and anti-tumor activity. In this study, we evaluated the anti-tumor activities of a series of semi-synthesized shikonin (SK) derivatives against human breast cancer cells.

Main Methods: The anti-proliferation activity of SK derivatives against human breast cancer cell lines was tested by CCK-8 and EdU assay. Flow cytometry was utilized to evaluate cell apoptosis, reactive oxygen species and cell cycle distribution. Cell migration ability was determined by wound healing and trans-well assay. PDK1 targeting effect was confirmed by western bolting, molecular docking, bio-layer interferometry and PDK1 enzyme activity assay. Nude-mouse transplanted tumor model was used to evaluate their anti-tumor effect in vivo.

Key Findings: Findings revealed that SK derivatives had good anti-proliferation ability against MDA-MB-231 cell. They induced cell apoptosis by regulating the mitochondrial apoptosis and death receptor pathway. They also inhibited cell migration by suppressing EMT progression. Molecular docking, PDK1 affinity and enzyme activity demonstrated their PDK1 targeting. In vivo antitumor experiment showed that E2 could significantly inhibit tumor growth with lower side-effect on mice than SK.

Significance: In conclusion, the novel SK derivatives E2 and E5 inhibited tumor glycolysis by targeting PDK1 and ultimately induced apoptosis. Our data demonstrated that E2 would be a good lead compound for the treatment of human TNBC as a novel PDK1 inhibitor.