Tris DBA Abrogates Tumor Progression in Hepatocellular Carcinoma and Multiple Myeloma Preclinical Models by Affecting Multiple Oncogenic Proteins

Background: STAT3 is an oncogenic transcription factor that controls the expression of genes associated with proliferation, apoptotic resistance, malignant transformation, and metastasis. Persistent activation of STAT3 is observed in many types of human malignancies including hepatocellular carcinoma (HCC) and multiple myeloma (MM). Methods: Here, we have investigated the action of Tris(dibenzylideneacetone) dipalladium 0 (Tris DBA), a palladium complex on STAT3 signaling cascade in HCC and MM. The cytotoxic and proapoptotic activity of Tris DBA was evaluated by various biochemical assays. The action of Tris DBA on cytokine-induced/constitutive activation of STAT3, non-receptor tyrosine kinases (NRTKs), and expression of STAT3 driven genes was evaluated. Nuclear translocation of STAT3 and its DNA interaction was also studied. The antitumor activity of Tris DBA was investigated in two different preclinical studies namely, xenograft MM and orthotopic HCC mice models.Results: Tris DBA decreased cell viability, increased the apoptosis, and inhibited the activation of STAT3 and NRTKs. Tris DBA downmodulated the nuclear translocation of STAT3 and reduced its DNA binding ability. It upregulated expression of SHP2 (protein and mRNA) to induce STAT3 dephosphorylation and inhibition of SHP2 reversed this effect. It downregulated the expression of STAT3-driven genes and suppressed cell motility. Tris DBA significantly inhibited tumor growth in xenograft MM and orthotopic HCC mice models with reduction in the expression of various prosurvival biomarkers in MM tumor tissues without displaying any significant toxicity. Conclusions: Tris DBA functions as a good inhibitor of STAT3 signaling in preclinical HCC and MM models.