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<p>Breast cancer remains a leading cause of mortality among women, underscoring the need for novel, low-toxicity therapeutic strategies. Piperine, a bioactive alkaloid derived from <i>Piper nigrum</i>, has shown promising anticancer activity; however, its mechanistic link to AMPK activation remains insufficiently explored. In this study, we investigated the role of AMPK modulation in piperine-induced apoptosis in MCF-7 (luminal A, ER-positive) breast cancer cells by integrating in silico molecular docking and 100&#xa0;ns molecular dynamics (MD) simulations with comprehensive in vitro validation. Molecular docking revealed that piperine binds at the AMPK α–β interface (ADaM-like site) with a favorable binding affinity (− 6.3&#xa0;kcal/mol), comparable to the reference AMPK activator metformin (− 6.8&#xa0;kcal/mol). MD simulations demonstrated stable ligand–protein interactions and conformational stabilization of AMPK over 100&#xa0;ns. Functionally, piperine exhibited a time-dependent cytotoxic effect with IC₅₀ values of 81&#xa0;µM (24&#xa0;h), 44&#xa0;µM (48&#xa0;h), and 15&#xa0;µM (72&#xa0;h) as determined by MTT assay. Annexin V-FITC/PI analysis showed significant apoptosis induction, with total apoptotic populations of 37.6 ± 2.95% at 50&#xa0;µM and 69.3 ± 2.85% at 100&#xa0;µM. Cell cycle analysis revealed a marked arrest at the G2/M phase (~ 20–22%).Additionally, piperine significantly inhibited cancer cell migration, reducing wound closure at 24&#xa0;h to 29.5 ± 0.3% (50&#xa0;µM) and 18.8 ± 0.2% (100&#xa0;µM) compared to 45.3 ± 0.4% in controls, and at 48&#xa0;h to 48.1 ± 0.2% and 27.6 ± 0.3%, respectively (control: 72.4 ± 0.6%). Collectively, these findings demonstrate that piperine effectively modulates AMPK signaling, correlating with apoptosis induction, cell-cycle arrest, and impaired migratory capacity in breast cancer cells, thereby highlighting its potential as an AMPK-targeting therapeutic candidate for luminal A breast cancer.</p>

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Piperine-induced AMPK activation and cell cycle arrest: insights from molecular simulations and experimental validation in breast cancer

  • 期刊论文

  • 发表日期：

    2026年3月3日

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  • Ifat Jan,
  • Tabasum Ali,
  • Rafat Ali,
  • Nida Jamil Khan,
  • Khurshid Iqbal Andrabi,
  • Ghulam Nabi Bader

摘要

Breast cancer remains a leading cause of mortality among women, underscoring the need for novel, low-toxicity therapeutic strategies. Piperine, a bioactive alkaloid derived from Piper nigrum, has shown promising anticancer activity; however, its mechanistic link to AMPK activation remains insufficiently explored. In this study, we investigated the role of AMPK modulation in piperine-induced apoptosis in MCF-7 (luminal A, ER-positive) breast cancer cells by integrating in silico molecular docking and 100 ns molecular dynamics (MD) simulations with comprehensive in vitro validation. Molecular docking revealed that piperine binds at the AMPK α–β interface (ADaM-like site) with a favorable binding affinity (− 6.3 kcal/mol), comparable to the reference AMPK activator metformin (− 6.8 kcal/mol). MD simulations demonstrated stable ligand–protein interactions and conformational stabilization of AMPK over 100 ns. Functionally, piperine exhibited a time-dependent cytotoxic effect with IC₅₀ values of 81 µM (24 h), 44 µM (48 h), and 15 µM (72 h) as determined by MTT assay. Annexin V-FITC/PI analysis showed significant apoptosis induction, with total apoptotic populations of 37.6 ± 2.95% at 50 µM and 69.3 ± 2.85% at 100 µM. Cell cycle analysis revealed a marked arrest at the G2/M phase (~ 20–22%).Additionally, piperine significantly inhibited cancer cell migration, reducing wound closure at 24 h to 29.5 ± 0.3% (50 µM) and 18.8 ± 0.2% (100 µM) compared to 45.3 ± 0.4% in controls, and at 48 h to 48.1 ± 0.2% and 27.6 ± 0.3%, respectively (control: 72.4 ± 0.6%). Collectively, these findings demonstrate that piperine effectively modulates AMPK signaling, correlating with apoptosis induction, cell-cycle arrest, and impaired migratory capacity in breast cancer cells, thereby highlighting its potential as an AMPK-targeting therapeutic candidate for luminal A breast cancer.