Monensin Inhibits Anaplastic Thyroid Cancer via Disrupting Mitochondrial Respiration and AMPK/mTOR Signaling

Abstract

Objective: The clinical management of anaplastic thyroid cancer (ATC) remains challenging and novel treatment methods are needed. Monensin is a carboxyl polyether ionophore that potently inhibits the growth of various cancer types. Our current work investigates whether monensin has selective anti-ATC activity and systematically explores its underlying mechanisms. Methods: Proliferation and apoptosis assays were performed using a panel of thyroid cancer cell lines. Mitochondrial biogenesis profiles, ATP levels, oxidative stress, AMPK and mTOR were examined in these cells after monensin treatment. Results: Monensin is effective to inhibit proliferation and induce apoptosis in a number of thyroid cancer cell lines. The results are consistent across cell lines of varying cellular origins and genetic mutations. Compared to other thyroid cancer cell types, ATC cell lines are the most sensitive to monensin. Of note, monensin used at our experimental concentration affects less of normal cells. Mechanistic studies reveal that monensin acts on ATC cells through disrupting mitochondrial function, inducing oxidative stress and damage, and AMPK activation-induced mTOR inhibition. We further show mitochondrial respiration is a critical target for monensin in ATC cells. Conclusions: Our pre-clinical findings demonstrate the selective anti-ATC activities of monensin. This is supported by increasing evidence monensin can to be repurposed as a potential anti-cancer drug.

Inhibition of Wnt/β-catenin signaling by monensin in cervical cancer

“…Our subsequent investigations focused on HeLa and CaSki cell lines, representing the least sensitive and most sensitive responses to monensin, respectively. Previous research has suggested that inducing oxidative stress is the underlying mechanism behind monensin's anti-cancer activity [ 9 , 28 , 29 ]. To investigate whether oxidative stress contributes to the inhibitory effects of monensin in cervical cancer, we measured ROS level in cervical cancer cells after monensin treatment.…”

“…Importantly, we utilized a dose of monensin that proved to be both effective and non-toxic, highlighting a promising therapeutic window for monensin in cancer treatment. Previous studies have also indicated that monensin exhibits greater toxicity towards tumors than normal cells, making it a potentially favorable candidate for selective cancer therapy [ 9 , 35 ]. Notably, monensin has been shown to suppress colorectal tumor growth without adverse effects on nonmalignant intestinal mucosa [ 21 ].…”

“…Monensin, an ionophore antibiotic produced by Streptomyces cinnamonensis, has been traditionally employed to combat bacterial, fungal, and parasitic infections [5]. Notably, polyether ionophore antibiotics, including monensin, salinomycin, and narasin, have garnered attention for their capacity to induce apoptosis and arrest the cell cycle in various cancer cell types [6][7][8][9][10][11]. Moreover, these antibiotics have demonstrated effectiveness in surmounting Fu B et al multidrug-resistant cancer cells and eradicating cancer stem cells [7,[12][13][14][15][16].…”

“…Moreover, these antibiotics have demonstrated effectiveness in surmounting Fu B et al multidrug-resistant cancer cells and eradicating cancer stem cells [7,[12][13][14][15][16]. Monensin has exhibited inhibitory effects on anaplastic thyroid cancer, ovarian cancer, leukemia, glioblastoma, nonsmall cell lung cancer, melanoma, and breast cancer [9][10][11][12][17][18][19][20]. However, its impact on cervical cancer had not been explored until now.…”

Novel Cerium(IV) Coordination Compounds of Monensin and Salinomycin

“…Thus, the formed cavity is highly hydrophilic and can host an alkaline cation or a water molecule. In addition to their main application—the treatment of parasitic disease coccidiosis—the polyether ionophores are also thought to possess anticancer activity and antibacterial effect [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. These findings make them attractive compounds when searching for new applications of already-known therapeutics.…”