Tigecycline Combined with Homoharringtonine Synergistically Exerts Anti-Leukemia Effects via AKT/mTOR/4EBP1 Pathway-Mediated Inhibition of Mitochondrial Translation
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Tigecycline (TIG), a derivative of tetracycline antibiotics, has exhibited antitumor activity against a range of solid tumors and hematologic malignancies, with combination regimens often yielding superior inhibition. To develop new TIG-based combinations for myeloid leukemia, we evaluated the differential efficacy of TIG paired with several anti-leukemia agents, and subsequently focused on its combination with homoharringtonine (HHT) to explore the underlying mechanisms. Apoptosis was measured by flow cytometry, and the synergistic anti-leukemia effect was validated in both myeloid leukemia cell lines and a tumor-bearing mouse model. Western blotting and immunohistochemistry were employed to assess the AKT/mTOR/4EBP1 pathway. The TIG + HHT combination produced potent synergistic cytotoxicity in myeloid leukemia cells and significantly delayed tumor progression in vivo. Mechanistically, this synergy was mediated by the suppression of mitochondrial translation, which led to the downregulation of the AKT/mTOR/4EBP1 signaling cascade and a consequent reduction in anti-apoptotic protein levels. Collectively, our findings reveal that TIG and HHT synergistically enhance anti-leukemia activity by downregulating anti-apoptotic proteins, and identify the inhibition of mitochondrial translation through the AKT/mTOR/4EBP1 axis as a key mechanism.
