Combined Hesperidin and Doxorubicin Treatment Induces Apoptosis and Modulates Inflammatory Cytokines in HeLa Cervical Cancer Cells

Özdemir İ., Afşin Y., Tuncer M. C., ÖZTÜRK Ş.

International Journal of Molecular Sciences, cilt.26, sa.17, 2025 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 26 Sayı: 17
  • Basım Tarihi: 2025
  • Doi Numarası: 10.3390/ijms26178753
  • Dergi Adı: International Journal of Molecular Sciences
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, CAB Abstracts, EMBASE, Food Science & Technology Abstracts, MEDLINE, Veterinary Science Database, Directory of Open Access Journals
  • Anahtar Kelimeler: apoptosis, cervical cancer, combination therapy, cytokines, doxorubicin, HeLa cells, hesperidin, RT-qPCR
  • Çanakkale Onsekiz Mart Üniversitesi Adresli: Evet

Özet

Cervical cancer is a major gynecological malignancy linked to hormonal dysregulation and genetic alterations. Chemotherapy is standard but limited by toxicity and chemoresistance, prompting interest in plant-derived adjuncts. This study examined the anticancer and immunomodulatory effects of Hesperidin (Hes), a citrus flavonoid, with Doxorubicin (DX) in HeLa cervical cancer cells. Cell viability was assessed by MTT assay, apoptotic markers (Bcl-2, Caspase-3) by RT-qPCR, and inflammatory cytokines (IL-1β, IL-6, TNF-α, IFN-γ) by ELISA. Cytokine levels were normalized to 104 viable cells, and mRNA expression of all four cytokines was quantified by RT-qPCR, confirming protein-level changes and showing the strongest IL-6 suppression with Hes+DX. Chou–Talalay combination index (CI) analysis demonstrated synergistic interactions (CI < 1.0) between Hes and DX across all tested concentrations, with strong synergism (CI < 0.7) at medium and high doses, particularly at 48 and 72 h. Hes alone showed dose-dependent cytotoxicity, while the combination markedly increased Caspase-3, reduced Bcl-2, and decreased IL-1β, IL-6, and TNF-α, indicating enhanced intrinsic apoptosis and complementary immunomodulation. These results suggest that Hes augments DX’s pro-apoptotic and anti-inflammatory effects, potentially allowing lower chemotherapy doses and reduced systemic toxicity in cervical cancer treatment.