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Sorafenib and Mesenchymal Stem Cell Therapy: A Promising Approach for Treatment of HCC.

ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most commonly diagnosed cancer and the second most common cause of cancer-related death worldwide. Sorafenib (Sora) is used as a targeted therapy for HCC treatment. Mesenchymal stem cells (MSCs) are applied as a new approach to fight malignancies. Drug resistance and side effects are the major concerns with Sora administration. The effect of using the combination of sorafenib and MSCs on tumor regression in xenograft HCC models was evaluated in this study. Methods and Materials. Human hepatocellular carcinoma cell lines (HepG2) were subcutaneously implanted into the flank of 18 nude mice. The animals were randomly divided into six groups (n?=?3); each received Sora (oral), MSCs (IV injection), MSCs (local injection), Sora?+?MSCs (IV injection), Sora?+?MSCs (local injection), or no treatment (the control group). Six weeks after tumor implantation, the mice were scarified and tumoral tissues were resected in their entirety. Histopathological and immunohistochemical evaluations were used to measure tumor proliferation and angiogenesis. Apoptotic cells were quantified using the TUNEL assay. Results. No significant difference was found in the tumor grade among the treatment groups. Differentiation features of the tumoral cells were histopathologically insignificant in all the groups. Tumor necrosis was highest in the hpMSC (local)?+?Sora group. Tumor cell proliferation was reduced in hpMSC (local)?+?Sora-treated and hpMSC (IV)?+?Sora-treated mice compared with the other groups. Apoptotic-positive cells occupied a greater proportion in the Sora, hpMSC (IV)?+?Sora, and hpMSC (local)?+?Sora groups. Conclusion. A combination of chemotherapy and MSC can yield to more favorable results in the treatment of HCC.

SUBMITTER: Hajighasemlou S

PROVIDER: S-EPMC7312705 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Sorafenib and Mesenchymal Stem Cell Therapy: A Promising Approach for Treatment of HCC.

Hajighasemlou Saieh S Nikbakht Mohsen M Pakzad Saeedreza S Muhammadnejad Samad S Gharibzadeh Safoora S Mirmoghtadaei Milad M Zafari Fariba F Seyhoun Iman I Ai Jafar J Verdi Javad J

Evidence-based complementary and alternative medicine : eCAM 20200614

Hepatocellular carcinoma (HCC) is the fifth most commonly diagnosed cancer and the second most common cause of cancer-related death worldwide. Sorafenib (Sora) is used as a targeted therapy for HCC treatment. Mesenchymal stem cells (MSCs) are applied as a new approach to fight malignancies. Drug resistance and side effects are the major concerns with Sora administration. The effect of using the combination of sorafenib and MSCs on tumor regression in xenograft HCC models was evaluated in this st ...[more]

PMID: 32617114

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Project description:Sorafenib, an oral multi-tyrosine kinase inhibitor, has been the first-line therapy for the treatment of patients with advanced HCC, providing a survival benefit of only three months in approximately 30% of patients. Cancer stem cells (CSCs) are a rare tumour subpopulation with self-renewal and differentiation capabilities, and have been implicated in tumour growth, recurrence and drug resistance. The process of epithelial-to-mesenchymal transition (EMT) contributes to the generation and maintenance of the CSC population, resulting in immune evasion and therapy resistance in several cancers, including HCC. The aim of this study is to target the chemoresistant CSC population in HCC by assessing the effectiveness of a combination treatment approach with Sorafenib, an EMT inhibitor and an immune checkpoint inhibitor (ICI). A stem-cell-conditioned serum-free medium was utilised to enrich the CSC population from the human HCC cell lines Hep3B, PLC/PRF/5 and HepG2. The anchorage independent spheres were characterised for CSC features. The human HCC-derived spheres were assessed for EMT status and expression of immune checkpoint molecules. The effect of combination treatment with SB431542, an EMT inhibitor, and siRNA-mediated knockdown of programmed cell death protein ligand-1 (PD-L1) or CD73 along with Sorafenib on human HCC-derived CSCs was examined with cell viability and apoptosis assays. The three-dimensional spheres enriched from human HCC cell lines demonstrated CSC-like features. The human HCC-derived CSCs also exhibited the EMT phenotype along with the upregulation of immune checkpoint molecules. The combined treatment with SB431542 and siRNA-mediated PD-L1 or CD73 knockdown effectively enhanced the cytotoxicity of Sorafenib against the CSC population compared to Sorafenib alone, as evidenced by the reduced size and proliferation of spheres. Furthermore, the combination treatment of Sorafenib with SB431542 and PD-L1 or CD73 siRNA resulted in an increased proportion of an apoptotic population, as evidenced by flow cytometry analysis. In conclusion, the combined targeting of EMT and immune checkpoint molecules with Sorafenib can effectively target the CSC tumour subpopulation.

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Sorafenib and Mesenchymal Stem Cell Therapy: A Promising Approach for Treatment of HCC.

Publications

Sorafenib and Mesenchymal Stem Cell Therapy: A Promising Approach for Treatment of HCC.

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