2. Academic Validation
  3. Revisiting multi-pathway modulation with theophylline derivatives: Targeting STAT3, NF-κB, and apoptotic signaling in breast cancer

Revisiting multi-pathway modulation with theophylline derivatives: Targeting STAT3, NF-κB, and apoptotic signaling in breast cancer

  • Bioorg Chem. 2025 Jun 30:163:108708. doi: 10.1016/j.bioorg.2025.108708.
Ola S Afifi 1,  Amira A Abdellatef 2,  Heba A Abd El Razik 1,  Shams El-Dine A Shams El-Dine 1,  Alaa A El-Tombary 1,  Mohamed A Elrewiny 3,  Yoshihiro Hayakawa 4,  Ahmed F El-Yazbi 5,  Hisham A Nematalla 6,  Perihan A Elzahhar 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
  • 2 Section of Host Defences, Institute of Natural Medicine, University of Toyama, Toyama, Japan; Nutrition Research Institute, University of North Carolina at Chapel Hill, 500 Laureate Way, Kannapolis, NC 28081, USA.
  • 3 Faculty of Pharmacy and the Research & Innovation Hub, Alamein International University, Alamein 51718, Egypt.
  • 4 Section of Host Defences, Institute of Natural Medicine, University of Toyama, Toyama, Japan. Electronic address: haya@inm.u-toyama.ac.jp.
  • 5 Faculty of Pharmacy and the Research & Innovation Hub, Alamein International University, Alamein 51718, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. Electronic address: ayazbi@aiu.edu.eg.
  • 6 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour 22516, Egypt. Electronic address: hisham.nematalla@pharm.dmu.edu.eg.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. Electronic address: perihan.elzahhar@alexu.edu.eg.
PMID: 40614544 DOI: 10.1016/j.bioorg.2025.108708
Abstract

Among female cancers, breast Cancer is the most prevalent type with a high tendency for metastasis, which makes it compelling to develop new therapeutic modalities in the battle against this disease. For this purpose, a new series of theophylline-based derivatives was designed as dual STAT3/NF-B signaling pathway inhibitors. The most active three compounds (12a, 12b and 17b) exhibited potent inhibition of both STAT3 and NF-κB activation in 4 T1 cells with IC50 values of 4.22-8.21 μM. They also exerted considerable Anticancer activity with IC50 values of 1.53 to 7.68 μM in 4 T1, MDA-MB-231, MDA-MB-468 and MCF-7 breast Cancer cell lines. These compounds demonstrated their ability to inhibit breast Cancer cell migration, and invasion in scratch and transwell assays, respectively. As a consequence of STAT3 inhibition, compound 12a was able to induce Apoptosis via its effects on key apoptotic regulators; caspases-3,9, Bax and Bcl-2. Besides, western blotting of 12a-treated MDA-MB-231 cells confirmed decreased expression of STAT3, p-STAT3, Bcl-xL, c-Myc and NF-κB. Moreover, compound 12a reduced tumor volume in a comparable manner to 5FU in an Ehrlich solid carcinoma model. Docking of these compounds into the active sites of STAT3 and NF-κB revealed adequate binding patterns, providing further support for their effectiveness. Hence, these compounds proved to possess structural determinants that could be further tuned into more potent Anticancer agents for breast Cancer.

Keywords

Apoptosis; Breast Cancer; NF-κB; Purine; STAT3; Theophylline.

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