Si-Jun-Zi-Tang potentiates temozolomide's anti-melanoma efficacy and reduces its hepatotoxicity

Malignant melanoma remains a major challenge in oncology, largely due to the limited efficacy and significant toxicity associated with treatments such as temozolomide (TMZ). Si-Jun-Zi-Tang (SJZT), a traditional Chinese medicine formula with documented anti-cancer properties, has shown potential in enhancing chemotherapy effectiveness and reducing treatment-related toxicity.

This study investigated the role of SJZT in improving TMZ treatment outcomes in melanoma.

The effects of SJZT on TMZ treatment outcomes were evaluated in melanoma cell lines and mouse models. Cell proliferation, apoptosis, DNA damage, and cell cycle distribution were assessed using CCK-8 assays, Annexin V/PI staining, γ-H2AX immunofluorescence, and flow cytometry, respectively. In vivo antitumor efficacy and hepatotoxicity were evaluated in melanoma-bearing mice. Mechanistic insights were explored via network pharmacology and RNA sequencing, and validated by RT-qPCR, Western blotting, and rescue experiments.

SJZT enhanced TMZ-induced inhibition of cell proliferation, apoptosis, and DNA strand breaks in melanoma cells. SJZT also attenuated TMZ-induced G2/M arrest, promoting mitotic catastrophe. In mouse models, SJZT enhanced the anti-tumor effects of TMZ and mitigated TMZ-induced hepatotoxicity. Mechanistically, network pharmacology and experimental validation revealed that simultaneous inhibition of Chk1 and promotion of MGMT proteasomal degradation mediated the enhanced anti-melanoma effects of TMZ with SJZT. RNA sequencing and experimental validation demonstrated that TMZ upregulated the bile salt transporter Slc10a1/Ntcp and downregulated detoxifying enzymes Ugt1a1 and Slco1b2/Oatp2, disrupting bile acid homeostasis. Notably, SJZT co-administration reversed these changes, restoring bile acid balance.

These findings reveal that SJZT can enhance TMZ's therapeutic efficacy while reducing hepatotoxicity, supporting its use as a promising adjuvant in melanoma treatment.