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Chemotherapy with doxorubicin induces senescence in multiple breast cancer subtypes (triple-negative MDA-MB-231, hormone-responsive MCF-7, and HER2+ MDA-MB-453) as well as in primary spinal osteoblasts, contributing to therapy resistance and pro-inflammatory signaling via the senescence-associated secretory phenotype (SASP). Combining doxorubicin with senolytic agents (RG-7112 and o-Vanillin) in co-culture spheroid models produced a significant additive reduction in tumor sphere viability, decreased SASP markers, reduced senescent cell burden, and increased apoptosis across all tested cancer subtypes and stromal cells. These findings suggest that sequential or combined senolytic treatment may improve chemotherapeutic efficacy by clearing therapy-induced senescent cells from both tumor and bone microenvironment compartments.
Why it matters
Therapy-induced senescence is an underappreciated driver of treatment resistance and metastasis in breast cancer; incorporating senolytic drugs into existing chemotherapy regimens could reduce relapse risk and limit secondary spread, particularly in the context of bone metastasis where stromal cells are also affected.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Chemotherapeutic treatment of breast cancer with Doxorubicin (DOX) 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. Exposure of triple-negative breast cancer (MDA-MB-231), hormone-responsive (MCF-7) and HER2+ (MDA-MB-453) cells, and primary spine osteoblasts to DOX showed significant induction of p21-positive senescent cells. DOX and senolytics (RG-7112, o-Vanillin) treatment of co-culture spheroids showed a significant additive effect in reducing tumor sphere viability and growth, indicating reduced metastatic potential. This was correlated with reduced SASP in triple-negative and hormone responsive lines and decreased levels of senescent cells in all subtypes and primary stromal cells, while proliferation was decreased, and apoptosis increased across all breast cancer subtypes. Future chemotherapeutic treatment in breast cancer models may be optimized by adding senolytic drugs to more effectively clear senescent tumor and stromal cells, reducing risk for relapse and metastatic potential, while allowing for tissue regeneration in the bone metastatic environment.