- Tetracyclines, traditionally known for their role as broad-spectrum antibiotics, have gained attention for their non-antibiotic properties, including anticancer activity.
- Among the tetracycline derivatives, doxycycline and minocycline have shown the most promise in cancer research due to their ability to modulate cellular pathways that are critical for tumor growth and metastasis. These compounds exhibit anti-proliferative, anti-angiogenic, pro-apoptotic, and anti-metastatic effects, making them attractive candidates for repurposing in oncology.
- One of the primary mechanisms by which tetracyclines exert anticancer effects is through the inhibition of matrix metalloproteinases (MMPs). MMPs are enzymes that degrade the extracellular matrix and are crucial for tumor invasion and metastasis. By suppressing MMP activity—particularly MMP-2 and MMP-9—tetracyclines can reduce tumor cell migration and the establishment of secondary tumors. This MMP-inhibitory action has been observed in cancers such as melanoma, breast cancer, glioblastoma, and prostate cancer.
- In addition to MMP inhibition, tetracyclines disrupt mitochondrial biogenesis and function. Doxycycline, for example, inhibits mitochondrial protein synthesis by targeting the mitochondrial ribosome, which closely resembles bacterial ribosomes. This interference can lead to mitochondrial dysfunction, decreased ATP production, increased oxidative stress, and eventually apoptosis in cancer cells, which are often heavily reliant on mitochondrial metabolism for survival and proliferation. Because cancer cells frequently exhibit altered metabolic dependencies (e.g., the Warburg effect), targeting mitochondria with tetracyclines provides a selective pressure that may not affect normal cells as severely.
- Tetracyclines have also demonstrated anti-angiogenic properties, impairing the formation of new blood vessels that tumors need to grow and access nutrients. This effect is mediated through the downregulation of angiogenic factors like vascular endothelial growth factor (VEGF) and the inhibition of endothelial cell proliferation and migration. These actions have been shown to contribute to tumor growth suppression in animal models and in vitro systems.
- Moreover, tetracyclines modulate immune and inflammatory responses within the tumor microenvironment. They can inhibit the activation of microglia and macrophages, reduce the secretion of pro-inflammatory cytokines, and dampen NF-κB signaling—a pathway often upregulated in cancer and associated with cell survival, inflammation, and resistance to therapy. By modulating this signaling, tetracyclines can sensitize tumors to chemotherapy and reduce resistance mechanisms.
- Clinically, while tetracyclines are not yet standard components of cancer treatment regimens, they are being investigated in combination with existing chemotherapeutic agents and targeted therapies. For example, doxycycline has been explored in combination with tyrosine kinase inhibitors and in cancer stem cell-targeting strategies. Minocycline has also shown promise in reducing chemotherapy-induced neuroinflammation and cognitive side effects, offering supportive care benefits in oncology settings.
