Synergistic Antitumor Effects and Reduced Systemic Toxicity of Berberine Chloride Combined With Cisplatin in a Female BALB/c Mouse Xenograft Model

ABSTRACT Breast cancer, especially triple‐negative breast cancer (TNBC), remains a significant clinical challenge due to limited treatment options, chemoresistance, and the toxic side effects of standard chemotherapy. Cisplatin (Cis) is commonly used but faces limitations from resistance and dose‐related toxicity. Berberine chloride (BRB), a natural alkaloid derived from Berberis vulgaris, shows promising anticancer effects. This study examined the antitumor activity and chemosensitizing potential of BRB combined with Cis. We initially examined the effects of BRB and Cis on murine 4T1 breast cancer cells. The results showed that both treatments inhibited cell viability, with IC50 values around 10 µM for BRB and 2.5 µM for Cis. Subsequently, we tested the synergistic effects using the Chou–Talalay method, which indicated that most of the 16 drug combinations exhibited synergy (CI < 1). The most effective combination (IC 50 /8) had a CI of 0.12 and a Fa of 0.8, greatly reducing cell viability compared to individual treatments. The combined BRB and Cis therapy was then tested in a BALB/c mouse xenograft model via intraperitoneal injection. Cis alone at 1 mg/kg weekly lowered tumor growth by 43.13% but caused notable systemic toxicity, including body weight loss and kidney and liver damage. BRB alone at 10 mg/kg every 2 days resulted in greater tumor suppression (61.17%) with fewer side effects. The BRB/Cis combo achieved the highest tumor growth inhibition (87.05%) and markedly reduced Cis‐related toxicity, evidenced by weight recovery and improved kidney and liver biochemical markers. These results indicate that BRB enhances cisplatin's antitumor effects while decreasing systemic toxicity, positioning BRB as a promising chemosensitizer for TNBC therapy.