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

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

  • Chem Biol Interact. 2025 Aug 25:417:111559. doi: 10.1016/j.cbi.2025.111559.
Xinwen Xu 1,  Jianyi Gu 2,  Peiwen Yang 3,  Lifang Huang 4,  Na Zhao 2,  Jingjing Tang 5,  Zifeng Liang 6,  Qiang Li 7,  Shunqian Wen 8,  Jianwei Jiang 9,  Qing Zhang 10
Affiliations

Affiliations

  • 1 Department of Breast Surgery, The Second People's Hospital of Foshan, Foshan, Guangdong, 528000, China; Department of Breast Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510632, China.
  • 2 Department of Biochemistry, Basic Medical College, Jinan University, Guangzhou, 510632, China.
  • 3 Department of Pulmonary and Critical Care Medicine, The Sixth Affiliated Hospital of Jinan University, Dongguan, 523573, China.
  • 4 Department of Thyroid Gland Breast Surgery, The Sixth Affiliated Hospital of Jinan University, Dongguan, 523573, China.
  • 5 Department of Breast Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510632, China; Department of Breast and Thyroid Surgery, The Central Hospital of Yongzhou, Yongzhou, Hunan, 425000, China.
  • 6 Department of Breast Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510632, China.
  • 7 Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510632, China.
  • 8 Department of Hepatobiliary Surgery, The Second People's Hospital of Foshan, Foshan, Guangdong, 528000, China.
  • 9 Department of Biochemistry, Basic Medical College, Jinan University, Guangzhou, 510632, China. Electronic address: jjw703@jnu.edu.cn.
  • 10 Department of Breast Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, 510632, China. Electronic address: zq1994@jnu.edu.cn.
PMID: 40389196 DOI: 10.1016/j.cbi.2025.111559
Abstract

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.

Keywords

ATM; Acetyl alkannin; Chemosensitization; Cisplatin; DNA damage response.

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