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Abstract
We recently isolated a cardiac glycoside (CG), αldiginoside, from an indigenous plant in Taiwan, which exhibits potent tumor-suppressive efficacy in oral squamous cell carcinoma (OSCC) cell lines (SCC2095 and SCC4, IC50 < 0.2 µM; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays). Here, we report that αldiginoside caused Sphase arrest and apoptosis, through the inhibition of a series of signaling pathways, including those mediated by cyclin E, phospho-CDC25C (p-CDC25C), and janus kinase/signal transducer and activator of transcription (JAK/STAT)3. αldiginoside induced apoptosis, as indicated by caspase activation and poly (ADP-ribose) polymerase (PARP) cleavage. Equally important, αldiginoside reduced Mcl-1 expression through protein degradation, and overexpression of Mcl-1 partially protected SCC2095 cells from αldiginoside’s cytotoxicity. Taken together, these data suggest the translational potential of αldiginoside to foster new therapeutic strategies for OSCC treatment.
Highlights
Oral squamous cell carcinoma (OSCC) is the 11th most common malignancy globally, with over 300,000 new cases and 140,000 deaths reported every year [1]
We further investigated the efficacy and antitumor mechanism of another cardiac glycoside (CG), α-l-diginoside, in oral squamous cell carcinoma (OSCC) cells
Propidium iodide (PI)/annexin V staining demonstrated that the proportion of apoptotic cells was increased by treatment with α-l-diginoside (Figure 3A,B), which was consistent with the observation of sub G1 phase in the cell cycle (Figure 2B)
Summary
Oral squamous cell carcinoma (OSCC) is the 11th most common malignancy globally, with over 300,000 new cases and 140,000 deaths reported every year [1]. In the past decade, increasing attention has focused on cardiac glycosides (CGs) in cancer treatment [7], as many CGs, including bufalin, ouabain, and digoxin, have been reported to suppress tumor cell growth by inducing apoptosis [8,9,10]. A number of antitumor targets have been reported for different CGs (oleandrin: nuclear factor-κB (NF-κB) [13] and signal transducer and activator of transcription (STAT)3 [14]; ouabain, digoxin, and proscillaridin: DNA topoisomerase II [15]; divaricoside: myeloid cell leukemia 1 (Mcl-1) [16], suggesting that individual CG might mediate their antitumor effect through distinct mechanisms. As part of our natural product-based drug development effort, we previously demonstrated the unique ability of one of the CGs isolated from this indigenous plant, divaricoside, to induce apoptosis in OSCC cells [16]. We further investigated the efficacy and antitumor mechanism of another CG, α-l-diginoside (structure shown in Figure 1A), in OSCC cells
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