Chemoproteomics-based profiling reveals the targeting molecular mechanism of reversal of cisplatin resistance by baicalin in head and neck squamous cell carcinoma.

Cisplatin resistance is a major cause of chemotherapy failure and poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC). The combination of natural compounds and platinum-based agents can overcome cisplatin resistance. Here, we demonstrate that baicalin, one of the major active flavonoids extracted from the root of the medicinal herb Scutellaria baicalensis Georgi, reverses cisplatin resistance in HNSCC in vitro and in vivo. Mechanistically, glutathione S-transferase (GST)-π subtype, also known as GSTP1, was identified as a direct target of baicalin, and the cysteine 47 (cys47) of GSTP1 is modified by baicalin, which is mediated by the Michael reaction. Moreover, baicalin increased the accumulation of cisplatin and activated the c-Jun N-terminal kinase (JNK) pathway in wild-type cisplatin-resistant HNSCC cells, but its effects were lost in cys47-mutated cisplatin-resistant HNSCC cells. Meanwhile, cys47 mutation of GSTP1 abrogated baicalin-induced reversal of cisplatin resistance in HNSCC cells. In conclusion, we demonstrate a novel mechanism for the reversal of cisplatin resistance by baicalin, confirming that baicalin can inhibit GSTP1 activity by interacting with the Cys47 residue of GSTP1, thereby enhancing intracellular accumulation of cisplatin or activation of the JNK pathway. This study lays the foundation for the use of baicalin to overcome cisplatin resistance in HNSCC.