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Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment
Published on: June 9, 2023
Mitochondrial ROS inhibition prevents doxorubicin-induced breast cancer cell migration and invasion
Tania Capeloa1, Justine A Van de Velde1, Erica Pranzini1,2
1Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
Abstract:
For cancer patients, metastasis is a life-threatening event limiting therapeutic options. Molecularly, the metastatic phenotype can be conferred by mitochondrial reactive oxygen species (mtROS) generated upon metabolic stress. Mitochondrial damage can also trigger mtROS production, which is particularly well illustrated for anthracyclines. Here, we tested in mouse models of murine and human breast cancer whether this type of chemotherapy can trigger metastasis. We report that subcytotoxic doses of doxorubicin mimicking the clinical situation in poorly perfused tumor areas sequential trigger mtROS production, activate TGFβ pathway effector Pyk2, and increase cancer cell migration and invasion. Fortunately, the metastatic switch was incompletely induced, and doxorubicin did not promote breast cancer metastasis in immunocompetent mice. Yet, MitoTEMPO fully prevented metastatic dissemination and did not interfere with doxorubicin cytotoxicity, making it attractive to combine anthracyclines with mitochondria-targeted antioxidants.
Insights
Sub-lethal doxorubicin chemotherapy can trigger cancer cell migration via mitochondrial reactive oxygen species (mtROS). However, combining anthracyclines with mitochondria-targeted antioxidants like MitoTEMPO may prevent metastasis without reducing chemotherapy effectiveness.
Area of Science:
- Oncology
- Mitochondrial Biology
- Cancer Metastasis Research
Background:
- Metastasis is a critical challenge in cancer therapy, often linked to mitochondrial reactive oxygen species (mtROS) production.
- Anthracyclines, like doxorubicin, can induce mitochondrial damage and subsequent mtROS generation.
Purpose of the Study:
- To investigate if sub-lethal doses of doxorubicin can trigger metastasis in breast cancer models.
- To evaluate the potential of mitochondria-targeted antioxidants to prevent chemotherapy-induced metastasis.
Main Methods:
- Utilized mouse models of murine and human breast cancer.
- Administered sub-lethal doses of doxorubicin to mimic clinical scenarios.
- Assessed mtROS production, TGFβ pathway activation (Pyk2), and cancer cell migration/invasion.
- Tested the efficacy of MitoTEMPO in preventing metastatic dissemination.
Main Results:
- Sub-lethal doxorubicin triggered mtROS production and activated Pyk2, enhancing cancer cell migration and invasion.
- Doxorubicin did not significantly promote metastasis in immunocompetent mice.
- MitoTEMPO completely prevented metastatic spread without compromising doxorubicin's anti-cancer effects.
Conclusions:
- Chemotherapy-induced mtROS can promote a metastatic phenotype, though incomplete in this model.
- Mitochondria-targeted antioxidants offer a promising strategy to mitigate chemotherapy-induced metastasis.
- Combining anthracyclines with antioxidants may improve cancer treatment outcomes by preventing dissemination.
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