Synergistic effects of sodium butyrate and cisplatin against cervical carcinoma in vitro and in vivo

Abstract

BackgroundsCisplatin-based chemotherapy has been considered as the pivotal option for treating cervical cancer. However, some patients may present a poor prognosis due to resistance to chemotherapy. As a metabolite of natural products, sodium butyrate (NaB) could inhibit the proliferation of several malignant cells, but little is known about its combination with cisplatin in the treatment of cervical cancer.Materials and methodsFlow cytometry, CCK-8 assay, and Transwell assay were utilized to analyze the cellular apoptosis, viability, cellular migration and invasion upon treating with NaB and/or cisplatin. The allograft mice model was established, followed by evaluating the tumor volume and necrotic area in mice treated with NaB and/or cisplatin. Western blot was performed for detecting protein expression involved in epithelial-mesenchymal transition (EMT) and the expression of MMPs. Immunohistochemical staining was conducted with the tumor sections. The transcription, expression, and cellular translocation of β-catenin were determined using luciferase reporter gene assay, Real-Time PCR, Western blot, and confocal laser scanning microscope, respectively.ResultsNaB combined with cisplatin inhibited cell viability by promoting apoptosis of cervical cancer cells. In vivo experiments indicated that NaB combined with cisplatin could inhibit tumor growth and induce cancer cell necrosis. Single application of NaB activated the Wnt signaling pathway and induced partial EMT. NaB alone up-regulated MMP2, MMP7 and MMP9 expression, and promoted the migration and invasion of cervical cancer cells. The combination of cisplatin and NaB inhibited cellular migration and invasion by abrogating the nuclear transition of β-catenin, reverse EMT and down-regulate MMP2, MMP7 and MMP9. Immunohistochemical staining indicated that NaB combined with cisplatin up-regulated the expression of E-cadherin and reverse the EMT phenotype in the mice model.ConclusionsNaB serves as a sensitizer for cisplatin, which may be a promising treatment regimen for cervical cancer when combined both. NaB alone should be utilized with caution for treating cervical cancer as it may promote the invasion and migration of cervical cancer cells.

Absence of the Klotho Function Causes Cornea Degeneration with Specific Features Resembling Fuchs Endothelial Corneal Dystrophy and Bullous Keratopathy

“…During EMT, epithelial E-cadherin is suppressed, concomitant with an increase in N-cadherin expression in the mesenchyme, a phenomenon called “the cadherin switch” [ 39 ]. Elevated expressions of MMP-2 and MMP-9 are related to EMT [ 39 , 40 , 41 ]. We found that both MMP-2 and MMP-9 were increased with the Klotho null mutation, in agreement with the commonly known increased MMP expression and decreased ECM proteins with aging, presumably due to the lack of a response from fibroblasts to the fibroblast growth factor in aged corneas [ 38 , 42 ].…”

Anticancer Effects of Gut Microbiota-Derived Short-Chain Fatty Acids in Cancers

“…To increase the therapeutic efficacy of chemotherapy in CC, a cotreatment consisting of NaB and cisplatin suppressed cell migration and invasion via the downregulation of matrix metallopeptidase 2 (MMP2), MMP7 and MMP9, regulation of the epithelial-mesenchymal transition (EMT) and reduced proliferation of HeLa and Siha cell lines. Additionally, in a mouse subcutaneous xenograft model, although single treatment with NaB or cisplatin presented tumor suppression, cotreatment with NaB and cisplatin showed more synergistic suppression of tumor volume than single treatments [ 36 ]. Additionally, combination treatment with NaB and 7-hydroxy-staurosporine (UCN-01) induced cell apoptosis.…”

The roles and applications of short-chain fatty acids derived from microbial fermentation of dietary fibers in human cancer

“…Recently, SCFAs have been studied as a sensitizer for radiotherapy and chemotherapy. Sodium butyrate combined with cisplatin has been described to promote apoptosis in different tumor cells, such as gastric cancer ( 76 ) and cervical cancer ( 77 ) in vitro and in vivo . In the tumor-bearing mouse model of gastric cancer, butyrate plus cisplatin inhibited tumor growth via the mitochondrial apoptosis-related pathway, surpassing other groups with monotherapy ( 76 ).…”

“…In the tumor-bearing mouse model of gastric cancer, butyrate plus cisplatin inhibited tumor growth via the mitochondrial apoptosis-related pathway, surpassing other groups with monotherapy ( 76 ). The combination of butyrate and cisplatin has been reported in the cervical cancer model (Hela and Siha cell lines and tumor cell-inoculation mice) that inhibited cell migration and invasion by blocking the nuclear conversion of β-catenin, reversing epithelial–mesenchymal transition, upregulating the expression of E-cadherin and downregulating matrix metalloproteinase (MMP)2, MMP7, and MMP9 ( 77 ). In addition, Park et al ( 78 ) investigated the effects of radiotherapy combined with butyrate, propionate, and acetate in organoids.…”