Harnessing HDAC-targeted oleanolic acid derivatives for combined anti-cancer and hepatoprotective effects

The development of anti-tumor drugs with hepatoprotective properties has always been highly valued due to their dual capabilities of safeguarding the liver and combating tumors. Moreover, when used in conjunction with specific chemotherapy drugs, they can enhance the efficacy of cancer treatment while simultaneously reducing liver damage caused by chemotherapeutic agents. Our research focused on oleanolic acid (OA), a natural compound known for its liver-protective effects. By incorporating an HDAC-targeting pharmacophore at the 28-COOH site of OA, we aimed to identify compounds that offer dual benefits of liver protection and anti-tumor activity. Compound 2c demonstrated significant inhibitory effects on the growth of RS4;11, K562, and RPMI8226 cells, showed cytotoxicity against HepG2 liver cancer cells, and exhibited favorable selectivity towards normal liver cells. Moreover, compound 2c induced apoptosis in HepG2 cells and arrested cell cycle progression at the G2 phase. Further investigations revealed that compound 2c could alleviate cisplatin-induced liver cell damage and animal liver injury by activating the NRF2/HO-1 pathway. In a HepG2 xenograft model, intravenous administration of compound 2c effectively suppressed tumor growth without eliciting adverse reactions, while enhanced NRF2 and HO-1 expression was observed in the liver tissues of mice treated with compound 2c. Besides, co-administration of cisplatin with compound 2c could significantly enhance the anti-tumor efficacy of cisplatin but minimize liver injury caused by the treatment of cisplatin. Our study provides a lead compound possessing hepatoprotective and antitumor activity, offering a novel strategy to avoid pharmacological liver injury.