2. Academic Validation
  3. Inhibition of phosphodiesterase 4 and 7 regulates breast cancer cell proliferation

Inhibition of phosphodiesterase 4 and 7 regulates breast cancer cell proliferation

  • Biochim Biophys Acta Gen Subj. 2025 Aug 13;1869(11):130850. doi: 10.1016/j.bbagen.2025.130850.
Carla Mayora Justel 1,  Tamara Valladares 2,  Lucía Gargiulo 3,  Verónica González-Pardo 4,  Maximiliano De Sousa 5,  María Del Carmen Esandi 6,  Carlos Davio 5,  Isabel Lüthy 7,  Ariana Bruzzone 8
Affiliations

Affiliations

  • 1 Instituto de Investigaciones Bioquímicas de Bahía Blanca INIBIBB-UNS-CONICET, Camino la Carrindanga Km 7, 8000 Bahía Blanca, Argentina; Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, San Juan 670, 8000 Bahía Blanca, Argentina. Electronic address: cmayorajustel@inibibb-conicet.gob.ar.
  • 2 Instituto de Investigaciones Bioquímicas de Bahía Blanca INIBIBB-UNS-CONICET, Camino la Carrindanga Km 7, 8000 Bahía Blanca, Argentina.
  • 3 Instituto de Biología y Medicina Experimental IBYME-CONICET, Vuelta de Obligado 2490, 1428 Ciudad Autónoma de Buenos Aires, Argentina.
  • 4 Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, San Juan 670, 8000 Bahía Blanca, Argentina; Instituto de Ciencias Biológicas y Biomédicas del Sur INBIOSUR-UNS-CONICET, San Juan 670, 8000 Bahía Blanca, Argentina. Electronic address: vgpardo@criba.edu.ar.
  • 5 Instituto de Investigaciones Farmacológicas ININFA-UBA-CONICET, Junín 456, C1113AAD Ciudad Autónoma de Buenos Aires, Argentina.
  • 6 Instituto de Investigaciones Bioquímicas de Bahía Blanca INIBIBB-UNS-CONICET, Camino la Carrindanga Km 7, 8000 Bahía Blanca, Argentina; Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, San Juan 670, 8000 Bahía Blanca, Argentina. Electronic address: cesandi@criba.edu.ar.
  • 7 Instituto de Biología y Medicina Experimental IBYME-CONICET, Vuelta de Obligado 2490, 1428 Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: i.luthy@ibyme.org.ar.
  • 8 Instituto de Investigaciones Bioquímicas de Bahía Blanca INIBIBB-UNS-CONICET, Camino la Carrindanga Km 7, 8000 Bahía Blanca, Argentina. Electronic address: abruzzone@inibibb-conicet.gob.ar.
PMID: 40816541 DOI: 10.1016/j.bbagen.2025.130850
Abstract

Purpose: cAMP regulates key processes in mammary Cell Biology. Previous studies suggested reduced cAMP production in more malignant cells. This study investigates the role of cAMP in mammary biology using non-tumor (MCF-10A and HBL-100) and tumor (MCF-7 and MDA-MB-231) human breast cell lines.

Methods: cAMP levels were quantified using a competitive radio-binding assay. Cell proliferation and viability were assessed by cell counting and MTT assay. Gene expression was analyzed by Real-Time PCR and immunofluorescence. Additional assays included migration, colony formation, annexin V/IP staining, comet assay, and Caspase-3 activity. Public datasets were consulted. Phosphodiesterase (PDE) inhibitors were tested: the broad-spectrum PDE inhibitor IBMX (3-Isobutyl-1-methylxanthine), the PDE4-selective inhibitor roflumilast, and the PDE7-selective inhibitor BRL-50481.

Results: Non-tumor cells produced more cAMP than tumor cells, with or without IBMX. IBMX decreases cell proliferation and viability in all cell lines. Gene expression data revealed higher ADCY2, 3, 4, 5, 6, and 8 expression in normal tissues. Roflumilast reduced cell viability in all tested cells, while the PDE7-specific inhibitor BRL-50481 only affected MCF-7 cells. All PDE inhibitors exhibited an additive effect with tamoxifen, reducing MCF-7 cell viability. In tumor cells roflumilast decreased cell migration. In MDA-MB-231 cells, although IBMX and roflumilast showed a trend toward further decreasing viability compared to doxorubicin or paclitaxel alone, the differences were not statistically significant.

Conclusion: The selective PDE4 Inhibitor roflumilast demonstrated potential as a therapeutic agent when combined with specific breast Cancer treatments, offering a novel approach in breast Cancer therapy.

Keywords

Breast neoplasm; Cell line; Cyclic AMP; Gene expression; Phosphodiesterase 4 inhibitor; Roflumilast.

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