Tris(dibenzylideneacetone)dipalladium(0) (Tris DBA) Abrogates Tumor Progression in Hepatocellular Carcinoma and Multiple Myeloma Preclinical Models by Regulating the STAT3 Signaling Pathway

SIMPLE SUMMARY: STAT3 is a major oncogenic transcription factor that is constitutively activated in many types of human cancers, including hepatocellular carcinoma (HCC) and multiple myeloma (MM). Many STAT3 inhibitors have gained momentum in clinical trials towards the treatment of various cancers. In the present study, we have investigated the STAT3 inhibitory efficacy of Tris DBA, a palladium-based compound, in HCC and MM cancer cells and preclinical cancer models. Tris(dibenzylideneacetone)dipalladium(0) (Tris DBA) abrogated the STAT3 signaling pathway in both models by elevating the expression of SHP2. Functionally, Tris DBA inhibited cell proliferation, migration, invasion, and regressed tumor metastasis. Although many studies propose Tris DBA as a modulator of MAPK, Akt, phospho-S6 kinase, and N-myristoyltransferase-1, we have comprehensively demonstrated for the first time that Tris DBA is an inhibitor of STAT3 signaling in preclinical cancer models. These results support the consideration of Tris DBA in clinical trials in translational relevance. ABSTRACT: STAT3 is an oncogenic transcription factor that controls the expression of genes associated with oncogenesis and malignant progression. Persistent activation of STAT3 is observed in human malignancies, including hepatocellular carcinoma (HCC) and multiple myeloma (MM). Here, we have investigated the action of Tris(dibenzylideneacetone) dipalladium 0 (Tris DBA) on STAT3 signaling in HCC and MM cells. Tris DBA decreased cell viability, increased apoptosis, and inhibited IL-6 induced/constitutive activation of STAT3, JAK1, JAK2, and Src in HCC and MM cells. Tris DBA downmodulated the nuclear translocation of STAT3 and reduced its DNA binding ability. It upregulated the expression of SHP2 (protein and mRNA) to induce STAT3 dephosphorylation, and the inhibition of SHP2 reversed this effect. Tris DBA downregulated the expression of STAT3-driven genes, suppressed cell migration/invasion. Tris DBA significantly inhibited tumor growth in xenograft MM and orthotopic HCC preclinical mice models with a reduction in the expression of various prosurvival biomarkers in MM tumor tissues without displaying significant toxicity. Overall, Tris DBA functions as a good inhibitor of STAT3 signaling in preclinical HCC and MM models.