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<p>Chemotherapeutic treatment of breast cancer with Doxorubicin can induce tumor and stromal cell senescence leading to therapy-resistance. Senescence-associated secretory phenotype (SASP) promotes secretion of pro-inflammatory and tumorigenic factors causing systemic inflammation. Combined, this can result in immune suppression, tumor growth and secondary spread of cancer. Targeting and removing senescent and cancerous cells using a combination of chemotherapeutic and senolytic drugs may reduce systemic inflammation, improve therapeutic efficacy, and prevent metastasis. Treatment of triple negative breast cancer (MDA-MB-231) cells and primary spine osteoblasts with 0.25 µM Doxorubicin showed significant induction of senescence indicated by p21 positive cells. Doxorubicin and senolytics (RG-7112, o-Vanillin) treatment of mono-culture MDA-MB-231, MCF7 and MDA-MB-453 breast cancer subtype spheroids indicated efficacy against growth and metabolic activity. Co-culture of triple negative spheroids with treat showed a significant additive effect on decreased tumor sphere viability and growth in a bone-like microenvironment. This was correlated with decreased p21 and Ki-67 proliferation marker in both the breast cancer and osteoblast cells. In all cases, combined Doxorubicin and senolytics significantly reduced sphere size and cancer cell outgrowth, indicating reduced metastatic potential. SASP analysis in the conditioned media from treated co-cultures indicated significant reduction in IL-6 protein secretion and trends in reduction of INFγ, TNFα and IL-1β. Our preclinical data suggests that adding senolytic drugs to chemotherapy could potentially improve clearance of tumors and help regenerate surrounding stroma tissue such as in the bone metastatic environment. </p>

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Targeting breast cancer senescence in 3D models of bone metastasis

  • 期刊论文

  • 发表日期：

    2026年4月10日

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  • Eleane C. B. Hamburger,
  • Mansoureh Mohseni Garakani,
  • Saber Ghazizadeh,
  • Saleh Alfaisali,
  • Jean A. Ouellet,
  • Michael H. Weber,
  • Livia Garzia,
  • Lisbet Haglund,
  • Derek H. Rosenzweig

摘要

Chemotherapeutic treatment of breast cancer with Doxorubicin can induce tumor and stromal cell senescence leading to therapy-resistance. Senescence-associated secretory phenotype (SASP) promotes secretion of pro-inflammatory and tumorigenic factors causing systemic inflammation. Combined, this can result in immune suppression, tumor growth and secondary spread of cancer. Targeting and removing senescent and cancerous cells using a combination of chemotherapeutic and senolytic drugs may reduce systemic inflammation, improve therapeutic efficacy, and prevent metastasis. Treatment of triple negative breast cancer (MDA-MB-231) cells and primary spine osteoblasts with 0.25 µM Doxorubicin showed significant induction of senescence indicated by p21 positive cells. Doxorubicin and senolytics (RG-7112, o-Vanillin) treatment of mono-culture MDA-MB-231, MCF7 and MDA-MB-453 breast cancer subtype spheroids indicated efficacy against growth and metabolic activity. Co-culture of triple negative spheroids with treat showed a significant additive effect on decreased tumor sphere viability and growth in a bone-like microenvironment. This was correlated with decreased p21 and Ki-67 proliferation marker in both the breast cancer and osteoblast cells. In all cases, combined Doxorubicin and senolytics significantly reduced sphere size and cancer cell outgrowth, indicating reduced metastatic potential. SASP analysis in the conditioned media from treated co-cultures indicated significant reduction in IL-6 protein secretion and trends in reduction of INFγ, TNFα and IL-1β. Our preclinical data suggests that adding senolytic drugs to chemotherapy could potentially improve clearance of tumors and help regenerate surrounding stroma tissue such as in the bone metastatic environment.