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

Loukik Arora; Chakrabhavi Dhananjaya Mohan; Min Hee Yang; Shobith Rangappa; Amudha Deivasigamani; Alan Prem Kumar; Ajaikumar B Kunnumakkara; Manoj Garg; Arunachalam Chinnathambi; Sulaiman Ali Alharbi; Tahani Awad Alahmadi; Kanchugarakoppal S Rangappa; Kam Man Hui; Gautam Sethi; Kwang Seok Ahn

doi:10.3390/cancers13215479

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

Cancers (Basel). 2021 Oct 31;13(21):5479. doi: 10.3390/cancers13215479.

Authors

Loukik Arora¹, Chakrabhavi Dhananjaya Mohan², Min Hee Yang³, Shobith Rangappa⁴, Amudha Deivasigamani⁵, Alan Prem Kumar^{1

6}, Ajaikumar B Kunnumakkara⁷, Manoj Garg⁸, Arunachalam Chinnathambi⁹, Sulaiman Ali Alharbi⁹, Tahani Awad Alahmadi¹⁰, Kanchugarakoppal S Rangappa¹¹, Kam Man Hui⁵, Gautam Sethi¹, Kwang Seok Ahn³

Affiliations

¹ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
² Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore 570006, India.
³ KHU-KIST Department of Converging Science and Technology and Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea.
⁴ Adichunchanagiri Institute for Molecular Medicine, Adichunchanagiri University, BG Nagara, Nagamangala Taluk 571448, India.
⁵ National Cancer Centre, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, Singapore 169610, Singapore.
⁶ Cancer Science Institute of Singapore, and Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
⁷ Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India.
⁸ Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida 201313, India.
⁹ Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
¹⁰ Department of Pediatrics, College of Medicine, King Saud University, King Khalid University Hospital, P.O. Box 2925, Riyadh 11461, Saudi Arabia.
¹¹ Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore 570006, India.

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.

Keywords: SHP2; STAT3 signaling inhibitor; Tris DBA; orthotopic; xenograft.