Abstract
BackgroundDespite being one of the leading cancer types in the world, the diagnosis of oral cancer and its suitable therapeutic options remain limited. This study aims to investigate the single and chemosensitizing effects of TW-37, a BH3 mimetic in oral cancer, on human oral cancer cell lines.MethodsWe assessed the single and chemosensitizing effects of TW-37 in vitro using trypan blue exclusion assay, Western blotting, DAPI staining, Annexin V–FITC/PI double staining, and quantitative real-time PCR. Mcl-1 overexpression models were established by transforming vector and transient transfection was performed to test for apoptosisResultsTW-37 enhanced the cytotoxicity of human oral cancer cell lines by inducing caspase-dependent apoptosis, which correlates with the reduction of the myeloid cell leukemia-1 (Mcl-1) expression via transcriptional and post-translational regulation. The ectopic expression of Mcl-1 partially attenuated the apoptosis-inducing capacity of TW-37 in human oral cancer cell lines. Besides, TW-37 decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and nuclear translocation in human oral cancer cell lines at the early time points. Furthermore, TW-37 potentiated chemosusceptibility of cryptotanshinone in human oral cancer cell lines by suppressing STAT3–Mcl-1 signaling compared with either TW-37 or cryptotanshinone alone, resulting in potent apoptosis.ConclusionsThis study not only unravels the single and chemosensitizing effects of TW-37 for treatment of human oral cancer but also highlights the likelihood of TW-37 as a good therapeutic strategy to enhance the prognosis of patients with oral cancer in the future.
Highlights
Despite being one of the leading cancer types in the world, the diagnosis of oral cancer and its suit‐ able therapeutic options remain limited
The findings provided above demonstrated that TW-37 elicits cytotoxicity in human oral cancer cell lines because of apoptosis induced by the caspase-dependent mechanism
The combined treatment of TW-37 and cryptotanshinone remarkably abolished the expression of p-signal transducer and activator of transcription 3 (STAT3) Tyr705 and myeloid cell leukemia-1 (Mcl-1) compared with either TW-37 or cryptotanshinone alone, resulting in a potent induction of apoptosis (Fig. 5c). These findings suggested that TW-37 can synergistically induce the chemosensitivity of cryptotanshinone by inducing apoptosis through suppressing STAT3–Mcl-1 signaling in human oral cancer cell lines
Summary
Despite being one of the leading cancer types in the world, the diagnosis of oral cancer and its suit‐ able therapeutic options remain limited. A growing number of studies have demonstrated the therapeutic potential of TW-37 against various types of cancer by inducing S-phase cell cycle arrest or apoptosis in vitro and in vivo [7,8,9]. Our team demonstrated that TW-37 functions as a potential apoptosis-inducing agent for the treatment of oral cancer by reducing heme oxygenase-1 and Bcl-2 [11, 12]. In combination with conventional chemotherapeutic drugs like cisplatin and 5-fluorouracil, TW-37 was sufficient in potentiating the chemosensitivity of tumors by inducing apoptosis [13, 14]. Therapeutic approaches by TW-37 alone or combined with chemotherapeutic drugs are crucial to augment the survival of patients with oral cancer
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