Jionoside B1 Sensitizes TNBC to Cisplatin by Inhibiting SIRT3-Mediated Oxidative Stress Defense

Area of Science:

• Mitochondrial biology
• Oncology
• Pharmacology

Background:

• Sirtuin 3 (SIRT3) is a mitochondrial regulator overexpressed in breast cancer, promoting chemoresistance.
• Targeting SIRT3 presents a strategy to overcome cancer drug resistance and enhance chemotherapy effectiveness.

Purpose of the Study:

• To identify and validate natural product inhibitors of SIRT3.
• To evaluate the efficacy of a novel SIRT3 inhibitor, Jionoside B1, in combination with cisplatin for breast cancer treatment.

Main Methods:

• Virtual screening using molecular docking identified Jionoside B1 from a natural product library.
• Molecular dynamics simulations and binding assays validated SIRT3 inhibition.
• In vitro and in vivo studies assessed Jionoside B1's impact on breast cancer cell viability, apoptosis, mitochondrial function, and tumor growth during cisplatin treatment.

Main Results:

• Jionoside B1 was confirmed as a potent SIRT3 inhibitor, increasing SOD2 acetylation and suppressing enzymatic activity.
• Jionoside B1 significantly enhanced cisplatin sensitivity in breast cancer cells, inducing ROS accumulation, mitochondrial dysfunction, and apoptosis.
• Combination therapy with Jionoside B1 and cisplatin demonstrated superior tumor growth inhibition in an orthotopic mouse model compared to cisplatin alone.

Conclusions:

• Jionoside B1 effectively sensitizes breast cancer cells to cisplatin by inhibiting SIRT3-mediated oxidative stress defense.
• Jionoside B1 is a promising therapeutic candidate for combination chemotherapy to improve cisplatin responsiveness in breast cancer treatment.