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Supplementary Table S1 and Figures S1-6 from Ascochlorin Enhances the Sensitivity of Doxorubicin Leading to the Reversal of Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma

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posted on 2023-04-03, 15:43 authored by Xiaoyun Dai, Kwang Seok Ahn, Ling Zhi Wang, Chulwon Kim, Amudha Deivasigamni, Frank Arfuso, Jae-Young Um, Alan Prem Kumar, Young-Chae Chang, Dhiraj Kumar, Gopal C. Kundu, Junji Magae, Boon Cher Goh, Kam Man Hui, Gautam Sethi

Table S1. The primer sequences of different genes; Figure S1: The chemical structure of ASC; Figure S2: ASC selectively enhanced DOX cytotoxicity in HCC cells; Figure S3: Immunofluorescence analysis of Vimentin protein; Figure S4: ASC co-treatment decreased DOX-induced migration in HCC cells; Figure S5: The combinatorial effect of ASC and DOX could be reversed by treatment with proteasome inhibitor; Figure S6: The combination treatment inhibits the expression of STAT3-regulated gene products.

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NUHS

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National Medical Research Council

National Research Foundation

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ARTICLE ABSTRACT

Increasing evidence has indicated that epithelial-to-mesenchymal transition (EMT) at the advanced stage of liver cancer not only has the ability to self-renew and progress cancer, but also enables greater resistance to conventional chemo- and radiotherapies. Here, we report that ascochlorin (ASC), an isoprenoid antibiotic, could potentiate the cytotoxic effect of doxorubicin on HCCLM3, SNU387, SNU49, and SK-Hep-1 hepatocellular carcinoma cells, which had a predominantly mesenchymal signature with low expression of E-cadherin but high expression of N-cadherin. Co-administration of ASC reduced doxorubicin-induced invasion/migration and modulated EMT characteristics in mesenchymal cells. This process was probably mediated by the E-cadherin repressors Snail and Slug. In addition, ASC increased sensitivity to doxorubicin treatment by directly inhibiting STAT3 binding to the Snail promoter. We also observed that ASC significantly enhanced the effect of doxorubicin against tumor growth and inhibited metastasis in an HCCLM3_Luc orthotopic mouse model. Collectively, our data demonstrate that ASC can increase sensitivity to doxorubicin therapy and reverse the EMT phenotype via the downregulation of STAT3-Snail expression, which could form the basis of a novel therapeutic approach against hepatocellular carcinoma. Mol Cancer Ther; 15(12); 2966–76. ©2016 AACR.

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    Molecular Cancer Therapeutics

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    ChemotherapyCombination chemotherapyDrug MechanismsCellular responses to anticancer drugsDrug ResistanceReversal of drug resistanceGastrointestinal CancersLiver cancerPreclinical ModelsAnimal models of cancerProgression, Invasion & MetastasisImaging of tumor progression and metastasisMigration and invasion

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