Acetyl alkannin, a Shikonin monomer, inhibits the ATM/DDR pathway by targeting ATM and sensitizes cisplatin in solid tumors.

Platinum-based chemotherapy is limited by drug resistance and severe adverse effects. Although the DNA damage response (DDR) is known to affect drug sensitivity across cancer types, the role of its upstream regulator ATM in modulating cisplatin (DDP) resistance remains unclear. In this study, we investigated the role of the ATM/DDR pathway to DDP resistance and proposed a potential targeted strategy. Bioinformatics analysis revealed significant overexpression of ATM and RAD51 in liver and lung cancers, which correlated with poor survival (p < 0.05). In vitro assays showed that DDP activated ATM to initiate the downstream DDR, thereby promoting chemoresistance; inhibition of ATM using KU-55933 or siRNA enhanced the anticancer effect of DDP. Among screened Shikonin derivatives, acetyl alkannin emerged as the most potent ATM-targeting analogue. Combination treatment with low-dose acetyl alkannin (2.5 μM or 2.6 μM) and DDP increased DDP sensitivity 8.0-fold in Huh-7 liver cancer cells and 22.5-fold in A549 lung cancer cells. Mechanistically, acetyl alkannin targets ATM and induces its caspase-dependent degradation, suppressing DDR signaling and promoting apoptosis. In vivo xenograft experiments confirmed the superior tumor growth inhibition of the combination treatment. These findings establish ATM-mediated DDR activation as a central mechanism of DDP resistance and identify acetyl alkannin as a candidate sensitizer for platinum-based chemotherapy.