Combining Sodium Butyrate With Cisplatin Increases the Apoptosis of Gastric Cancer In Vivo and In Vitro via the Mitochondrial Apoptosis Pathway

Abstract

Introduction: The gastrointestinal malignancy, gastric cancer (GC), has a high incidence worldwide. Cisplatin is a traditional chemotherapeutic drug that is generally applied to treat cancer; however, drug tolerance affects its efficacy. Sodium butyrate is an intestinal flora derivative that has general anti-cancer effects in vitro and in vivo via pro-apoptosis effects and can improve prognosis in combination with traditional chemotherapy drugs. The present study aimed to assess the effect of sodium butyrate combined with cisplatin on GC.Methods: A Cell Counting Kit-8 assay was used to assess the viability of GC cells in vitro. Hoechst 33,258 staining and Annexin V-Phycoerythrin/7-Aminoactinomycin D were used to qualitatively and quantitatively detect apoptosis in GC cells. Intracellular reactive oxygen species (ROS) measurement and a mitochondrial membrane potential (MMP) assay kit were used to qualitatively and quantitatively reflect the function of mitochondria in GC cells. Western blotting was used to verify the above experimental results. A nude mouse xenograft tumor model was used to evaluate the anti-tumor efficacity of sodium and cisplatin butyrate in vivo.Results: Cisplatin combined with sodium butyrate increased the apoptosis of GC cells. In the nude mouse xenograft tumor model, sodium butyrate in combination with cisplatin markedly inhibited the growth of the tumor more effectively than either single agent. The combination of sodium butyrate and cisplatin increased the intracellular ROS, decreased the MMP, and suppressed the invasion and migration abilities of GC cells. Western blotting verified that the combination of sodium butyrate and cisplatin remarkably enhanced the levels of mitochondrial apoptosis-related pathway proteins.Conclusion: Sodium butyrate, a histone acetylation inhibitor produced by intestinal flora fermentation, combined with cisplatin enhanced the apoptosis of GC cells through the mitochondrial apoptosis-related pathway, which might be considered as a therapeutic option for GC.

Gut Microbiota-Derived Short-Chain Fatty Acids: Impact on Cancer Treatment Response and Toxicities

“…Furthermore, treating pancreatic carcinoma cell lines with sodium butyrate increases cell sensitivity to SN-38, cisplatin, and fluorouracil chemotherapies by inducing histone acetylation and p53 expression and subsequently increasing apoptosis [ 58 ]. A similar synergic effect was also observed after combined butyrate treatment with docetaxel, irinotecan, gemcitabine, or cisplatin both in vitro and in vivo against various types of tumors [ 45 , 46 , 47 , 59 ]. The co-administration of docetaxel and butyrate enhanced docetaxel response by upregulation and downregulation of apoptosis and proliferation-related proteins, respectively, [ 59 ].…”

“…Combined gemcitabine and butyrate treatment also further prompted apoptosis and reduced tumor-associated stromatogenesis in pancreatic ductal adenocarcinoma models [ 46 ]. Additionally, butyrate enhanced tumor apoptosis and the suppression of tumor growth, migration, and invasion capacity of gastric cancer cell lines treated with cisplatin [ 47 ] ( Figure 2 ). Similar to butyrate, it has been demonstrated that propionate enhances the anti-tumor activity of cisplatin against human hepatocellular carcinoma cells.…”

WP1234—A Novel Anticancer Agent with Bifunctional Activity in a Glioblastoma Model

“…It was further confirmed by Engelhardt et al [ 26 ] in studies using an in vivo GBM rat model. Moreover, several studies showed that combined treatment with butyrate and already available drugs (such as docetaxel or cisplatin) significantly improved their therapeutic effects [ 27 , 28 , 29 ]. Our research confirmed that targeting cell metabolism and epigenetic modifications is a powerful anti-cancer strategy.…”

Cratoxylumxanthone C, a natural xanthone, inhibits lung cancer proliferation and metastasis by regulating STAT3 and FAK signal pathways

“…The detection of cell apoptosis affected by cratoxylumxanthone C was accomplished by flow cytometry ( Li et al, 2021a ; Zhang et al, 2021a ). Briefly, A549 cells were harvested and seeded in 12-well plates (1 × 10 5 cells per well) and incubated for 24 h at 37°C.…”