ABT‑737 increases cisplatin sensitivity through the ROS‑ASK1‑JNK MAPK signaling axis in human ovarian cancer cisplatin‑resistant A2780/DDP cells

Oncol Rep. 2024 Sep;52(3):122. doi: 10.3892/or.2024.8781. Epub 2024 Jul 26.

Abstract

Ovarian cancer is a gynecological malignant tumor with the highest mortality rate, and chemotherapy resistance seriously affects patient therapeutic outcomes. It has been shown that the high expression of anti‑apoptotic proteins Bcl‑2 and Bcl‑xL is closely related to ovarian cancer chemotherapy resistance. Therefore, reducing Bcl‑2 and Bcl‑xL expression levels may be essential for reversing drug resistance in ovarian cancer. ABT‑737 is a BH3‑only protein mimetic, which can effectively inhibit the expression of the anti‑apoptotic proteins Bcl‑xL and Bcl‑2. Although it has been shown that ABT‑737 can increase the sensitivity of ovarian cancer cells to cisplatin, the specific molecular mechanism remains unclear and requires further investigation. In the present study, the results revealed that ABT‑737 can significantly increase the activation levels of JNK and ASK1 induced by cisplatin in A2780/DDP cells, which are cisplatin‑resistant ovarian cancer cells. Inhibition of the JNK and ASK1 pathway could significantly reduce cisplatin cytotoxicity increased by ABT‑737 in A2780/DDP cells, while inhibiting the ASK1 pathway could reduce JNK activation. In addition, it was further determined that ABT‑737 could increase reactive oxygen species (ROS) levels in A2780/DDP cells induced by cisplatin. Furthermore, the inhibition of ROS could significantly reduce JNK and ASK1 activation and ABT‑737‑mediated increased cisplatin cytotoxicity in A2780/DDP cells. Overall, the current data identified that activation of the ROS‑ASK1‑JNK signaling axis plays an essential role in the ability of ABT‑737 to increase cisplatin sensitivity in A2780/DDP cells. Therefore, upregulation the ROS‑ASK1‑JNK signaling axis is a potentially novel molecular mechanism by which ABT‑737 can enhance cisplatin sensitivity of ovarian cancer cells. In addition, the present research can also provide new therapeutic strategies and new therapeutic targets for patients with cisplatin‑resistant ovarian cancer with high Bcl‑2/Bcl‑xL expression patterns.

Keywords: ABT‑737; ROS‑ASK1‑JNK signaling axis; cisplatin sensitivity; ovarian cancer.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Biphenyl Compounds* / pharmacology
  • Cell Line, Tumor
  • Cisplatin* / pharmacology
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Synergism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase Kinase 5* / metabolism
  • MAP Kinase Signaling System* / drug effects
  • Nitrophenols* / pharmacology
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / pathology
  • Piperazines* / pharmacology
  • Reactive Oxygen Species* / metabolism
  • Sulfonamides* / pharmacology

Substances

  • Cisplatin
  • Reactive Oxygen Species
  • MAP Kinase Kinase Kinase 5
  • Biphenyl Compounds
  • ABT-737
  • MAP3K5 protein, human
  • Sulfonamides
  • Nitrophenols
  • Piperazines
  • Antineoplastic Agents
  • JNK Mitogen-Activated Protein Kinases

Grants and funding

The present study was supported by the National Natural Science Foundation of China (grant no. 32300641), the Shanxi Department of Human Resources and Social Security (grant no. 20230024), the General project of Shanxi Natural Science Foundation (grant nos. 20210302123322, 202103021224238 and 202103021224240), the Shanxi Scholarship Council of China (grant no. 2022-118), the Key R&D program of Shanxi (grant no. 201903D321101), the Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, China (grant no. CELLPHYSIOL/SXMU-2021-13) and the Science and Technology Innovation Team of Shanxi (grant no. 202204051002030).