gambogic-acid and Head-and-Neck-Neoplasms

Gambogic acid (GA), a natural and bioactive compound from the gamboge resin, has been reported to exhibit many oncostatic activities against several types of malignancies. However, its effects on the progression of oral squamous cell carcinoma (OSCC) remain largely unexplored. To fill this gap, we investigated the anticancer role of GA and molecular mechanisms underlying GA's actions in combating oral cancer. We found that GA negatively regulated the viability of OSCC cells, involving induction of the sub-G1 phase and cell apoptosis. In addition, a specific signature of apoptotic proteome, such as upregulation of heme oxygenase-1 (HO-1) and activation of caspase cascades, was identified in GA-treated OSCC. Moreover, such induction of HO-1 expression and caspase cleavage by GA was significantly diminished through the pharmacological inhibition of p38 kinase. In conclusion, these results demonstrate that GA promotes cell apoptosis in OSCC, accompanied with the activation of a p38-dependent apoptotic pathway. Our findings provide potential avenues for the use of GA with high safety and therapeutic implications in restraining oral cancer.

Topics: Apoptosis; Carcinoma, Squamous Cell; Caspases; Cell Line, Tumor; Cell Proliferation; Head and Neck Neoplasms; Heme Oxygenase-1; Humans; Mouth Neoplasms; Squamous Cell Carcinoma of Head and Neck; Xanthones

Oral squamous cell carcinoma (OSCC) accounts for nearly 90% of oral cavity malignancies. However, despite significant advances in the last four decades, little improvement has been achieved in the overall survival rates for OSCC patients. While gambogic acid (GA) is a potential candidate compound for treating a variety of malignancies, its anti-cancer impact on OSCC has not to be completely investigated. The tumor immune microenvironment (TIME) has been proven to play a crucial role in the prognosis of cancer patients. Although there are few reports on the T cell activation effect of GA, the regulation of GA on the TIME of OSCC has barely been studied yet. In this study, GA was applied to treat OSCC-bearing mice through in situ controlled release. First, GA-loaded mPEG

Topics: Animals; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Hydrogels; Mice; Mouth Neoplasms; Polyethylene Glycols; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment

The transcription factor, STAT3, is associated with proliferation, survival, and metastasis of cancer cells. We investigated whether gambogic acid (GA), a xanthone derived from the resin of traditional Chinese medicine, Garcinia hanburyi (mangosteen), can regulate the STAT3 pathway, leading to suppression of growth and sensitization of cancer cells. We found that GA induced apoptosis in human multiple myeloma cells that correlated with the inhibition of both constitutive and inducible STAT3 activation. STAT3 phosphorylation at both tyrosine residue 705 and serine residue 727 was inhibited by GA. STAT3 suppression was mediated through the inhibition of activation of the protein tyrosine kinases Janus-activated kinase 1 (JAK1) and JAK2. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the GA-induced downregulation of STAT3, suggesting the involvement of a PTP. We also found that GA induced the expression of the PTP SHP-1. Deletion of the SHP-1 gene by siRNA suppressed the ability of GA to inhibit STAT3 activation and to induce apoptosis, suggesting the critical role of SHP-1 in its action. Moreover, GA downregulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) proteins, and this correlated with suppression of proliferation and induction of apoptosis. Overall, these results suggest that GA blocks STAT3 activation, leading to suppression of tumor cell proliferation and induction of apoptosis.

Topics: Apoptosis; Blotting, Western; Breast Neoplasms; Carcinoma, Squamous Cell; Cell Proliferation; DNA, Neoplasm; Electrophoretic Mobility Shift Assay; Female; Head and Neck Neoplasms; Humans; Immunoenzyme Techniques; Janus Kinase 1; Janus Kinase 2; Male; Multiple Myeloma; Phosphorylation; Prostatic Neoplasms; Protein Transport; Protein Tyrosine Phosphatase, Non-Receptor Type 6; RNA, Small Interfering; STAT3 Transcription Factor; Tumor Cells, Cultured; Xanthones