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Given the lack of advances in Oral Squamous Cell Carcinoma (OSCC) therapy in recent years, pharmacological strategies to block OSCC-related signaling pathways have gained prominence. The present study aimed to evaluate the therapeutic potential of Arsenic Trioxide (ATO) concerning its antitumoral effects and the inhibition of the Hedgehog (HH) pathway in OSCC. Initially, ATO cytotoxicity was assessed in a panel of cell lines. Cell viability, cell cycle, death patterns, and cell morphology were analyzed, as well as the effect of ATO on the expression of HH pathway components. After the cytotoxic assay, HSC3 cells were chosen for all in vitro assays. ATO increased apoptotic cell death and nuclear fragmentation in the sub-G1 cell cycle phase and promoted changes in cell morphology. In addition, the reduced expression of GLI1 indicated that ATO inhibits HH activity. The present study provides evidence of ATO as an effective cytotoxic drug for oral cancer treatment in vitro. [ABSTRACT FROM AUTHOR]

Abstract β-Lapachone is a natural naphthoquinone originally obtained from the bark of the purple Ipe (Tabebuia avellanedae Lor, Bignoniaceae) and its therapeutic potential in human cancer cells has been evaluated in several studies. In this study, we examined the effects of β-lapachone and its 3-iodine derivatives (3-I-α-lapachone and 3-I-β-lapachone) on cell proliferation, cell death, and cancer-related gene expression in human oral squamous cell carcinoma cells. β-Lapachone and its 3-iodine derivatives showed potent cytotoxicity against different types of human cancer cell lines. Indeed, treatment with these compounds induced cell cycle arrest at G 2 /M phase, followed by internucleosomal DNA fragmentation, and caused significant increases in phosphatidylserine externalization, caspase-8 and -9 activation, mitochondrial membrane depolarization, reactive oxygen species (ROS) production, and apoptotic cell death morphology. The apoptosis induced by the compounds was prevented by pretreatment with a pan-caspase inhibitor (Z-VAD-FMK) and an antioxidant (N-acetyl- l -cysteine). In vivo, β-lapachone and its 3-iodine derivatives significantly reduced tumor burden and did not alter any of the biochemical, hematological, or histological parameters of the animals. Overall, β-lapachone and its 3-iodine derivatives showed promising cytotoxic activity due to their ability to induce cell cycle arrest at G 2 /M phase and promote caspase- and ROS-mediated apoptosis. In addition, β-lapachone and its 3-iodine derivatives were able to suppress tumor growth in vivo, indicating that these compounds may be new antitumor drug candidates. Graphical abstract fx1 Highlights • β-Lapachone and its 3-iodine derivatives induce apoptosis in human OSCC cells. • β-Lapachone and its 3-iodine derivatives increase ROS levels in human OSCC cells. • β-Lapachone and its 3-iodine derivatives reduce cell growth in a xenograft model. [ABSTRACT FROM AUTHOR]

Due to its importance in the pathogenesis of oral squamous cell carcinoma (OSCC), the Hedgehog (HH) pathway is considered a potential therapeutic target. We investigated the effects of GANT61, a GLI inhibitor, on HH gene expression, as well as on metastatic OSCC cell proliferation and death. Following culture in DMEM medium, cytotoxicity of GANT61 against different tumor and non-tumor cell types was assessed by alamarBlue assays. Cytotoxicity analysis revealed that the metastatic HSC3 cell line was the most sensitive (IC50: 36 µM) to the tested compound. The compound's effects on the expression of HH pathways components were analyzed by qPCR and Western blot; cell viability was analyzed by trypan blue assay and flow cytometry were used to investigate cell cycle phase, morphology, and death patterns in HSC3 cells. A significant reduction in mRNA levels of the GLI1 transcription factor was found after 12 h of treatment withGANT61. Protein expression levels of other HH pathway components (PTCH1, SHH, and Gli1) and HSC3 cell viability also decreased after 24 h of treatment. Cell cycle analysis and death pattern evaluations revealed significantly increased nuclear fragmentation in sub-G1 phase, as well as cell death due to apoptosis. In conclusion, the significantly reduced GLI1 gene expression seen in response to the GLI inhibitor indicates diminished downstream activation in HH pathway components. GANT61 significantly reduced cell viability in the metastatic cell line of OSCC and promoted a significant increase in nuclear fragmentation and cell death by apoptosis. [ABSTRACT FROM AUTHOR]